Research Spotlight

Schiller, L. R. (2019). “Network meta-analysis in chronic constipation: what have we learned?” Lancet: Gastroenterology and Hepatology 4(11): 812-813.

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Constipation is a common complaint among patients with gastrointestinal disorders, and many pharmacological therapies have been introduced in the last 20 years to treat them. Commonly, a new drug is tested against placebo in a randomised controlled trial to be approved by regulatory authorities; a trial needs to show that the drug is more efficacious than placebo and has minimal or manageable side-effects.

Zhou, K., A. S. Wahed, S. Cooper, A. M. Di Bisceglie, R. J. Fontana, M. G. Ghany, M. Khalili, A. S. Lok, R. Perrillo, W. M. Lee, D. T. Y. Lau, R. Sterling, H. L. A. Janssen and N. A. Terrault (2019). “Phase Transition Is Infrequent Among North American Adults With e-Antigen-Negative Chronic Hepatitis B and Low-Level Viremia.” Am J Gastroenterol Oct 24. [Epub ahead of print].

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INTRODUCTION: Patients with hepatitis B early antigen (HBeAg)-negative chronic hepatitis B (CHB) and low-level viremia are a heterogeneous group. Identifying those at risk of developing active CHB requiring antiviral therapy is important. In this study, we prospectively characterize incidence rates and predictors of transitioning from inactive to active CHB in a North American adult cohort. METHODS: Participants in the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Hepatitis B Research Network cohort who were HBeAg negative with baseline hepatitis B virus (HBV) DNA 10,000 IU/mL and alanine aminotransferase (ALT) > 2x upper limit of normal or initiated treatment during follow-up. RESULTS: Of 970 participants meeting inclusion criteria, 15% experienced phase transition or initiated treatment over a median follow-up of 4 years: 9% of those with baseline HBV DNA 1,000 IU/mL, and hyperlipidemia. Only higher ALT, higher HBV DNA, and lower platelets were associated with phase transition when patients starting treatment were censored. DISCUSSION: Most adults in this North American cohort with HBeAg-negative CHB and low-level viremia remained inactive and off treatment over 4 years. Transition from inactive to active CHB is infrequent and predominantly associated with viral rather than host factors.

Yamamura, K., D. Izumi, R. Kandimalla, F. Sonohara, Y. Baba, N. Yoshida, Y. Kodera, H. Baba and A. Goel (2019). “Intratumoral Fusobacterium Nucleatum Levels Predict Therapeutic Response to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.” Clin Cancer Res 25(20): 6170-6179.

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PURPOSE: Emerging evidence indicates that gut microbiome plays a crucial role in the cancer pathogenesis. Although Fusobacterium nucleatum (F. nucleatum) is associated with poor prognosis in multiple cancers, its clinical significance in predicting response to chemotherapy in patients with esophageal squamous cell carcinoma (ESCC) remains unclear. EXPERIMENTAL DESIGN: The F. nucleatum levels were quantified by qPCR assays in tumor tissues from 551 patients with ESCC from two independent cohorts, including 101 patients who received neoadjuvant chemotherapy prior to curative resection. Associations between F. nucleatum burden and recurrence-free survival (RFS), as well with chemotherapeutic response were evaluated using response evaluation criteria in solid tumors (RECISTs), primary tumor metabolic response defined by maximum standardized uptake value (SUVmax) changes in positron emission tomography-CT (PET/CT), and pathologic tumor regression grade (TRG). RESULTS: High burden of F. nucleatum in patients with ESCC associated with poor RFS in both training [log-rank P = 0.02; HR = 1.61; P = 0.03] and validation cohorts (log-rank P = 0.003; HR = 1.96; P = 0.004). Importantly, patients with ESCC with high levels of F. nucleatum displayed poor chemotherapeutic response for all three evaluation methods: RECIST (P = 0.04), SUVmax change in PET/CT (P = 0.0004), and TRG (P = 0.003). CONCLUSIONS: We conclude that high levels of intratumoral F. nucleatum have a prognostic significance for predicting poor RFS in patients with ESCC. More importantly, our data indicates that higher F. nucleatum burden correlates with poor response to neoadjuvant chemotherapy, suggesting the possibility that an antibiotic intervention against this bacterium may significantly improve therapeutic response in patients with ESCC.

Wall, A. (2019). “The Qualitative Value of Social Support for Liver Transplantation.” Am J Bioeth 19(11): 25-26.

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Last week, I had to respect the decision of my patient’s family to withdraw ventilatory support on a patient who was 3 months post liver transplant with a functional liver and a reversible disease process. Not only did we lose a completely salvageable patient, but we also lost the liver graft and we lost the opportunity to transplant a different patient who might have had a better outcome. This type of loss (salvageable patient with a functioning graft) is thankfully uncommon in liver transplantation, but when it happens, it leaves a mark on the entire team. We question what we could have done better to affect a different outcome and we relive all the decisions that led up to this ultimate decision to stop fighting for the life of the patient and the life of the graft. In this case, my team kept returning to the social-work evaluation and the decision that we made to push the limits of our social support criteria for post-transplant care. This patient’s family members all lived far away so his support consisted of a neighbor and paid nursing staff. After getting out of the hospital, the patient continually fired the nursing staff so there was always a different caregiver to communicate with. When the patient got readmitted for a complication, the neighbor came with him but had to leave to get back to his own work . . . One of the comments that Berry and colleagues make in their article is that if weakly supported patients are less able to manage the extreme demands of transplantation, which includes follow-up care, new medications, and the ongoing risk of organ rejection, then the use of social support criteria can be supported from a utilitarian standpoint. The extreme demands of liver transplantation are not the frequent clinic appointments or the medication regimens. Those are the standard requirements for routine postoperative care . . . The true extreme demands of liver transplantation happen to the minority of patients who have complicated postoperative courses, spend weeks to months in the intensive care unit, and have to build themselves back up from nothing through rehabilitation; learning to walk, talk, and eat again. These are the patients who need the strong emotional component of social support. They need their family and friends to be with them, encourage them, push them and support them through the intense recovery process. They also need adequate preoperative physical functioning and reserve, which is why frailty in liver transplantation has become such an important predictive tool. Frail patients who have severe complications do not have the physical reserve to rebound. Likewise, unsupported patients who have severe complications do not have the emotional support reserve to rebound . . . The evidence for social support is weak and is biased, as every program has some threshold for social support as a criterion for listing. While this commentary describes a single case, it is not a fluke. I would argue that every liver transplant surgeon can discuss a situation in which the lack of social support contributed in a real way to the loss of a patient after transplantation. I have been in practice for 1 year, and I can name five patients whose lack of social support significantly impacted their postoperative care, leading to complications, and in some cases death. On the other hand, I can name five patients who are alive and thriving today almost solely because of the support of their families and friends . . . While social support will always have subjectivity and will never be studied in a randomized control trial, it remains qualitatively important and should not be abandoned in the considerations for listing for liver transplantation. (Excerpts from text of this commentary, p. 25-26, which refers to a study in the same issue, Berry, K., N. Daniels, and K. Ladin. 2019. Should lack of social support prevent access to organ transplantation? The American Journal of Bioethics 19(11): 13–24.)

Tripathy, D., A. Brufsky, M. Cobleigh, M. Jahanzeb, P. A. Kaufman, G. Mason, J. O’Shaughnessy, H. S. Rugo, S. M. Swain, D. A. Yardley, L. Chu, H. Li, V. Antao and S. A. Hurvitz (2019). “De Novo Versus Recurrent HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from the SystHERs Registry.” Oncologist Oct 14. [Epub ahead of print].

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BACKGROUND: Limited data exist describing real-world treatment of de novo and recurrent HER2-positive metastatic breast cancer (MBC). MATERIALS AND METHODS: The Systemic Therapies for HER2-Positive Metastatic Breast Cancer Study (SystHERs) was a fully enrolled (2012-2016), observational, prospective registry of patients with HER2-positive MBC. Patients aged >/=18 years and less-than-or-equal-to 6 months from HER2-positive MBC diagnosis were treated and assessed per their physician’s standard practice. The primary endpoint was to characterize treatment patterns by de novo versus recurrent MBC status, compared descriptively. Secondary endpoints included patient characteristics, progression-free and overall survival (PFS and OS, by Kaplan-Meier method; hazard ratio [HR] and 95% confidence interval [CI] by Cox regression), and patient-reported outcomes. RESULTS: Among 977 eligible patients, 49.8% (n = 487) had de novo and 50.2% (n = 490) had recurrent disease. A higher proportion of de novo patients had hormone receptor-negative disease (34.9% vs. 24.9%), bone metastasis (57.1% vs. 45.9%), and/or liver metastasis (41.9% vs. 33.1%), and a lower proportion had central nervous system metastasis (4.3% vs. 13.5%). De novo patients received first-line regimens containing chemotherapy (89.7%), trastuzumab (95.7%), and pertuzumab (77.8%) more commonly than recurrent patients (80.0%, 85.9%, and 68.6%, respectively). De novo patients had longer median PFS (17.7 vs. 11.9 months; HR, 0.69; 95% CI, 0.59-0.80; p < .0001) and OS (not estimable vs. 44.5 months; HR, 0.55; 95% CI, 0.44-0.69; p < .0001). CONCLUSION: Patients with de novo versus recurrent HER2-positive MBC exhibit different disease characteristics and survival durations, suggesting these groups have distinct outcomes. These differences may affect future clinical trial design. Clinical trial identification number. NCT01615068 (clinicaltrials.gov). IMPLICATIONS FOR PRACTICE: SystHERs was an observational registry of patients with HER2-positive metastatic breast cancer (MBC), which is a large, modern, real-world data set for this population and, thereby, provides a unique opportunity to study patients with de novo and recurrent HER2-positive MBC. In SystHERs, patients with de novo disease had different baseline demographics and disease characteristics, had superior clinical outcomes, and more commonly received first-line chemotherapy and/or trastuzumab versus those with recurrent disease. Data from this and other studies suggest that de novo and recurrent MBC have distinct outcomes, which may have implications for disease management strategies and future clinical study design.