Chhavi Jain

Inflammatory bowel disease (IBD) and Crohn’s disease (CD), in particular, are characterized by an unusual ectopic extension of mesenteric adipose tissue. This intra-abdominal fat, also known as “creeping fat,” which wraps around the intestine during the onset of CD, is associated with inflammation and ulceration of the small or large intestine. The role of this fat in the development of CD, and whether it is protective or harmful, however, is not clear.

The current study demonstrates that adipose-derived stromal cells (ADSCs), the precursor cell population of adipose tissue, promote colonocyte proliferation and exhibit a differential gene expression profile in a disease-dependent manner. CD patient–derived ADSCs attenuated the severity of experimental colitis by releasing extracellular mediators, which exhibits a protective role for mesenteric adipose tissue during intestinal inflammation, according to Jill M. Hoffman, MD, and her colleagues at the University of California, Los Angeles. Increased expression and release of lactoferrin by ADSCs – an iron-binding glycoprotein and antimicrobial peptide usually found in large quantities in breast milk – was shown to be a likely mediator that could regulate inflammatory responses during CD. These results were published in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2018.02.001).

Intestinal inflammation is primarily mediated by cytokine production, and targeted anticytokine therapy is the current standard for IBD treatment. The cytokine profile from CD patient–derived mesenteric ADSCs and fat tissue was significantly different from that of these patients’ disease-free counterparts. The authors hypothesized that mesenteric ADSCs release adipokines in response to disease-associated signals; this release of adipokines results from differential gene expression of mesenteric ADSCs in CD versus control patients. To test this hypothesis, conditioned media from CD patient–derived ADSCs was used to study gene expression in colonic intestinal epithelial cells in vitro and in mice with experimental colitis in vivo.

Using the Human LncRNA Expression Microarray V4.0, expression of 20,730 protein-coding mRNA targets was analysed, and 992 mRNA transcripts were found to be differentially (less than or equal to twofold change) expressed in CD patient–derived ADSCs, compared with control patient–derived ADSCs. Subsequent pathway analysis suggested activation of cellular growth and proliferation pathways with caspase 8 and p42/44 as top predicted networks that are differentially regulated in CD patient–derived ADSCs with respect to those of control patients.

The investigators treated intestinal epithelial cells – specifically, NCM460 – with conditioned 233 media from the same CD or control patient–derived ADSCs; subsequent microarray profiling using the GeneChip Human Gene ST Array showed increased expression of interleukin-17A, CCL23, and VEGFA. Ingenuity Pathway Analysis of mRNA expression indicated convergence in injury and inflammation pathways with the SERPINE1 gene, which suggests it’s the central regulator of the differential gene expression network.

In vivo, mice with active dextran sulfate sodium (DSS) colitis that were treated with daily injections of conditioned media from CD patients showed attenuation of colitis as compared with mice treated with vehicle or conditioned media from control patients. Furthermore, the mRNA expression of proinflammatory cytokines was reduced with increased proliferative response (as measured by Ki67 expression) in intestinal epithelial cells in the dextran sulfate sodium–treated mice receiving media from CD patients, compared with that in mice receiving media from control patients or vehicle-treated mice.

Cell proliferation was studied in real time (during a period of 120 hours) using the xCELLigence platform. The authors suggested that mesenteric adipose tissue–derived mediators may regulate proliferative responses in intestinal epithelial cells during intestinal inflammation, as observed by enhanced cell-doubling time in conditioned media from CD patient–derived ADSCs.

SOURCE: Hoffman J et al. Cell Molec Gastro Hepatol. doi: 10.1016/j.jcmgh.2018.02.001.

Inflammatory bowel disease (IBD) and Crohn’s disease (CD), in particular, are characterized by an unusual ectopic extension of mesenteric adipose tissue. This intra-abdominal fat, also known as “creeping fat,” which wraps around the intestine during the onset of CD, is associated with inflammation and ulceration of the small or large intestine. The role of this fat in the development of CD, and whether it is protective or harmful, however, is not clear.

The current study demonstrates that adipose-derived stromal cells (ADSCs), the precursor cell population of adipose tissue, promote colonocyte proliferation and exhibit a differential gene expression profile in a disease-dependent manner. CD patient–derived ADSCs attenuated the severity of experimental colitis by releasing extracellular mediators, which exhibits a protective role for mesenteric adipose tissue during intestinal inflammation, according to Jill M. Hoffman, MD, and her colleagues at the University of California, Los Angeles. Increased expression and release of lactoferrin by ADSCs – an iron-binding glycoprotein and antimicrobial peptide usually found in large quantities in breast milk – was shown to be a likely mediator that could regulate inflammatory responses during CD. These results were published in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2018.02.001).

Intestinal inflammation is primarily mediated by cytokine production, and targeted anticytokine therapy is the current standard for IBD treatment. The cytokine profile from CD patient–derived mesenteric ADSCs and fat tissue was significantly different from that of these patients’ disease-free counterparts. The authors hypothesized that mesenteric ADSCs release adipokines in response to disease-associated signals; this release of adipokines results from differential gene expression of mesenteric ADSCs in CD versus control patients. To test this hypothesis, conditioned media from CD patient–derived ADSCs was used to study gene expression in colonic intestinal epithelial cells in vitro and in mice with experimental colitis in vivo.

Using the Human LncRNA Expression Microarray V4.0, expression of 20,730 protein-coding mRNA targets was analysed, and 992 mRNA transcripts were found to be differentially (less than or equal to twofold change) expressed in CD patient–derived ADSCs, compared with control patient–derived ADSCs. Subsequent pathway analysis suggested activation of cellular growth and proliferation pathways with caspase 8 and p42/44 as top predicted networks that are differentially regulated in CD patient–derived ADSCs with respect to those of control patients.

The investigators treated intestinal epithelial cells – specifically, NCM460 – with conditioned 233 media from the same CD or control patient–derived ADSCs; subsequent microarray profiling using the GeneChip Human Gene ST Array showed increased expression of interleukin-17A, CCL23, and VEGFA. Ingenuity Pathway Analysis of mRNA expression indicated convergence in injury and inflammation pathways with the SERPINE1 gene, which suggests it’s the central regulator of the differential gene expression network.

In vivo, mice with active dextran sulfate sodium (DSS) colitis that were treated with daily injections of conditioned media from CD patients showed attenuation of colitis as compared with mice treated with vehicle or conditioned media from control patients. Furthermore, the mRNA expression of proinflammatory cytokines was reduced with increased proliferative response (as measured by Ki67 expression) in intestinal epithelial cells in the dextran sulfate sodium–treated mice receiving media from CD patients, compared with that in mice receiving media from control patients or vehicle-treated mice.

Cell proliferation was studied in real time (during a period of 120 hours) using the xCELLigence platform. The authors suggested that mesenteric adipose tissue–derived mediators may regulate proliferative responses in intestinal epithelial cells during intestinal inflammation, as observed by enhanced cell-doubling time in conditioned media from CD patient–derived ADSCs.

SOURCE: Hoffman J et al. Cell Molec Gastro Hepatol. doi: 10.1016/j.jcmgh.2018.02.001.

Inflammatory bowel disease (IBD) and Crohn’s disease (CD), in particular, are characterized by an unusual ectopic extension of mesenteric adipose tissue. This intra-abdominal fat, also known as “creeping fat,” which wraps around the intestine during the onset of CD, is associated with inflammation and ulceration of the small or large intestine. The role of this fat in the development of CD, and whether it is protective or harmful, however, is not clear.

The current study demonstrates that adipose-derived stromal cells (ADSCs), the precursor cell population of adipose tissue, promote colonocyte proliferation and exhibit a differential gene expression profile in a disease-dependent manner. CD patient–derived ADSCs attenuated the severity of experimental colitis by releasing extracellular mediators, which exhibits a protective role for mesenteric adipose tissue during intestinal inflammation, according to Jill M. Hoffman, MD, and her colleagues at the University of California, Los Angeles. Increased expression and release of lactoferrin by ADSCs – an iron-binding glycoprotein and antimicrobial peptide usually found in large quantities in breast milk – was shown to be a likely mediator that could regulate inflammatory responses during CD. These results were published in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2018.02.001).

Intestinal inflammation is primarily mediated by cytokine production, and targeted anticytokine therapy is the current standard for IBD treatment. The cytokine profile from CD patient–derived mesenteric ADSCs and fat tissue was significantly different from that of these patients’ disease-free counterparts. The authors hypothesized that mesenteric ADSCs release adipokines in response to disease-associated signals; this release of adipokines results from differential gene expression of mesenteric ADSCs in CD versus control patients. To test this hypothesis, conditioned media from CD patient–derived ADSCs was used to study gene expression in colonic intestinal epithelial cells in vitro and in mice with experimental colitis in vivo.

Using the Human LncRNA Expression Microarray V4.0, expression of 20,730 protein-coding mRNA targets was analysed, and 992 mRNA transcripts were found to be differentially (less than or equal to twofold change) expressed in CD patient–derived ADSCs, compared with control patient–derived ADSCs. Subsequent pathway analysis suggested activation of cellular growth and proliferation pathways with caspase 8 and p42/44 as top predicted networks that are differentially regulated in CD patient–derived ADSCs with respect to those of control patients.

The investigators treated intestinal epithelial cells – specifically, NCM460 – with conditioned 233 media from the same CD or control patient–derived ADSCs; subsequent microarray profiling using the GeneChip Human Gene ST Array showed increased expression of interleukin-17A, CCL23, and VEGFA. Ingenuity Pathway Analysis of mRNA expression indicated convergence in injury and inflammation pathways with the SERPINE1 gene, which suggests it’s the central regulator of the differential gene expression network.

In vivo, mice with active dextran sulfate sodium (DSS) colitis that were treated with daily injections of conditioned media from CD patients showed attenuation of colitis as compared with mice treated with vehicle or conditioned media from control patients. Furthermore, the mRNA expression of proinflammatory cytokines was reduced with increased proliferative response (as measured by Ki67 expression) in intestinal epithelial cells in the dextran sulfate sodium–treated mice receiving media from CD patients, compared with that in mice receiving media from control patients or vehicle-treated mice.

Cell proliferation was studied in real time (during a period of 120 hours) using the xCELLigence platform. The authors suggested that mesenteric adipose tissue–derived mediators may regulate proliferative responses in intestinal epithelial cells during intestinal inflammation, as observed by enhanced cell-doubling time in conditioned media from CD patient–derived ADSCs.

SOURCE: Hoffman J et al. Cell Molec Gastro Hepatol. doi: 10.1016/j.jcmgh.2018.02.001.

CHICAGO – A combination of an immunostimulatory IL-15-based agent, ALT-803, with a therapeutic monoclonal antibody (mAb) against CD20, was well tolerated and had clinical activity in patients with indolent non-Hodgkin lymphoma (iNHL), according to preliminary findings from a phase 1 study.

“The cancer immunotherapy breakthrough that happened several years ago continues year after year, with a plethora of different modalities of immunotherapy at our disposal,” Todd A. Fehniger, MD, PhD, said at the annual meeting of the American Association for Cancer Research.

Immunotherapy with anti-CD20 mAbs, alone or in combination with chemotherapy, is a standard therapy for iNHL patients. Since iNHL cells express CD20, targeting it with mAbs triggers antitumor responses via cell surface receptors resulting in a potent antibody-dependent cellular toxicity. However, response in patients is highly heterogeneous, with relapse within a few months in a subset of patients. In addition, chemotherapeutic combinations can be toxic and result in serious and long-term complications.

“Relapsed or refractory iNHL is not curable and treatment strategies without long-term complications are needed,” said Dr. Fehniger, associate professor of medicine at Washington University, St. Louis.

In an attempt to address this, Dr. Fehniger and his colleagues combined rituximab, an anti-CD20 antibody, with a relatively new IL-15 agonist immunostimulatory agent called ALT-803.

In the phase 1 trial, the researchers enrolled patients with indolent non-Hodgkin lymphoma who had relapsed after at least 1 prior to CD20 antibody containing therapy. The study was a standard 3+3 dose escalation design with rituximab administered by intravenous infusion, 375 mg/m² in four weekly doses, followed by a rest and four consolidation doses every 8 weeks for four cycles.

ALT-803 was administered concurrently at dose levels of 1 mcg/kg, 3 mcg/kg, and 6 mcg/kg IV followed by 6 mcg/kg, 10 mcg/kg, 15 mcg/kg, and 20 mcg/kg subcutaneously.

SOURCE: Fehniger TA et al. AACR Annual Meeting, Abstract CT146.

CHICAGO – A combination of an immunostimulatory IL-15-based agent, ALT-803, with a therapeutic monoclonal antibody (mAb) against CD20, was well tolerated and had clinical activity in patients with indolent non-Hodgkin lymphoma (iNHL), according to preliminary findings from a phase 1 study.

“The cancer immunotherapy breakthrough that happened several years ago continues year after year, with a plethora of different modalities of immunotherapy at our disposal,” Todd A. Fehniger, MD, PhD, said at the annual meeting of the American Association for Cancer Research.

Immunotherapy with anti-CD20 mAbs, alone or in combination with chemotherapy, is a standard therapy for iNHL patients. Since iNHL cells express CD20, targeting it with mAbs triggers antitumor responses via cell surface receptors resulting in a potent antibody-dependent cellular toxicity. However, response in patients is highly heterogeneous, with relapse within a few months in a subset of patients. In addition, chemotherapeutic combinations can be toxic and result in serious and long-term complications.

“Relapsed or refractory iNHL is not curable and treatment strategies without long-term complications are needed,” said Dr. Fehniger, associate professor of medicine at Washington University, St. Louis.

In an attempt to address this, Dr. Fehniger and his colleagues combined rituximab, an anti-CD20 antibody, with a relatively new IL-15 agonist immunostimulatory agent called ALT-803.

In the phase 1 trial, the researchers enrolled patients with indolent non-Hodgkin lymphoma who had relapsed after at least 1 prior to CD20 antibody containing therapy. The study was a standard 3+3 dose escalation design with rituximab administered by intravenous infusion, 375 mg/m² in four weekly doses, followed by a rest and four consolidation doses every 8 weeks for four cycles.

ALT-803 was administered concurrently at dose levels of 1 mcg/kg, 3 mcg/kg, and 6 mcg/kg IV followed by 6 mcg/kg, 10 mcg/kg, 15 mcg/kg, and 20 mcg/kg subcutaneously.

SOURCE: Fehniger TA et al. AACR Annual Meeting, Abstract CT146.

CHICAGO – A combination of an immunostimulatory IL-15-based agent, ALT-803, with a therapeutic monoclonal antibody (mAb) against CD20, was well tolerated and had clinical activity in patients with indolent non-Hodgkin lymphoma (iNHL), according to preliminary findings from a phase 1 study.

“The cancer immunotherapy breakthrough that happened several years ago continues year after year, with a plethora of different modalities of immunotherapy at our disposal,” Todd A. Fehniger, MD, PhD, said at the annual meeting of the American Association for Cancer Research.

Immunotherapy with anti-CD20 mAbs, alone or in combination with chemotherapy, is a standard therapy for iNHL patients. Since iNHL cells express CD20, targeting it with mAbs triggers antitumor responses via cell surface receptors resulting in a potent antibody-dependent cellular toxicity. However, response in patients is highly heterogeneous, with relapse within a few months in a subset of patients. In addition, chemotherapeutic combinations can be toxic and result in serious and long-term complications.

“Relapsed or refractory iNHL is not curable and treatment strategies without long-term complications are needed,” said Dr. Fehniger, associate professor of medicine at Washington University, St. Louis.

In an attempt to address this, Dr. Fehniger and his colleagues combined rituximab, an anti-CD20 antibody, with a relatively new IL-15 agonist immunostimulatory agent called ALT-803.

In the phase 1 trial, the researchers enrolled patients with indolent non-Hodgkin lymphoma who had relapsed after at least 1 prior to CD20 antibody containing therapy. The study was a standard 3+3 dose escalation design with rituximab administered by intravenous infusion, 375 mg/m² in four weekly doses, followed by a rest and four consolidation doses every 8 weeks for four cycles.

ALT-803 was administered concurrently at dose levels of 1 mcg/kg, 3 mcg/kg, and 6 mcg/kg IV followed by 6 mcg/kg, 10 mcg/kg, 15 mcg/kg, and 20 mcg/kg subcutaneously.

SOURCE: Fehniger TA et al. AACR Annual Meeting, Abstract CT146.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The combination of nivolumab plus ipilimumab prolonged progression-free survival (PFS), in comparison with platinum based chemotherapy, as initial treatment for advanced non–small cell lung cancer (NSCLC) patients with a high tumor mutation burden (TMB), regardless of PDL-1 status, according to the first analysis of Checkmate 227.

Median PFS was 7.2 months for patients receiving the immunotherapy combination (95% confidence interval, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) for those receiving platinum-based chemotherapy (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001).

The trial results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection, Matthew D. Hellmann, MD, said at the annual meeting of the American Association for Cancer Research.

“Checkmate 227 is the pivotal phase 3 study to validate TMB as an important and independent biomarker to be routinely tested in treatment-naive advanced NSCLC,” he said.

Overall survival data with the combination versus chemotherapy was “encouraging” but not yet complete in patients with high TMB, Dr. Hellmann said.

Results from this first analysis (part 1) of Checkmate 227, a multipart trial, were simultaneously published in the New England Journal of Medicine.

The trial was designed prior to emerging data about TMB. The study was later amended prior to initial analysis to include a second coprimary endpoint evaluating PFS with nivolumab plus ipilimumab versus chemotherapy among patients with a tumor mutational burden of at least 10 mutations per megabase (mut/Mb), irrespective of PD-L1 expression level.

For part 1 of the trial, patients were randomized 1:1:1 to nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks; histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles; and nivolumab 240 mg every 2 weeks or nivolumab 360 mg plus histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles, followed by nivolumab monotherapy.

Of all randomized patients in part 1 (n=1,739), 1,004 (58%) were evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had TMB greater than or equal to 10 mut/Mb, including 139 patients randomized to nivolumab plus ipilimumab and 160 patients randomized to chemotherapy. TMB was assessed using the validated assay, FoundationOne CDx.

One-year PFS was higher with nivolumab plus ipilimumab than with chemotherapy among all randomized patients in part 1 (30.9% vs. 17.0%; HR for disease progression or death, 0.83; 95% CI, 0.72-0.96).

The PFS was significantly prolonged with the combination, compared with chemotherapy among patients with a high TMB; the 1-year PFS rate was 42.6% versus 13.2%, respectively, and the median PFS was 7.2 months (95% CI, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) respectively (HR for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001). In a subgroup analysis, PFS was longer with nivolumab plus ipilimumab versus chemotherapy for patients with a programmed death ligand 1 expression level of at least 1% and those with a level of less than 1%, reported Dr. Hellmann of Memorial Sloan Kettering Cancer Center, New York.

Safety was manageable and consistent with previous reports of nivolumab plus low-dose ipilimumab in NSCLC. Grade 3-4 treatment-related adverse events with the combination were skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic (15%), pulmonary (8%), hypersensitivity (4%), and renal (4%) events. Overall, treatment-related deaths occurred in 1% of patients treated in both the combination and chemotherapy arms.

Results from Checkmate 227 may introduce two new standards of care for the first-line treatment of NSCLC, Dr. Hellmann said. The immunotherapy combination is introduced as a new option for the first-line treatment of NSCLC with a high TMB, sparing first-line chemotherapy, and it validates TMB as an “important and independent biomarker to be routinely tested in treatment-naive, advanced NSCLC,” he concluded.

Dr. Hellmann disclosed relationships with Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, and Shattuck Labs.

SOURCE: Hellmann MD et al. AACR Annual Meeting, Abstract CT077.

CHICAGO – The combination of nivolumab plus ipilimumab prolonged progression-free survival (PFS), in comparison with platinum based chemotherapy, as initial treatment for advanced non–small cell lung cancer (NSCLC) patients with a high tumor mutation burden (TMB), regardless of PDL-1 status, according to the first analysis of Checkmate 227.

Median PFS was 7.2 months for patients receiving the immunotherapy combination (95% confidence interval, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) for those receiving platinum-based chemotherapy (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001).

The trial results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection, Matthew D. Hellmann, MD, said at the annual meeting of the American Association for Cancer Research.

“Checkmate 227 is the pivotal phase 3 study to validate TMB as an important and independent biomarker to be routinely tested in treatment-naive advanced NSCLC,” he said.

Overall survival data with the combination versus chemotherapy was “encouraging” but not yet complete in patients with high TMB, Dr. Hellmann said.

Results from this first analysis (part 1) of Checkmate 227, a multipart trial, were simultaneously published in the New England Journal of Medicine.

The trial was designed prior to emerging data about TMB. The study was later amended prior to initial analysis to include a second coprimary endpoint evaluating PFS with nivolumab plus ipilimumab versus chemotherapy among patients with a tumor mutational burden of at least 10 mutations per megabase (mut/Mb), irrespective of PD-L1 expression level.

For part 1 of the trial, patients were randomized 1:1:1 to nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks; histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles; and nivolumab 240 mg every 2 weeks or nivolumab 360 mg plus histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles, followed by nivolumab monotherapy.

Of all randomized patients in part 1 (n=1,739), 1,004 (58%) were evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had TMB greater than or equal to 10 mut/Mb, including 139 patients randomized to nivolumab plus ipilimumab and 160 patients randomized to chemotherapy. TMB was assessed using the validated assay, FoundationOne CDx.

One-year PFS was higher with nivolumab plus ipilimumab than with chemotherapy among all randomized patients in part 1 (30.9% vs. 17.0%; HR for disease progression or death, 0.83; 95% CI, 0.72-0.96).

The PFS was significantly prolonged with the combination, compared with chemotherapy among patients with a high TMB; the 1-year PFS rate was 42.6% versus 13.2%, respectively, and the median PFS was 7.2 months (95% CI, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) respectively (HR for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001). In a subgroup analysis, PFS was longer with nivolumab plus ipilimumab versus chemotherapy for patients with a programmed death ligand 1 expression level of at least 1% and those with a level of less than 1%, reported Dr. Hellmann of Memorial Sloan Kettering Cancer Center, New York.

Safety was manageable and consistent with previous reports of nivolumab plus low-dose ipilimumab in NSCLC. Grade 3-4 treatment-related adverse events with the combination were skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic (15%), pulmonary (8%), hypersensitivity (4%), and renal (4%) events. Overall, treatment-related deaths occurred in 1% of patients treated in both the combination and chemotherapy arms.

Results from Checkmate 227 may introduce two new standards of care for the first-line treatment of NSCLC, Dr. Hellmann said. The immunotherapy combination is introduced as a new option for the first-line treatment of NSCLC with a high TMB, sparing first-line chemotherapy, and it validates TMB as an “important and independent biomarker to be routinely tested in treatment-naive, advanced NSCLC,” he concluded.

Dr. Hellmann disclosed relationships with Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, and Shattuck Labs.

SOURCE: Hellmann MD et al. AACR Annual Meeting, Abstract CT077.

CHICAGO – The combination of nivolumab plus ipilimumab prolonged progression-free survival (PFS), in comparison with platinum based chemotherapy, as initial treatment for advanced non–small cell lung cancer (NSCLC) patients with a high tumor mutation burden (TMB), regardless of PDL-1 status, according to the first analysis of Checkmate 227.

Median PFS was 7.2 months for patients receiving the immunotherapy combination (95% confidence interval, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) for those receiving platinum-based chemotherapy (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001).

The trial results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection, Matthew D. Hellmann, MD, said at the annual meeting of the American Association for Cancer Research.

“Checkmate 227 is the pivotal phase 3 study to validate TMB as an important and independent biomarker to be routinely tested in treatment-naive advanced NSCLC,” he said.

Overall survival data with the combination versus chemotherapy was “encouraging” but not yet complete in patients with high TMB, Dr. Hellmann said.

Results from this first analysis (part 1) of Checkmate 227, a multipart trial, were simultaneously published in the New England Journal of Medicine.

The trial was designed prior to emerging data about TMB. The study was later amended prior to initial analysis to include a second coprimary endpoint evaluating PFS with nivolumab plus ipilimumab versus chemotherapy among patients with a tumor mutational burden of at least 10 mutations per megabase (mut/Mb), irrespective of PD-L1 expression level.

For part 1 of the trial, patients were randomized 1:1:1 to nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks; histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles; and nivolumab 240 mg every 2 weeks or nivolumab 360 mg plus histology-based platinum-doublet chemotherapy every 3 weeks for up to four cycles, followed by nivolumab monotherapy.

Of all randomized patients in part 1 (n=1,739), 1,004 (58%) were evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had TMB greater than or equal to 10 mut/Mb, including 139 patients randomized to nivolumab plus ipilimumab and 160 patients randomized to chemotherapy. TMB was assessed using the validated assay, FoundationOne CDx.

One-year PFS was higher with nivolumab plus ipilimumab than with chemotherapy among all randomized patients in part 1 (30.9% vs. 17.0%; HR for disease progression or death, 0.83; 95% CI, 0.72-0.96).

The PFS was significantly prolonged with the combination, compared with chemotherapy among patients with a high TMB; the 1-year PFS rate was 42.6% versus 13.2%, respectively, and the median PFS was 7.2 months (95% CI, 5.5-13.2) versus 5.5 months (95% CI, 4.4-5.8) respectively (HR for disease progression or death, 0.58; 97.5% CI, 0.41-0.81; P less than .001). In a subgroup analysis, PFS was longer with nivolumab plus ipilimumab versus chemotherapy for patients with a programmed death ligand 1 expression level of at least 1% and those with a level of less than 1%, reported Dr. Hellmann of Memorial Sloan Kettering Cancer Center, New York.

Safety was manageable and consistent with previous reports of nivolumab plus low-dose ipilimumab in NSCLC. Grade 3-4 treatment-related adverse events with the combination were skin reactions (34%), endocrine (23%), gastrointestinal (18%), hepatic (15%), pulmonary (8%), hypersensitivity (4%), and renal (4%) events. Overall, treatment-related deaths occurred in 1% of patients treated in both the combination and chemotherapy arms.

Results from Checkmate 227 may introduce two new standards of care for the first-line treatment of NSCLC, Dr. Hellmann said. The immunotherapy combination is introduced as a new option for the first-line treatment of NSCLC with a high TMB, sparing first-line chemotherapy, and it validates TMB as an “important and independent biomarker to be routinely tested in treatment-naive, advanced NSCLC,” he concluded.

Dr. Hellmann disclosed relationships with Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, and Shattuck Labs.

SOURCE: Hellmann MD et al. AACR Annual Meeting, Abstract CT077.

CHICAGO – Median overall survival (OS) in patients with HER2-negative metastatic breast cancer (mBC) and germline BRCA mutation (gBRCAm), although not statistically significant, was 2.2 months longer with olaparib versus physician’s choice chemotherapy (TPC), according to the final analysis of the OlympiAD study.

The results suggested the possibility of greater benefit among chemotherapy naive patients for metastatic breast cancer, with no cumulative toxicity reported with extended exposure, Mark E. Robson, MD, said at the annual meeting of the American Association for Cancer Research.

OlympiAD was a randomized, controlled, open-label, multicenter, phase 3 study of olaparib tablet monotherapy (300 mg, twice daily) compared with predeclared TPC monotherapy (capecitabine, vinorelbine, or eribulin). Patients were stratified by prior chemotherapy, prior platinum, and receptor status (ER+ and/or PR+ vs. TNBC). Of 302 randomized patients, 205 received olaparib and 91 received TPC (6 TPC patients declined treatment). Eligible patients had HER2-negative mBC and a germline BRCA mutation. In addition, patients should have received less than or equal to two chemotherapy lines in the metastatic setting, with prior anthracycline and taxane treatment either as (neo)adjuvant therapy or in the metastatic setting.

The data presented at AACR was a follow-up on the primary progression-free survival (PFS) analysis, which demonstrated significant benefit in olaparib over standard chemotherapy TPC (7.0 vs 4.2 months, HR 0.58, 95% confidence interval, 0.43-0.80, P less than .001). Overall response rate (ORR) in the olaparib arm was double of that observed on the TPC arm in measurable disease patients (59.9% vs. 28.8%).

SOURCE: Robson ME et al. AACR Annual Meeting Abstract CT038.

CHICAGO – Median overall survival (OS) in patients with HER2-negative metastatic breast cancer (mBC) and germline BRCA mutation (gBRCAm), although not statistically significant, was 2.2 months longer with olaparib versus physician’s choice chemotherapy (TPC), according to the final analysis of the OlympiAD study.

The results suggested the possibility of greater benefit among chemotherapy naive patients for metastatic breast cancer, with no cumulative toxicity reported with extended exposure, Mark E. Robson, MD, said at the annual meeting of the American Association for Cancer Research.

OlympiAD was a randomized, controlled, open-label, multicenter, phase 3 study of olaparib tablet monotherapy (300 mg, twice daily) compared with predeclared TPC monotherapy (capecitabine, vinorelbine, or eribulin). Patients were stratified by prior chemotherapy, prior platinum, and receptor status (ER+ and/or PR+ vs. TNBC). Of 302 randomized patients, 205 received olaparib and 91 received TPC (6 TPC patients declined treatment). Eligible patients had HER2-negative mBC and a germline BRCA mutation. In addition, patients should have received less than or equal to two chemotherapy lines in the metastatic setting, with prior anthracycline and taxane treatment either as (neo)adjuvant therapy or in the metastatic setting.

The data presented at AACR was a follow-up on the primary progression-free survival (PFS) analysis, which demonstrated significant benefit in olaparib over standard chemotherapy TPC (7.0 vs 4.2 months, HR 0.58, 95% confidence interval, 0.43-0.80, P less than .001). Overall response rate (ORR) in the olaparib arm was double of that observed on the TPC arm in measurable disease patients (59.9% vs. 28.8%).

SOURCE: Robson ME et al. AACR Annual Meeting Abstract CT038.

CHICAGO – Median overall survival (OS) in patients with HER2-negative metastatic breast cancer (mBC) and germline BRCA mutation (gBRCAm), although not statistically significant, was 2.2 months longer with olaparib versus physician’s choice chemotherapy (TPC), according to the final analysis of the OlympiAD study.

The results suggested the possibility of greater benefit among chemotherapy naive patients for metastatic breast cancer, with no cumulative toxicity reported with extended exposure, Mark E. Robson, MD, said at the annual meeting of the American Association for Cancer Research.

OlympiAD was a randomized, controlled, open-label, multicenter, phase 3 study of olaparib tablet monotherapy (300 mg, twice daily) compared with predeclared TPC monotherapy (capecitabine, vinorelbine, or eribulin). Patients were stratified by prior chemotherapy, prior platinum, and receptor status (ER+ and/or PR+ vs. TNBC). Of 302 randomized patients, 205 received olaparib and 91 received TPC (6 TPC patients declined treatment). Eligible patients had HER2-negative mBC and a germline BRCA mutation. In addition, patients should have received less than or equal to two chemotherapy lines in the metastatic setting, with prior anthracycline and taxane treatment either as (neo)adjuvant therapy or in the metastatic setting.

The data presented at AACR was a follow-up on the primary progression-free survival (PFS) analysis, which demonstrated significant benefit in olaparib over standard chemotherapy TPC (7.0 vs 4.2 months, HR 0.58, 95% confidence interval, 0.43-0.80, P less than .001). Overall response rate (ORR) in the olaparib arm was double of that observed on the TPC arm in measurable disease patients (59.9% vs. 28.8%).

SOURCE: Robson ME et al. AACR Annual Meeting Abstract CT038.

Psychogastroenterology is the science of applying psychological principles and techniques to alleviate the burden of chronic digestive diseases. This burden includes digestive symptoms and disease severity, as well as patients’ ability to cope with them. Chronic digestive diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychosocial context. In this regard, the role of gastroenterologists in promoting best practices for the assessment and referral of patients across the spectrum of disease to brain-gut psychotherapies is crucial.

A review by Laurie Keefer, PhD, AGAF, and her coauthors, published in the April issue of Gastroenterology, provided a clinical update on the structure and efficacy of two major classes of psychogastroenterology – cognitive-behavioral therapy (CBT) and gut-directed hypnotherapy (HYP). The review discussed the effects of these therapies on GI symptoms and the patients’ ability to improve coping, resilience, and self-regulation. The review also provided a framework to understand the scientific rationale and best practices associated with incorporating brain-gut psychotherapies into routine GI care. Furthermore, it presented recommendations on how to address psychological issues and make effective referrals in routine practice.

Previous studies had highlighted that the burden of chronic digestive diseases is amplified by psychosocial factors, including poor coping, depression, and poor social support. Mental health professionals specializing in psychogastroenterology integrate the use of brain-gut psychotherapies into GI practice settings, which may help reduce health care utilization and symptom burden.

The article contains best practice advice based on a review of the literature, including existing systematic reviews and expert opinions. These best practices include the following:

• Gastroenterologists routinely should assess health-related quality of life, symptom-specific anxieties, early-life adversity, and functional impairment related to a patient’s digestive complaints.
• Gastroenterologists should master patient-friendly language to help explain the brain-gut pathway and how this pathway can become dysregulated by any number of factors, the psychosocial risks perpetuating and maintaining factors of GI diseases, and why the gastroenterologist is referring a patient to a mental health provider.
• Gastroenterologists should know the structure and core features of the most effective brain-gut psychotherapies.
• Gastroenterologists should establish a direct referral and ongoing communication pathway with one or two qualified mental health providers and assure patients that he/she will remain a part of the care team.
• Gastroenterologists should familiarize themselves with one or two neuromodulators that can be used to augment behavioral therapies when necessary.

Patient education about the referral to a mental health provider is difficult and requires attention to detail and fostering a good physician-patient relationship. It is important to help patients understand why they are being referred to a psychologist for a gastrointestinal complaint and that their physical symptoms are not being discounted. Failure to properly explain the reason for referral may lead to poor follow-through and even lead the patient to seek care with another provider.

In order to foster widespread integration of these services, research and clinical gaps need to be addressed. Research gaps include the lack of prospective trials that compare the relative effectiveness of brain-gut psychotherapies with each other and/or with that of psychotropic medications. Other promising brain-gut therapies, such as mindfulness meditation or acceptance-based approaches, lack sufficient research to be included in clinical practice. Limited evidence supports the effect of psychotherapies have in accelerating or enhancing the efficacy of pharmacologic therapies and on improving disease course or inflammation in conditions such as Crohn’s and ulcerative colitis.

SOURCE: Keefer L et al. Gastroenterology. doi: 10.1053/j.gastro.2018.01.045.

Psychogastroenterology is the science of applying psychological principles and techniques to alleviate the burden of chronic digestive diseases. This burden includes digestive symptoms and disease severity, as well as patients’ ability to cope with them. Chronic digestive diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychosocial context. In this regard, the role of gastroenterologists in promoting best practices for the assessment and referral of patients across the spectrum of disease to brain-gut psychotherapies is crucial.

A review by Laurie Keefer, PhD, AGAF, and her coauthors, published in the April issue of Gastroenterology, provided a clinical update on the structure and efficacy of two major classes of psychogastroenterology – cognitive-behavioral therapy (CBT) and gut-directed hypnotherapy (HYP). The review discussed the effects of these therapies on GI symptoms and the patients’ ability to improve coping, resilience, and self-regulation. The review also provided a framework to understand the scientific rationale and best practices associated with incorporating brain-gut psychotherapies into routine GI care. Furthermore, it presented recommendations on how to address psychological issues and make effective referrals in routine practice.

Previous studies had highlighted that the burden of chronic digestive diseases is amplified by psychosocial factors, including poor coping, depression, and poor social support. Mental health professionals specializing in psychogastroenterology integrate the use of brain-gut psychotherapies into GI practice settings, which may help reduce health care utilization and symptom burden.

The article contains best practice advice based on a review of the literature, including existing systematic reviews and expert opinions. These best practices include the following:

• Gastroenterologists routinely should assess health-related quality of life, symptom-specific anxieties, early-life adversity, and functional impairment related to a patient’s digestive complaints.
• Gastroenterologists should master patient-friendly language to help explain the brain-gut pathway and how this pathway can become dysregulated by any number of factors, the psychosocial risks perpetuating and maintaining factors of GI diseases, and why the gastroenterologist is referring a patient to a mental health provider.
• Gastroenterologists should know the structure and core features of the most effective brain-gut psychotherapies.
• Gastroenterologists should establish a direct referral and ongoing communication pathway with one or two qualified mental health providers and assure patients that he/she will remain a part of the care team.
• Gastroenterologists should familiarize themselves with one or two neuromodulators that can be used to augment behavioral therapies when necessary.

Patient education about the referral to a mental health provider is difficult and requires attention to detail and fostering a good physician-patient relationship. It is important to help patients understand why they are being referred to a psychologist for a gastrointestinal complaint and that their physical symptoms are not being discounted. Failure to properly explain the reason for referral may lead to poor follow-through and even lead the patient to seek care with another provider.

In order to foster widespread integration of these services, research and clinical gaps need to be addressed. Research gaps include the lack of prospective trials that compare the relative effectiveness of brain-gut psychotherapies with each other and/or with that of psychotropic medications. Other promising brain-gut therapies, such as mindfulness meditation or acceptance-based approaches, lack sufficient research to be included in clinical practice. Limited evidence supports the effect of psychotherapies have in accelerating or enhancing the efficacy of pharmacologic therapies and on improving disease course or inflammation in conditions such as Crohn’s and ulcerative colitis.

SOURCE: Keefer L et al. Gastroenterology. doi: 10.1053/j.gastro.2018.01.045.

Psychogastroenterology is the science of applying psychological principles and techniques to alleviate the burden of chronic digestive diseases. This burden includes digestive symptoms and disease severity, as well as patients’ ability to cope with them. Chronic digestive diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychosocial context. In this regard, the role of gastroenterologists in promoting best practices for the assessment and referral of patients across the spectrum of disease to brain-gut psychotherapies is crucial.

A review by Laurie Keefer, PhD, AGAF, and her coauthors, published in the April issue of Gastroenterology, provided a clinical update on the structure and efficacy of two major classes of psychogastroenterology – cognitive-behavioral therapy (CBT) and gut-directed hypnotherapy (HYP). The review discussed the effects of these therapies on GI symptoms and the patients’ ability to improve coping, resilience, and self-regulation. The review also provided a framework to understand the scientific rationale and best practices associated with incorporating brain-gut psychotherapies into routine GI care. Furthermore, it presented recommendations on how to address psychological issues and make effective referrals in routine practice.

Previous studies had highlighted that the burden of chronic digestive diseases is amplified by psychosocial factors, including poor coping, depression, and poor social support. Mental health professionals specializing in psychogastroenterology integrate the use of brain-gut psychotherapies into GI practice settings, which may help reduce health care utilization and symptom burden.

The article contains best practice advice based on a review of the literature, including existing systematic reviews and expert opinions. These best practices include the following:

• Gastroenterologists routinely should assess health-related quality of life, symptom-specific anxieties, early-life adversity, and functional impairment related to a patient’s digestive complaints.
• Gastroenterologists should master patient-friendly language to help explain the brain-gut pathway and how this pathway can become dysregulated by any number of factors, the psychosocial risks perpetuating and maintaining factors of GI diseases, and why the gastroenterologist is referring a patient to a mental health provider.
• Gastroenterologists should know the structure and core features of the most effective brain-gut psychotherapies.
• Gastroenterologists should establish a direct referral and ongoing communication pathway with one or two qualified mental health providers and assure patients that he/she will remain a part of the care team.
• Gastroenterologists should familiarize themselves with one or two neuromodulators that can be used to augment behavioral therapies when necessary.

Patient education about the referral to a mental health provider is difficult and requires attention to detail and fostering a good physician-patient relationship. It is important to help patients understand why they are being referred to a psychologist for a gastrointestinal complaint and that their physical symptoms are not being discounted. Failure to properly explain the reason for referral may lead to poor follow-through and even lead the patient to seek care with another provider.

In order to foster widespread integration of these services, research and clinical gaps need to be addressed. Research gaps include the lack of prospective trials that compare the relative effectiveness of brain-gut psychotherapies with each other and/or with that of psychotropic medications. Other promising brain-gut therapies, such as mindfulness meditation or acceptance-based approaches, lack sufficient research to be included in clinical practice. Limited evidence supports the effect of psychotherapies have in accelerating or enhancing the efficacy of pharmacologic therapies and on improving disease course or inflammation in conditions such as Crohn’s and ulcerative colitis.

SOURCE: Keefer L et al. Gastroenterology. doi: 10.1053/j.gastro.2018.01.045.

Socioeconomic status, as measured by insurance status, was associated with survival among patients with non–small cell lung cancer (NSCLC) and pretreatment cancer-associated weight loss, in a retrospective review of medical records.

Investigators identified 1,366 patients with NSCLC who had been consecutively treated at a tertiary care health system between Jan. 1, 2006, and Dec. 31, 2013, and obtained their insurance status from an institutional tumor registry.

Cancer-associated weight loss was present at the time of diagnosis in 30% of the patients. Among those patients with pretreatment weight loss, uninsured patients had worse survival compared with those who had private insurance (hazard ratio, 1.63; 95% confidence interval, 1.14-2.35). However, no association was found for patients without pretreatment weight loss, wrote Steven Lau, MD, of the University of Texas Southwestern Medical Center, Dallas, and his associates. The report was published in the Journal of Oncology Practice.

After the researchers controlled for other prognostic factors, Medicaid insurance (odds ratio, 2.17; 95% CI, 1.42-3.30) and lack of insurance (OR, 2.32; 95% CI, 1.50-3.58) were independently associated with pretreatment weight loss.

“Patients with NSCLC of lower SES as measured by primary payer are disproportionately affected by cancer-associated weight loss, which in turn is prognostic of diminished survival ... These findings suggest early recognition and management of cachexia, even at the time of cancer diagnosis, could result in improved survival,” Dr. Lau and his associates concluded.

The study was supported in part by National Center for Advancing Translational Sciences grants TL1TR001104 and UL1TR001105. Dr. Lau reported employment with LabCorp by an immediate family member. Coauthors reported financial ties to Advenchen Laboratories, Macrogen, Peregrine Pharmaceuticals, and DFINE.

SOURCE: Lau S et al. J Oncol Pract. 2018 Mar 20. doi: 10.1200/JOP.2017.025239

Socioeconomic status, as measured by insurance status, was associated with survival among patients with non–small cell lung cancer (NSCLC) and pretreatment cancer-associated weight loss, in a retrospective review of medical records.

Investigators identified 1,366 patients with NSCLC who had been consecutively treated at a tertiary care health system between Jan. 1, 2006, and Dec. 31, 2013, and obtained their insurance status from an institutional tumor registry.

Cancer-associated weight loss was present at the time of diagnosis in 30% of the patients. Among those patients with pretreatment weight loss, uninsured patients had worse survival compared with those who had private insurance (hazard ratio, 1.63; 95% confidence interval, 1.14-2.35). However, no association was found for patients without pretreatment weight loss, wrote Steven Lau, MD, of the University of Texas Southwestern Medical Center, Dallas, and his associates. The report was published in the Journal of Oncology Practice.

After the researchers controlled for other prognostic factors, Medicaid insurance (odds ratio, 2.17; 95% CI, 1.42-3.30) and lack of insurance (OR, 2.32; 95% CI, 1.50-3.58) were independently associated with pretreatment weight loss.

“Patients with NSCLC of lower SES as measured by primary payer are disproportionately affected by cancer-associated weight loss, which in turn is prognostic of diminished survival ... These findings suggest early recognition and management of cachexia, even at the time of cancer diagnosis, could result in improved survival,” Dr. Lau and his associates concluded.

The study was supported in part by National Center for Advancing Translational Sciences grants TL1TR001104 and UL1TR001105. Dr. Lau reported employment with LabCorp by an immediate family member. Coauthors reported financial ties to Advenchen Laboratories, Macrogen, Peregrine Pharmaceuticals, and DFINE.

SOURCE: Lau S et al. J Oncol Pract. 2018 Mar 20. doi: 10.1200/JOP.2017.025239

Socioeconomic status, as measured by insurance status, was associated with survival among patients with non–small cell lung cancer (NSCLC) and pretreatment cancer-associated weight loss, in a retrospective review of medical records.

Investigators identified 1,366 patients with NSCLC who had been consecutively treated at a tertiary care health system between Jan. 1, 2006, and Dec. 31, 2013, and obtained their insurance status from an institutional tumor registry.

Cancer-associated weight loss was present at the time of diagnosis in 30% of the patients. Among those patients with pretreatment weight loss, uninsured patients had worse survival compared with those who had private insurance (hazard ratio, 1.63; 95% confidence interval, 1.14-2.35). However, no association was found for patients without pretreatment weight loss, wrote Steven Lau, MD, of the University of Texas Southwestern Medical Center, Dallas, and his associates. The report was published in the Journal of Oncology Practice.

After the researchers controlled for other prognostic factors, Medicaid insurance (odds ratio, 2.17; 95% CI, 1.42-3.30) and lack of insurance (OR, 2.32; 95% CI, 1.50-3.58) were independently associated with pretreatment weight loss.

“Patients with NSCLC of lower SES as measured by primary payer are disproportionately affected by cancer-associated weight loss, which in turn is prognostic of diminished survival ... These findings suggest early recognition and management of cachexia, even at the time of cancer diagnosis, could result in improved survival,” Dr. Lau and his associates concluded.

The study was supported in part by National Center for Advancing Translational Sciences grants TL1TR001104 and UL1TR001105. Dr. Lau reported employment with LabCorp by an immediate family member. Coauthors reported financial ties to Advenchen Laboratories, Macrogen, Peregrine Pharmaceuticals, and DFINE.

SOURCE: Lau S et al. J Oncol Pract. 2018 Mar 20. doi: 10.1200/JOP.2017.025239

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

A minority of patients (43.5%) with an indication for breast cancer genetic risk evaluation actually received formal genetic counseling in clinical practice, according to an analysis of NCI Surveillance, Epidemiology, and End Results (SEER) data published in Journal of Clinical Oncology.

More expertise is required in genetic counseling, either formal counseling given by an expert, or by a cancer physician (physician-directed), wrote Steven J. Katz and his colleagues at the University of Michigan, Ann Arbor. With BRCA1/2-only testing, being replaced by multi-gene panel testing, further consideration and/or discussion of results and formulation of a management plan is required, they said.

In addition, younger women more often reported some type of counseling (odds ratio, 4.5;95% confidence interval, 2.6-8.0; 1.9;95% CI, 1.1-3.3; and 1.5;95% CI, 1.0-2.3 for women younger than 50 years of age, 50-59 years of age, and 60-69 years of age, respectively, versus those 70 years of age and older).

Patients’ assessment of the amount of information they received about whether to have testing was high, “whether they received formal genetic counseling or a physician-directed discussion only (80.8% v 79.4% stated information was ‘just right’; P = .58),” the researchers noted.

As high-throughput molecular testing becomes increasingly complex, personalizing and tailoring the information to a individual patients’ need is crucial, the authors said. They further suggest a multipronged strategy that will train oncologists to integrate genetic testing into clinical decision making; including timely testing of patients at an elevated risk.

The study was supported by Grant P01 CA163233 to the University of Michigan from the National Cancer Institute. Potential conflict of interests were reported by Lauren P. Wallner, PhD (GlaxoSmithKline); Monica Morrow, MD (Genomic Health); Reshma Jagsi, MD (Amgen and AbbVie); and Allison W. Kurian, MD (Myriad Genetics, Invitae, Ambry Genetics, Genomic Health, GeneDx/BioReference, Genentech (a member of the Roche Group).

SOURCE: Katz SJ et al. J Clin Oncol. 2018 Mar 12. doi: 10.1200/JCO.2017.76.2369.

A minority of patients (43.5%) with an indication for breast cancer genetic risk evaluation actually received formal genetic counseling in clinical practice, according to an analysis of NCI Surveillance, Epidemiology, and End Results (SEER) data published in Journal of Clinical Oncology.

More expertise is required in genetic counseling, either formal counseling given by an expert, or by a cancer physician (physician-directed), wrote Steven J. Katz and his colleagues at the University of Michigan, Ann Arbor. With BRCA1/2-only testing, being replaced by multi-gene panel testing, further consideration and/or discussion of results and formulation of a management plan is required, they said.

In addition, younger women more often reported some type of counseling (odds ratio, 4.5;95% confidence interval, 2.6-8.0; 1.9;95% CI, 1.1-3.3; and 1.5;95% CI, 1.0-2.3 for women younger than 50 years of age, 50-59 years of age, and 60-69 years of age, respectively, versus those 70 years of age and older).

Patients’ assessment of the amount of information they received about whether to have testing was high, “whether they received formal genetic counseling or a physician-directed discussion only (80.8% v 79.4% stated information was ‘just right’; P = .58),” the researchers noted.

As high-throughput molecular testing becomes increasingly complex, personalizing and tailoring the information to a individual patients’ need is crucial, the authors said. They further suggest a multipronged strategy that will train oncologists to integrate genetic testing into clinical decision making; including timely testing of patients at an elevated risk.

The study was supported by Grant P01 CA163233 to the University of Michigan from the National Cancer Institute. Potential conflict of interests were reported by Lauren P. Wallner, PhD (GlaxoSmithKline); Monica Morrow, MD (Genomic Health); Reshma Jagsi, MD (Amgen and AbbVie); and Allison W. Kurian, MD (Myriad Genetics, Invitae, Ambry Genetics, Genomic Health, GeneDx/BioReference, Genentech (a member of the Roche Group).

SOURCE: Katz SJ et al. J Clin Oncol. 2018 Mar 12. doi: 10.1200/JCO.2017.76.2369.

A minority of patients (43.5%) with an indication for breast cancer genetic risk evaluation actually received formal genetic counseling in clinical practice, according to an analysis of NCI Surveillance, Epidemiology, and End Results (SEER) data published in Journal of Clinical Oncology.

More expertise is required in genetic counseling, either formal counseling given by an expert, or by a cancer physician (physician-directed), wrote Steven J. Katz and his colleagues at the University of Michigan, Ann Arbor. With BRCA1/2-only testing, being replaced by multi-gene panel testing, further consideration and/or discussion of results and formulation of a management plan is required, they said.

In addition, younger women more often reported some type of counseling (odds ratio, 4.5;95% confidence interval, 2.6-8.0; 1.9;95% CI, 1.1-3.3; and 1.5;95% CI, 1.0-2.3 for women younger than 50 years of age, 50-59 years of age, and 60-69 years of age, respectively, versus those 70 years of age and older).

Patients’ assessment of the amount of information they received about whether to have testing was high, “whether they received formal genetic counseling or a physician-directed discussion only (80.8% v 79.4% stated information was ‘just right’; P = .58),” the researchers noted.

As high-throughput molecular testing becomes increasingly complex, personalizing and tailoring the information to a individual patients’ need is crucial, the authors said. They further suggest a multipronged strategy that will train oncologists to integrate genetic testing into clinical decision making; including timely testing of patients at an elevated risk.

The study was supported by Grant P01 CA163233 to the University of Michigan from the National Cancer Institute. Potential conflict of interests were reported by Lauren P. Wallner, PhD (GlaxoSmithKline); Monica Morrow, MD (Genomic Health); Reshma Jagsi, MD (Amgen and AbbVie); and Allison W. Kurian, MD (Myriad Genetics, Invitae, Ambry Genetics, Genomic Health, GeneDx/BioReference, Genentech (a member of the Roche Group).

SOURCE: Katz SJ et al. J Clin Oncol. 2018 Mar 12. doi: 10.1200/JCO.2017.76.2369.

Racial and regional disparities in liver transplant allocation persist despite multiple allocation schemes as identified in a large dataset spanning at least 30 years, according to a study.

The Model for End-Stage Liver Disease (MELD) score was put forth in 1998 by the Organ Procurement and Transplantation Network under the guidance of the Centers for Medicare & Medicaid Services and the Department of Health & Human Services, to indicate that organs should be allocated to the sickest patients as interpreted by the MELD score. Since then, four separate liver allocation systems are being followed across the country owing to disagreements over a universal allocation scheme. These include MELD score, the initial three-tier UNOS (United Network for Organ Sharing) Status, Share 35, and now MELD Na.

VILevi/Thinkstock

Unfavorable supply and demand ratios for liver allograft allocation persist across the country with differential and limited access to care, which leads to decreased wellness, lower life expectancies, and higher baseline morbidity and mortality rates in some areas. Furthermore, a short cold storage capacity of liver allografts limits greater allocation and distribution schema.

Dominique J. Monlezun, MD, PhD, MPH, and his colleagues at the Tulane Transplant Institute at Tulane University, New Orleans, evaluated the effect of MELD and other allocation schemes on the incidence of racial and regional disparities in a study published in Surgery. They performed fixed-effects multivariate logistic regression augmented by modified forward and backward stepwise-regression of transplanted patients from the United Network for Organ Sharing Standard Transplant Analysis and Research database (1985-2016) to assess causal inference of such disparities.

“Significant disparities in the odds of receiving a liver were found: African Americans, odds ratio, 1.12 (95% confidence interval, 1.08-1.17); Asians, 1.12 (95% CI, 1.07-1.18); females, 0.80 (95% CI, 0.78-0.83); and malignancy 1.18 (95% CI, 1.13-1.22). Significant racial disparities by region were identified using Caucasian Region 7 (Ill., Minn., N.D., S.D., and Wisc.) as the reference: Hispanic Region 9 (N.Y., West Vt.) 1.22 (1.02-1.45), Hispanic Region 1 (New England) 1.26 (1.01-1.57), Hispanic Region 4 (Ok., Tex.) 1.23 (1.05-1.43), and Asian Region 4 (Ok., Tex.) 1.35 (1.05-1.73).” Since the transplantation rate in Region 7 closely approximated the sex and race-matched rate of the national post–Share 35 average, it was used as a reference in the study.

“Although traditional disparities as with African Americans and [whites] have been improved during the past 30 years, new disparities as with Hispanics and Asians have developed in certain regions,” stated the authors.

They acknowledged the limitations in the observational nature of the study and those of the statistical analyses, which could only approximate, rather than perfectly replicate, a randomized trial. Big Data tools such as artificial intelligence–based machine learning can provide real-time analysis of large heterogeneous datasets for patients across different regions.

The authors reported no conflicts of interest.

SOURCE: Monlezun DJ et al. Surgery. 2018 doi: 10.1016/j.surg.2017.10.009.

Racial and regional disparities in liver transplant allocation persist despite multiple allocation schemes as identified in a large dataset spanning at least 30 years, according to a study.

The Model for End-Stage Liver Disease (MELD) score was put forth in 1998 by the Organ Procurement and Transplantation Network under the guidance of the Centers for Medicare & Medicaid Services and the Department of Health & Human Services, to indicate that organs should be allocated to the sickest patients as interpreted by the MELD score. Since then, four separate liver allocation systems are being followed across the country owing to disagreements over a universal allocation scheme. These include MELD score, the initial three-tier UNOS (United Network for Organ Sharing) Status, Share 35, and now MELD Na.

VILevi/Thinkstock

Unfavorable supply and demand ratios for liver allograft allocation persist across the country with differential and limited access to care, which leads to decreased wellness, lower life expectancies, and higher baseline morbidity and mortality rates in some areas. Furthermore, a short cold storage capacity of liver allografts limits greater allocation and distribution schema.

Dominique J. Monlezun, MD, PhD, MPH, and his colleagues at the Tulane Transplant Institute at Tulane University, New Orleans, evaluated the effect of MELD and other allocation schemes on the incidence of racial and regional disparities in a study published in Surgery. They performed fixed-effects multivariate logistic regression augmented by modified forward and backward stepwise-regression of transplanted patients from the United Network for Organ Sharing Standard Transplant Analysis and Research database (1985-2016) to assess causal inference of such disparities.

“Significant disparities in the odds of receiving a liver were found: African Americans, odds ratio, 1.12 (95% confidence interval, 1.08-1.17); Asians, 1.12 (95% CI, 1.07-1.18); females, 0.80 (95% CI, 0.78-0.83); and malignancy 1.18 (95% CI, 1.13-1.22). Significant racial disparities by region were identified using Caucasian Region 7 (Ill., Minn., N.D., S.D., and Wisc.) as the reference: Hispanic Region 9 (N.Y., West Vt.) 1.22 (1.02-1.45), Hispanic Region 1 (New England) 1.26 (1.01-1.57), Hispanic Region 4 (Ok., Tex.) 1.23 (1.05-1.43), and Asian Region 4 (Ok., Tex.) 1.35 (1.05-1.73).” Since the transplantation rate in Region 7 closely approximated the sex and race-matched rate of the national post–Share 35 average, it was used as a reference in the study.

“Although traditional disparities as with African Americans and [whites] have been improved during the past 30 years, new disparities as with Hispanics and Asians have developed in certain regions,” stated the authors.

They acknowledged the limitations in the observational nature of the study and those of the statistical analyses, which could only approximate, rather than perfectly replicate, a randomized trial. Big Data tools such as artificial intelligence–based machine learning can provide real-time analysis of large heterogeneous datasets for patients across different regions.

The authors reported no conflicts of interest.

SOURCE: Monlezun DJ et al. Surgery. 2018 doi: 10.1016/j.surg.2017.10.009.

Racial and regional disparities in liver transplant allocation persist despite multiple allocation schemes as identified in a large dataset spanning at least 30 years, according to a study.

The Model for End-Stage Liver Disease (MELD) score was put forth in 1998 by the Organ Procurement and Transplantation Network under the guidance of the Centers for Medicare & Medicaid Services and the Department of Health & Human Services, to indicate that organs should be allocated to the sickest patients as interpreted by the MELD score. Since then, four separate liver allocation systems are being followed across the country owing to disagreements over a universal allocation scheme. These include MELD score, the initial three-tier UNOS (United Network for Organ Sharing) Status, Share 35, and now MELD Na.

VILevi/Thinkstock

Unfavorable supply and demand ratios for liver allograft allocation persist across the country with differential and limited access to care, which leads to decreased wellness, lower life expectancies, and higher baseline morbidity and mortality rates in some areas. Furthermore, a short cold storage capacity of liver allografts limits greater allocation and distribution schema.

Dominique J. Monlezun, MD, PhD, MPH, and his colleagues at the Tulane Transplant Institute at Tulane University, New Orleans, evaluated the effect of MELD and other allocation schemes on the incidence of racial and regional disparities in a study published in Surgery. They performed fixed-effects multivariate logistic regression augmented by modified forward and backward stepwise-regression of transplanted patients from the United Network for Organ Sharing Standard Transplant Analysis and Research database (1985-2016) to assess causal inference of such disparities.

“Significant disparities in the odds of receiving a liver were found: African Americans, odds ratio, 1.12 (95% confidence interval, 1.08-1.17); Asians, 1.12 (95% CI, 1.07-1.18); females, 0.80 (95% CI, 0.78-0.83); and malignancy 1.18 (95% CI, 1.13-1.22). Significant racial disparities by region were identified using Caucasian Region 7 (Ill., Minn., N.D., S.D., and Wisc.) as the reference: Hispanic Region 9 (N.Y., West Vt.) 1.22 (1.02-1.45), Hispanic Region 1 (New England) 1.26 (1.01-1.57), Hispanic Region 4 (Ok., Tex.) 1.23 (1.05-1.43), and Asian Region 4 (Ok., Tex.) 1.35 (1.05-1.73).” Since the transplantation rate in Region 7 closely approximated the sex and race-matched rate of the national post–Share 35 average, it was used as a reference in the study.

“Although traditional disparities as with African Americans and [whites] have been improved during the past 30 years, new disparities as with Hispanics and Asians have developed in certain regions,” stated the authors.

They acknowledged the limitations in the observational nature of the study and those of the statistical analyses, which could only approximate, rather than perfectly replicate, a randomized trial. Big Data tools such as artificial intelligence–based machine learning can provide real-time analysis of large heterogeneous datasets for patients across different regions.

The authors reported no conflicts of interest.

SOURCE: Monlezun DJ et al. Surgery. 2018 doi: 10.1016/j.surg.2017.10.009.