A phase 1-2 trial of DA-EPOCH-R plus ixazomib for MYC-aberrant lymphoid malignancies: the DACIPHOR regimen.

ABSTRACT: MYC-aberrant non-Hodgkin lymphoma (NHL) is associated with poor outcomes with conventional chemotherapy. Ixazomib is an orally bioavailable proteasome inhibitor that targets drivers of MYC expression and has demonstrated preclinical activity in aggressive MYC-aberrant NHL. We conducted a phase 1/2 study evaluating the safety and efficacy of DA-EPOCH-R with adjunctive ixazomib in aggressive MYC-aberrant NHL. For induction, patients received 6 cycles of DA-EPOCH-R with ixazomib administered twice per 21-day cycle; responders continued weekly ixazomib maintenance for up to 1 year. Primary objectives were to determine the maximum tolerated dose in phase 1 and efficacy of DA-EPOCH-R with ixazomib as measured by 12-month progression-free survival (PFS) rate in phase 2. Thirty-six patients were evaluable for response. Median age was 63 years (range, 31-77) and 44% had double-hit lymphoma (DHL)/triple-hit lymphoma (THL). In phase 1, 3 mg of ixazomib was established as recommended phase 2 dose. Twenty-nine (76.3%) patients completed 6 cycles of DA-EPOCH-R and 25 (65.8%) underwent dose escalations. The ORR after induction was 97% (95% confidence interval, 81-100) with a CR rate of 69%. At median follow-up of 18.8 months, the 12-month PFS and overall survival (OS) rates were 78% and 86%, respectively. For DHL/THL vs dual expressor lymphomas (DEL), 12-month PFS rates were 53% vs 95% and 12-month OS rates were 65% vs 100%, respectively. Grade ≥3 toxicities were predominantly hematologic. Twenty-seven (75%) of patients experienced neuropathy, nearly all low-grade. DA-EPOCH-R induction with adjunctive ixazomib is feasible and appears effective in patients with DEL. This trial was registered at www.clinicaltrials.gov as #NCT02481310.

Ibrutinib maintenance after frontline treatment in patients with mantle cell lymphoma.

Maintenance rituximab in mantle cell lymphoma (MCL) has improved survival and supports exploration of maintenance with novel agents. We evaluated the safety and efficacy of ibrutinib maintenance (I-M) after induction in patients with treatment-naive MCL. Patients with MCL with complete response (CR) or partial response to frontline chemoimmunotherapy ± autologous stem cell transplantation (auto-SCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3-year progression-free survival (PFS) rate from initiation of I-M. Minimal residual disease (MRD) assessments by next-generation sequencing (NGS) on peripheral blood were measured before I-M initiation and at 1, 6, and 18 to 24 months after initiation. Among 36 patients, the median age was 60 years (range, 46-90). For frontline treatment, 18 patients (50%) had consolidation with auto-SCT in CR1 before I-M. At median follow-up of 55.7 months, 17 patients (47%) completed full course I-M (median, 37.5 cycles; range, 2-52). The 3-year PFS and overall survival (OS) rates were 94% and 97%, respectively. With prior auto-SCT, 3-year PFS and OS rates were both 100%. The most common treatment-related adverse event with I-M was infection (n = 31; 86%), typically low grade; the most common grade 3/4 toxicities were hematologic. In 22 patients with MRD assessments, all were MRD negative after induction. Six became MRD positive on I-M, with 2 reverting to MRD-negative status with continued I-M, and all maintain radiographic CR with the exception of 1 with disease progression. I-M is feasible in MCL after frontline chemoimmunotherapy with manageable toxicities although significant. Changes in NGS-MRD were noted in limited patients during maintenance with few progression and survival events. This trial was registered at www.clinicaltrials.gov as #NCT02242097.

Prevalence of signs of lower urinary tract disease and positive urine culture in dogs with diabetes mellitus: A retrospective study.

BACKGROUND: No recent studies have evaluated the association between clinical signs of lower urinary tract disease (LUTD) and positive urine culture in dogs with diabetes mellitus. OBJECTIVE: Determine the prevalence of subclinical bacteriuria (ie, positive urine culture without signs of LUTD) in dogs with diabetes mellitus. ANIMALS: One hundred seven dogs with diabetes mellitus were evaluated at a university veterinary hospital. METHODS: Retrospective study evaluating diabetic dogs with a single sample paired urinalysis and urine culture. Relationship between the presence of signs of LUTD, pyuria, and bacteriuria and urine culture results were compared using Fisher exact testing. RESULTS: Fifteen dogs (14%) had a positive urine culture via cystocentesis or free catch, of which 8 (53%) had pyuria, and 4 (27%) had signs of LUTD. Of the 88 dogs (82%) without signs of LUTD, 11 (13%) had a positive culture. A significant association was found between a positive urine culture and pyuria (OR infinity; 95% CI 20.34-infinity, P < .00001) and bacteriuria (OR infinity; 95% CI 164.4-infinity, P < .00001). No association was found between urine culture results and signs of LUTD (OR 1.87; 95% CI 0.59-6.85, P = .46). CONCLUSION AND CLINICAL IMPORTANCE: Subclinical bacteriuria occurred in this cohort of dogs, and our findings reinforce the recommendation that urine cultures should not be routinely performed in diabetic dogs particularly if pyuria and bacteriuria are absent.

Efficacy and safety of tivozanib in recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer, an NCCN phase II trial.

OBJECTIVE: Tivozanib is a potent selective pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor with a long half-life. This study assessed its activity in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer (OC). METHODS: This open-label phase II study used a Simon's two-stage design. Eligible patients had recurrent, platinum-resistant OC and measurable or detectable disease. There was no limit on the number of prior regimens. Treatment consisted of tivozanib 1.5 mg orally once daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity assessment. RESULTS: Thirty-one patients were enrolled, and 30 were treated. The median age was 59.5 years, and median number of prior regimens was 4 (range 1-9). Twenty-four patients were evaluable for response, and four (16.7%) achieved a partial response (PR; ORR = 16.7%). An additional fourteen (58.3%) patients had stable disease (SD). The clinical benefit rate (PR + SD) was 75.0%, and the median duration of objective response was 5.7 months. For all patients on trial, the median PFS was 4.1 months (95% confidence interval (CI): 1.7-5.8) and OS 8.6 months (95% CI: 5.4-12.5). There were no treatment-related deaths. Serious adverse events occurred in 13.3% of patients and included small intestinal perforation or obstruction and stroke. Grade 3-4 adverse events occurred in 60% of patients, including hypertension (26.7%) and fatigue (10%). CONCLUSIONS: Tivozanib is effective in patients with recurrent OC, with moderate toxicity and no treatment-related deaths, supporting its further development.

Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer.

BACKGROUND: Response rates to single agent immune checkpoint blockade in unselected pretreated HER2-negative metastatic breast cancer (MBC) are low. However, they may be augmented when combined with chemotherapy. METHODS: We conducted a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) MBC who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. The primary end point was median progression-free survival (mPFS) compared with historic controls and secondary end points were overall response rate (ORR), safety and tolerability. The study had 80% power to detect a 2-month improvement in mPFS with the addition of pembrolizumab over historic controls treated with capecitabine alone. RESULTS: Thirty patients, 16 TN and 14 HR+ MBC, were enrolled from 2017 to 2018. Patients had a median age of 51 years and received a median of 1 (range 0-6) prior lines of therapy for MBC. Of 29 evaluable patients, the mPFS was 4.0 (95% CI 2.0 to 6.4) months and was not significantly longer than historic controls of 3 months. The median overall survival was 15.4 (95% CI 8.2 to 20.3) months. The ORR was 14% (n=4), stable disease (SD) was 41% (n=12) and clinical benefit rate (CBR=partial response+SD>6 months) was 28% (n=8). The ORR and CBR were not significantly different between disease subtypes (ORR 13% and 14%, CBR 25% and 29% for TN and HR+, respectively). The 1-year PFS rate was 20.7% and three patients have ongoing responses. The most common adverse events were low grade and consistent with those seen in MBC patients receiving capecitabine, including hand-foot syndrome, gastrointestinal symptoms, fatigue and cytopenias. Toxicities at least possibly from pembrolizumab included grade 3 or 4 liver test abnormalities (7%), rash (7%) and diarrhea (3%), as well as grade 5 hepatic failure in a patient with liver metastases. CONCLUSIONS: Compared with historical controls, pembrolizumab with capecitabine did not improve PFS in this biomarker unselected, pretreated cohort. However, some patients had prolonged disease control. TRIAL REGISTRATION NUMBER: NCT03044730.

Multidrug- and colistin-resistant Salmonella enterica 4,[5],12:i:- sequence type 34 carrying the mcr-3.1 gene on the IncHI2 plasmid recovered from a human.

A colistin-resistant Salmonella enterica 4, [5],12:i:- sequence type (ST) 34 harbouring mcr-3.1 was recovered from a patient who travelled to China 2 weeks prior to diarrhoea onset. Genomic analysis revealed the presence of the mcr-3.1 gene located in the globally disseminated IncHI2 plasmid, highlighting the intercontinental dissemination of the colistin-resistant S. enterica 4, [5],12:i:- ST34 pandemic clone.

Epidemiology of Anal Canal Cancer.

Anal cancer is a rare malignancy, although its incidence has been increasingly in recent decades. This article discusses risk factors for anal cancer and how these risk factors affect the changing demographics of this disease.

Ethics education in family medicine training in the United States: a national survey.

BACKGROUND AND OBJECTIVES: Although professional organizations endorse ethics education in family medicine training, there is little published evidence that ethics teaching occurs. This survey collated data on the aims, content, pedagogical methods, assessment, and barriers relating to formal ethics education in family medicine residency programs in the United States. METHODS: A questionnaire surveyed all 445 family medicine residency programs in the United States. RESULTS: Forty percent of programs responded (178/445). Of these, 95% formally teach at least one ethics topic, 68.2% teach six or more topics, and 7.1% teach all 13 core topics specified in the questionnaire. Programs show variation, providing between zero to 100 hours' ethics education over the 3 years of residency training. Of the responding programs, 3.5% specify well-defined aims for ethics teaching, 25.9% designate overall responsibility for the ethics curriculum to one individual, and 33.5% formally assess ethics competencies. The most frequent barriers to ethics education are finding time in residents' schedules (59.4%) and educator expertise (21.8%). CONCLUSIONS: Considerable variation in ethics education is apparent in both curricular content and delivery among family medicine residency programs in the United States. Additional findings included a lack of specification of explicit curricular aims for ethics teaching allied to ACGME or AAFP competencies, a tendency not to designate one faculty member with lead responsibility for ethics teaching in the residency program, and a lack of formal assessment of ethics competencies. This has occurred in the context of an absence of robust assessment of ethics competencies at board certification level.

Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.

Fecal microbiota transplantation (FMT) has emerged as a highly effective therapy for refractory, recurrent Clostridium difficile infection (CDI), which develops following antibiotic treatments. Intestinal microbiota play a critical role in the metabolism of bile acids in the colon, which in turn have major effects on the lifecycle of C. difficile bacteria. We hypothesized that fecal bile acid composition is altered in patients with recurrent CDI and that FMT results in its normalization. General metabolomics and targeted bile acid analyses were performed on fecal extracts from patients with recurrent CDI treated with FMT and their donors. In addition, 16S rRNA gene sequencing was used to determine the bacterial composition of pre- and post-FMT fecal samples. Taxonomic bacterial composition of fecal samples from FMT recipients showed rapid change and became similar to the donor after the procedure. Pre-FMT fecal samples contained high concentrations of primary bile acids and bile salts, while secondary bile acids were nearly undetectable. In contrast, post-FMT fecal samples contained mostly secondary bile acids, as did non-CDI donor samples. Therefore, our analysis showed that FMT resulted in normalization of fecal bacterial community structure and metabolic composition. Importantly, metabolism of bile salts and primary bile acids to secondary bile acids is disrupted in patients with recurrent CDI, and FMT corrects this abnormality. Since individual bile salts and bile acids have pro-germinant and inhibitory activities, the changes suggest that correction of bile acid metabolism is likely a major mechanism by which FMT results in a cure and prevents recurrence of CDI.

Status of targeted therapies in the adjuvant treatment of colon cancer.

Colon cancer is the 4(th) most common malignancy with 80% of patients diagnosed with early stage disease that is potentially curable with surgery and the addition of adjuvant chemotherapy in select Stage II and all Stage III patients. Adjuvant chemotherapy with 5-flurouracil based regimens has been shown to have overall survival benefit in Stage III disease with some benefit shown in certain sub-populations in Stage II disease. In recent years, targeted therapies directed against vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EFGR) have shown improved survival in metastatic colon cancer. However, trials of these agents in the adjuvant setting showed no benefit. Reasons for failure of these agents in trials thus far include differences in the molecular biology of macrometastatic versus micrometastatic disease and the lack of biologic predictive markers to target the appropriate patient populations for these agents.

Next generation of mammalian target of rapamycin inhibitors for the treatment of cancer.

INTRODUCTION: Because of the central role of the mammalian target of rapamycin (mTOR) pathway in the control and distribution of signals essential for mRNA translation of mitogenic genes and generation of oncogenic proteins, effective targeting of mTOR remains a major goal in medical oncology. AREAS COVERED: This article summarizes preclinical and clinical studies relating to the next generation of mTOR inhibitors. While rapalogs have shown activity in the treatment of breast, renal and neuroendocrine tumors, these agents do not block mTORC2, one of the two major protein complexes in which mTOR participates. In addition, there is emerging evidence that these agents only partially block mTORC1, underscoring the need for more effective mTOR inhibitors. In recent years, catalytic mTOR inhibitors have been developed, which block both mTORC1 and mTORC2. Such inhibitors show generally better activity in preclinical models than rapalogs and some of them have been or are in clinical trials in humans. EXPERT OPINION: It is anticipated that with the continuous expansion of work in this research field, the therapeutic potential of targeting the mTOR pathway for the treatment of several malignancies will reach a maximum point in the next few years and may ultimately change the way we treat several malignant tumors.

Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC.

The discovery of epidermal growth-factor receptor (EGFR)-activating mutations and the introduction of oral EGFR tyrosine kinase inhibitors (EGFR-TKIs) have expanded the treatment options for patients with non-small cell lung cancer. The first two reversible EGFR-TKIs, erlotinib and gefitinib, are approved for use in the first-line setting in patients with known EGFR-activating mutations and in the second- and third-line settings for all NSCLC patients. These first-generation EGFR-TKIs improve progression-free survival when compared to chemotherapy in patients with EGFR-activating mutations in the first-line setting. However, nearly all patients develop resistance to EGFR-directed agents. There is a need for further therapy options for patients with disease progression after treatment with reversible EGFR-TKIs. Afatinib is an irreversible ErbB family blocker that inhibits EGFR, HER2, and HER4. In vitro and in vivo, afatinib have shown increased inhibition of the common EGFR-activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib. Clinically, afatinib has been evaluated in the LUX-Lung series of trials, with improvement in progression-free survival reported in patients with EGFR-activating mutations in both first- and second-/third-line settings when compared to chemotherapy. Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non-small cell lung cancer and EGFR-activating mutations.

Pathological complete response after neoadjuvant therapy for rectal cancer and the role of adjuvant therapy.

Both the addition of neoadjuvant chemoradiation therapy and improvements in surgical techniques have improved local control and overall survival for locally advanced rectal cancer patients over the past few decades. The addition of adjuvant chemotherapy has likely improved outcomes as well, though the contribution has been more difficult to quantify. At present, the majority of resected locally advanced rectal cancer patients receive adjuvant chemotherapy, though there is great variability in this practice based on both patient and institution characteristics. Recently, questions have been raised regarding which sub-groups of patients benefit most from adjuvant chemotherapy. As pathologic complete response (pCR) is increasingly found to be a reasonable surrogate for long-term favorable outcomes, some have questioned the need for adjuvant therapy in this select group of patients. Multiple retrospective analyses have shown minimal to no benefit for adjuvant chemotherapy in this group. Indeed, the patients most consistently shown to benefit from adjuvant therapy both in terms of disease free survival (DFS) and overall survival (OS) are those who achieve an intermediate pathologic response to neoadjuvant treatment. Tumors that have high expression of thymidylate synthetase have also shown to benefit from adjuvant therapy. More study is needed into clinical and molecular features that predict patient benefit from adjuvant therapy.