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Background Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. Objective To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. Design, setting, and participants This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. Intervention Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily. Outcome measurements and statistical analysis The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. Results and limitations The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12–45). Median PFS was 9.2 mo (95% CI 5.5–not estimable), and median OS was 15.6 mo (95% CI 9.2–not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. Conclusions Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. Patient summary We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. Clinical registration This trial is registered at ClinicalTrials.Gov as NCT02915783.

Pembrolizumab, a programmed death 1 ligand (PD-1) checkpoint inhibitor, has elicited responses in mismatch repair (MMR)–deficient advanced solid tumors, leading to its agnostic approval by the US Food and Drug Administration in 2017 when no other therapeutic options are available. However, there are still insufficient data on the response to checkpoint inhibitors in advanced endometrial cancer related to Lynch syndrome (LS) and, specifically, in uterine serous carcinoma, which is uncommon in LS. Here we report a case of metastatic uterine serous carcinoma due to a germline MSH6 mutation (Lynch syndrome) that was discovered because of a patient's tumor MMR deficiency. The patient was started on first-line pembrolizumab in 2018 and sustained a partial response. She remains asymptomatic and progression free for more than 2 years. Tumor sequencing showed a high mutational burden and an upstream somatic mutation in the same gene, p.F1088fs. Immunohistochemical staining was negative for PD-L1 expression. We discuss clinical characteristics of the patient, molecular features of her tumor, and the mechanism of her tumor response. We also discuss the duration of immunotherapy in her case. Our case demonstrated a partial response and a long-term remission from the frontline single-agent pembrolizumab in a woman with metastatic uterine serous carcinoma and Lynch syndrome due to a germline MSH6 gene mutation. Our experience suggests a potential significant clinical benefit of checkpoint inhibitors used as single agents early on in the treatment of MMR-deficient/high microsatellite instability/hypermutated uterine cancers in women with Lynch syndrome. Key Points Even though checkpoint inhibitors are effective in mismatch repair-deficient endometrial cancer, it is unknown whether the response to them differs between women with endometrial cancer due to germline mutations in a mismatch repair gene (Lynch syndrome) and women with sporadic endometrial cancer. In our case, a patient with Lynch syndrome and recurrent mismatch repair-deficient serous endometrial cancer achieved a durable remission on the first-line therapy with the checkpoint inhibitor pembrolizumab and remains progression free after more than 2 years. Based on our observation and the data, suggesting the stronger immune activation in women with Lynch syndrome–associated endometrial cancer, we propose to use checkpoint inhibitor monotherapy early in the course of their treatment and stratify patients for the presence of Lynch syndrome in clinical trials.

BACKGROUND. Intravenous immune checkpoint inhibition is an effective anti-cancer strategy for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) but may be associated with greater systemic toxicity compared to localized therapies. OBJECTIVE: We assessed the safety and antitumor activity of intravesical pembrolizumab combined with BCG. DESIGN, SETTING AND PARTICIPANTS: A 3+3 phase I trial of pembrolizumab + BCG was conducted in patients with BCG-unresponsive NMIBC (NCT02808143). INTERVENTION: Pembrolizumab was given intravesically (1–5 mg/kg for 2 hours) beginning 2 weeks prior to BCG induction until recurrence. Urine profiling during treatment and spatial transcriptomic profiling of pre- and post- treatment tumors was conducted to identify biomarkers that correlated with response. OUTCOMES AND STATISTICAL ANALYSIS: Safety, tolerability with Kaplan-Meier survival analysis. RESULTS AND LIMITATIONS: Nine patients completed therapy. Median follow-up was 35 months for 5 patients still alive at the end of the trial. The trial was closed due to the Covid19 pandemic. Grade 1–2 urinary symptoms were common. The maximum tolerated dose was not reached, however one dose-limiting toxicity was reported (grade 2 diarrhea) in the only patient who reached 52-weeks without recurrence. One death occurred from myasthenia gravis that was deemed potentially related to treatment. The 6-month and 1-year recurrence-free rates were 67% (95% CI: 42–100%) and 22% (95% CI: 6.5–75%) respectively. Pembrolizumab was detected in the urine and not in blood. CD4(+) T cells were significantly increased in the urine post-treatment, and transcriptomic analysis identified decreased expression of T-cell exhaustion markers in late recurrences. CONCLUSION: We demonstrate that intravesical pembrolizumab is safe, feasible and capable of eliciting strong immune responses in a clinical setting and should be investigated further PATIENT SUMMARY: Direct application of pembrolizumab to the bladder is a promising alternative for BCG-unresponsive NMIBC and should be investigated further.

INTRODUCTION: The number of fellowship options for emergency medicine (EM) physicians continues to expand. While guides exist to help residents explore individual fellowship pathways, we aimed to create a comprehensive guide for all residents considering fellowship. METHODS: At the direction of the Society for Academic Emergency Medicine (SAEM) Board, 9 members of the Fellowship Guide Workgroup, including members of the Fellowship Approval Committee, and 2 members of SAEM Residents and Medical Students (RAMS) group collaboratively developed the guide using available evidence and expert opinion when high‐quality evidence was unavailable. The guide was reviewed and approved by all members. RESULTS: The guide offers advice to EM residents on how to conceptualize key aspects of their training with respect to preparation for fellowship, including scholarship, teaching, leadership, and electives. Additionally, it offers perspective on selecting a fellowship that matches the resident's interests and goals and successfully applying. CONCLUSION: This fellowship guide for EM residents considering fellowship summarizes the best currently available advice for residents considering fellowship training after residency.

Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.

Little is known about what determines strategy implementation around quality improvement (QI) in small- and medium-sized practices. Key questions are whether QI strategies are associated with practice readiness and practice characteristics. Grounded in organizational readiness theory, we examined how readiness and practice characteristics affect QI strategy implementation. The study was a component of a larger practice-level intervention, Heart of Virginia Healthcare, which sought to transform primary care while improving cardiovascular care. This observational study analyzed practice correlates of QI strategy implementation in primary care at 3 and 12 months. Data were derived from surveys completed by clinicians and staff and from assessments by practice coaches. A total of 175 small- and medium-sized primary care practices were included. Outcome was QI strategy implementation in three domains: (1) aspirin, blood pressure, cholesterol, and smoking cessation (ABCS); (2) care coordination; and (3) organizational-level improvement. Coaches assessed implementation at 3 and 12 months. Readiness was measured by baseline member surveys, 1831 responses from 175 practices, a response rate of 73%. Practice survey assessed practice characteristics, a response rate of 93%. We used multivariate regression. QI strategy implementation increased from 3 to 12 months: the mean for ABCS from 1.20 to 1.59, care coordination from 2.15 to 2.75, organizational improvement from 1.37 to 1.78 (95% CI). There was no statistically significant association between readiness and QI strategy implementation across domains. Independent practice implementation was statistically significantly higher than hospital-owned practices at 3 months for ABCS (95% CI, P = 0.01) and care coordination (95% CI, P = 0.03), and at 12 months for care coordination (95% CI, P = 0.04). QI strategy implementation varies by practice ownership. Independent practices focus on patient care–related activities. FQHCs may need additional time to adopt and implement QI activities. Practice readiness may require more structural and organizational changes before starting a QI effort.

Through a multitude of studies, the gut microbiota has been recognized as a significant influencer of both homeostasis and pathophysiology. Certain microbial taxa can even affect treatments such as cancer immunotherapies, including the immune checkpoint blockade. These taxa can impact such processes both individually as well as collectively through mechanisms from quorum sensing to metabolite production. Due to this overarching presence of the gut microbiota in many physiological processes distal to the GI tract, we hypothesized that mice bearing tumors at extraintestinal sites would display a distinct intestinal microbial signature from non-tumor-bearing mice, and that such a signature would involve taxa that collectively shift with tumor presence. Microbial OTUs were determined from 16S rRNA genes isolated from the fecal samples of C57BL/6 mice challenged with either B16-F10 melanoma cells or PBS control and analyzed using QIIME. Relative proportions of bacteria were determined for each mouse and, using machine-learning approaches, significantly altered taxa and co-occurrence patterns between tumor- and non-tumor-bearing mice were found. Mice with a tumor had elevated proportions of Ruminococcaceae, Peptococcaceae.g_rc4.4, and Christensenellaceae, as well as significant information gains and ReliefF weights for Bacteroidales.f__S24.7, Ruminococcaceae, Clostridiales, and Erysipelotrichaceae. Bacteroidales.f__S24.7, Ruminococcaceae, and Clostridiales were also implicated through shifting co-occurrences and PCA values. Using these seven taxa as a melanoma signature, a neural network reached an 80% tumor detection accuracy in a 10-fold stratified random sampling validation. These results indicated gut microbial proportions as a biosensor for tumor detection, and that shifting co-occurrences could be used to reveal relevant taxa.

Infection is a major co-morbidity that contributes to impaired healing in diabetic wounds. Although impairments in diabetic neutrophils have been blamed for this co-morbidity, what causes these impairments and whether they can be overcome, remain largely unclear. Diabetic neutrophils, isolated from diabetic individuals, exhibit chemotaxis impairment but this peculiar functional impairment has been largely ignored because it appears to contradict the clinical findings which blame excessive neutrophil influx as a major impediment to healing in chronic diabetic ulcers. Here, we report that exposure to glucose in diabetic range results in impaired chemotaxis signaling through the formyl peptide receptor (FPR) in neutrophils, culminating in reduced chemotaxis and delayed neutrophil trafficking in the wound of Leprdb (db/db) type two diabetic mice, rendering diabetic wound vulnerable to infection. We further show that at least some auxiliary receptors remain functional under diabetic conditions and their engagement by the pro-inflammatory cytokine CCL3, overrides the requirement for FPR signaling and substantially improves infection control by jumpstarting the neutrophil trafficking toward infection, and stimulates healing in diabetic wound. We posit that CCL3 may have therapeutic potential for the treatment of diabetic foot ulcers if it is applied topically after the surgical debridement process which is intended to reset chronic ulcers into acute fresh wounds.

Extramammary Paget disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms.To develop recommendations for the care of adults with EMPD.A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD.The key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. (5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years.Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

PURPOSE: Despite the growing popularity of stepped-wedge cluster randomized trials (SW-CRTs) for practice-based research, the design’s advantages and challenges are not well documented. The objective of this study was to identify the advantages and challenges of the SW-CRT design for large-scale intervention implementations in primary care settings. METHODS: The EvidenceNOW: Advancing Heart Health initiative, funded by the Agency for Healthcare Research and Quality, included a large collection of SW-CRTs. We conducted qualitative interviews with 17 key informants from EvidenceNOW grantees to identify the advantages and challenges of using SW-CRT design. RESULTS: All interviewees reported that SW-CRT can be an effective study design for large-scale intervention implementations. Advantages included (1) incentivized recruitment, (2) staggered resource allocation, and (3) statistical power. Challenges included (1) time-sensitive recruitment, (2) retention, (3) randomization requirements and practice preferences, (4) achieving treatment schedule fidelity, (5) intensive data collection, (6) the Hawthorne effect, and (7) temporal trends. CONCLUSIONS: The challenges experienced by EvidenceNOW grantees suggest that certain favorable real-world conditions constitute a context that increases the odds of a successful SW-CRT. An existing infrastructure can support the recruitment of many practices. Strong retention plans are needed to continue to engage sites waiting to start the intervention. Finally, study outcomes should be ones already captured in routine practice; otherwise, funders and investigators should assess the feasibility and cost of data collection. VISUAL ABSTRACT

Additional file 1. Supplementary Figures S1–S35.

Pseudomonas aeruginosa is an important Gram-negative opportunistic pathogen which causes many severe acute and chronic infections with high morbidity, and mortality rates as high as 40%. What makes P. aeruginosa a particularly challenging pathogen is its high intrinsic and acquired resistance to many of the available antibiotics. In this review, we review the important acute and chronic infections caused by this pathogen. We next discuss various animal models which have been developed to evaluate P. aeruginosa pathogenesis and assess therapeutics against this pathogen. Next, we review current treatments (antibiotics and vaccines) and provide an overview of their efficacies and their limitations. Finally, we highlight exciting literature on novel antibiotic-free strategies to control P. aeruginosa infections.

Significance Immunotherapy has revolutionized cancer treatment, yielding unprecedented long-term responses and survival. However, a significant proportion of patients remain refractory, which correlates with the absence of immune-infiltrated (“hot”) tumors. Here, we observed that FDA-approved unadjuvanted seasonal influenza vaccines administered via intratumoral injection not only provide protection against active influenza virus lung infection, but also reduce tumor growth by increasing antitumor CD8+ T cells and decreasing regulatory B cells within the tumor. Ultimately, intratumoral unadjuvanted seasonal influenza vaccine converts immunologically inactive “cold” tumors to “hot,” generates systemic responses, and sensitizes resistant tumors to checkpoint blockade. Repurposing the “flu shot” may increase response rates to immunotherapy, and based on its current FDA approval and safety profile, may be quickly translated for clinical care., Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated “hot” tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts “cold” tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.