Clinical and Histological Response to Talimogene Laherparepvec Therapy in Advanced Melanoma: Impact on Overall Survival.

BACKGROUND: Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic herpesvirus therapy used for unresectable stage IIIB through IV metastatic melanoma. However, the correlation between clinical complete response (cCR) and pathologic complete response (pCR) in patients treated with T-VEC is understudied. STUDY DESIGN: We conducted a retrospective study from a prospectively maintained IRB-approved melanoma single-center database in patients treated with T-VEC from October 2015 to April 2022. Patients were categorized into 3 groups: cCR with pCR, cCR without pCR, and less than cCR. The primary endpoint was overall survival. We used descriptive statistics, chi-square tests, and Wilcoxon rank-sum tests to compare key covariates among exposure groups. We used survival analysis to compare survival curves and reported hazard ratio of death (95% CI) across exposure groups. RESULTS: We included 116 patients with a median overall survival (interquartile range) of 22.7 (14.8-39.3) months. The majority were men (69%) and White (97.4%), with a median age of 74.5 years. More than half of patients (n = 60, 51.6%) achieved cCR. Distribution among the groups was as follows: cCR with pCR (35.3%), cCR without pCR (16.3%), and less than cCR (48.4%). Median overall survival time (interquartile range) was 26.5 (18.6-36.0) months for cCR with pCR, 22.7 (14.4-35.5) months for cCR without pCR, and 17.8 (9.2-47.0) months for less than cCR (log-rank p value = 0.0033). CONCLUSIONS: Patients achieving cCR with pCR after T-VEC therapy have the most favorable overall survival outcomes, whereas those achieving cCR without pCR have inferior survival and those achieving less than cCR have the poorest overall survival outcomes. These findings emphasize the importance of histological confirmation and provide insights for optimizing T-VEC therapy in patients with advanced melanoma.

Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.

Nodal Recurrence is a Primary Driver of Early Relapse for Patients with Sentinel Lymph Node-Positive Melanoma in the Modern Therapeutic Era.

BACKGROUND: Management of patients with sentinel lymph node (SLN)-positive melanoma has changed dramatically over the last few years such that completion lymph node dissection (CLND) has become uncommon, and many patients receive adjuvant immunotherapy or targeted therapy. This study seeks to characterize patterns and predictors of early recurrence in this setting. PATIENTS AND METHODS: All patients with primary cutaneous melanoma undergoing sentinel lymph node biopsy (SLNB) between 3/2016 and 12/2019 were identified. The subset with a positive SLN who did not undergo CLND were examined for further analysis of outcomes and predictors of recurrence. RESULTS: Overall, 215 patients with SLN-positive melanoma who did not have CLND were identified. Adjuvant systemic therapy was administered to 102 (47%), with 93% of this subset receiving immunotherapy (n = 95). Median follow-up from SLNB was 20 months (IQR 12-28.5 months), and 57 patients (27%) recurred during this time. The SLN basin was the most common site of recurrence (n = 38, 67% of recurrence), with isolated nodal recurrence being the most common first site of recurrent disease (n = 22, 39% of recurrence). On multivariable analysis, lymphovascular invasion (LVI) of the primary tumor, two or more involved nodes, and > 1 mm nodal deposit were independently associated with higher rates of nodal relapse. CONCLUSIONS: Nodal recurrence is a primary driver of early disease relapse for patients with SLN-positive melanoma who do not undergo CLND in the era of effective adjuvant systemic therapy. LVI, ≥ 2 nodes, or > 1 mm nodal disease identifies patients at particularly high risk of nodal relapse.

Incidental finding of double appendix during laparotomy for intussusception: A case report.

INTRODUCTION: A double caecal appendix is an uncommon anatomical variation with significant surgical implications. A few cases of the double caecal appendix have been reported worldwide, mostly in adults. The diagnosis is, usually incidental, typically made intraoperatively. CASE REPORT: We present the case of a 6-month-old boy with an incidental diagnosis of the double appendix during laparotomy for intussusception. DISCUSSION: The double appendix can be classified using the Cave-Wallbridge classification, which identifies three types of the duplicated appendix: A, B, and C. The complication of appendiceal duplications includes acute appendicitis, colonic perforation, obstruction, bleeding, pain, failure to thrive, abdominal mass. In the case of abdominal pain with diagnostic uncertainty, with appropriate patient selection (without hemodynamic instability), diagnostic laparoscopy may be offered as an initial intraoperative evaluation, and if the procedure cannot be safely completed laparoscopically, it can be converted to a laparotomy. CONCLUSION: Although uncommon, knowledge of appendiceal duplication is of great significance in the surgical patient, as a missed diagnosis or delay in diagnosis in symptomatic patients may result in increased morbidity and possibly mortality secondary to sepsis, with its medico-legal ramifications in today's practice of medicine.

Uncovering the role of the gut microbiota in immune checkpoint blockade therapy: A mini-review.

In recent years, the microbiota has been implicated as a key factor associated with both response and toxicity from immune checkpoint blockade therapy. Numerous studies have been published that specifically highlight the importance of the microbiome as a distinct influencer of anti-PD-1/PD-L1 and anti-CTLA-4 activity in cancer patients, but a full understanding of mechanisms behind these interactions has yet to be achieved. With greater insight into how the microbiome can modulate immune checkpoint blockade comes the potential to target the microbiome to improve response rates and minimize toxicities. This mini-review looks at noteworthy studies that have explored the relationship between the microbiome and immune checkpoint blockade response and toxicity in both preclinical and clinical studies, with an emphasis on current hypotheses regarding mechanisms of action and potential microbiome-targeted therapeutic strategies under development.

Gut Microbiome Modulation Via Fecal Microbiota Transplant to Augment Immunotherapy in Patients with Melanoma or Other Cancers.

PURPOSE OF REVIEW: We review emerging evidence regarding the impact of gut microbes on antitumor immunity, and ongoing efforts to translate this in clinical trials. RECENT FINDINGS: Pre-clinical models and human cohort studies support a role for gut microbes in modulating overall immunity and immunotherapy response, and numerous trials are now underway exploring strategies to modulate gut microbes to enhance responses to cancer therapy. This includes the use of fecal microbiota transplant (FMT), which is being used to treat patients with Clostridium difficile infection among other non-cancer indications. The use of FMT is now being extended to modulate gut microbes in patients being treated with cancer immunotherapy, with the goal of enhancing responses and/or to ameliorate toxicity. However, significant complexities exist with such an approach and will be discussed herein. Data from ongoing studies of FMT in cancer will provide critical insights for optimization of this approach.

The human tumor microbiome is composed of tumor type-specific intracellular bacteria.

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.

Gut Microbiome Modulates Response to Cancer Immunotherapy.

With the advent of next-generation sequencing approaches, there has been a renaissance in the microbiome field. Microbial taxonomy and function can now be characterized relatively easily and rapidly-no longer mandating complex culturing approaches. With this renaissance, there is now a strong and growing appreciation for the role of the microbiome (referring to microbes and their genomes) in modulating many facets of physiology-including overall immunity. This is particularly true of the gut microbiome, and there is now an evolving body of the literature demonstrating a role for gut microbes in modulating responses to cancer treatment-particularly immunotherapy. Gut microbes can modulate immunity and anti-tumor responses via a number of different interactions, and these will be discussed herein. Additionally, data regarding the impact of gut microbes on cancer immunotherapy response will be discussed, as will strategies to manipulate the microbiome to enhance therapeutic responses. These efforts to date are not completely optimized; however, there is evidence of efficacy though much additional work is needed in this space. Nonetheless, it is clear that the microbiome plays a central role in health and disease, and strategies to manipulate it in cancer and overall precision health are being explored.

A novel protocol to maintain continuous access to thawed plasma at a rural trauma center.

BACKGROUND: Early administration of plasma improves mortality in massively transfused patients, but the thawing process causes delay. Small rural centers have been reluctant to maintain thawed plasma due to waste concerns. Our 254-bed rural Level II trauma center initiated a protocol allowing continuous access to thawed plasma, and we hypothesized its implementation would not increase waste or cost. METHODS: Two units of thawed plasma are continuously maintained in the trauma bay blood refrigerator. After 3 days, these units are replaced with freshly thawed plasma and returned to the blood bank for utilization prior to their 5-day expiration date. The blood bank monitors and rotates the plasma. Only trauma surgeons can use the plasma stored in the trauma bay. Wasted units and cost were measured over a 12-month period and compared with the previous 2 years. RESULTS: The blood bank thawed 1127 units of plasma during the study period assigning 274 to the trauma bay. When compared with previous years, we found a significant increase in waste (p < 0.001) and cost (p = 0.020) after implementing our protocol. It cost approximately US $125/month extra to maintain continuous access to thawed plasma during the study period. DISCUSSION: A protocol to maintain thawed plasma in the trauma bay at a rural Level II trauma center resulted in a miniscule increase in waste and cost when considering the scope of maintaining a trauma center. We think this cost is also minimal when compared with the value of having immediate access to thawed plasma. Constant availability of thawed plasma can be offered at smaller rural centers without a meaningful impact on cost. LEVEL OF EVIDENCE: Economic and Value-based Evaluations, Level III.

A Giant Adrenal Mass in a Super Obese Patient.

Giant pheochromocytomas (Pheo) are rare entities requiring clinical suspicion coupled with strategic diagnostic evaluation to confirm the diagnosis. The majority of cases are discovered incidentally. The diagnosis consists of biochemical evaluation and imaging study to localize the mass. Pathological examination confirms the diagnosis. The female patient in this case report presented with chest pain, palpitation of three weeks duration and was found on evaluation to have an abdominal mass concerning for pheochromocytoma. She was treated with surgical resection. The pheo measured 20.5 x 18 x 10 cm and weighed 2,582 grams. Pathological examination confirmed the diagnosis of pheochromocytoma.

Large Unilateral Adrenal Mass with Surrounding Brown Fat: A Case Report.

Pheochromocytomas are rare tumors derived from chromaffin cells located in the adrenal and extra adrenal tissues. Pheochromocytomas are diagnosed biochemically and localized using different imaging modalities. The definitive management is surgical resection. Brown adipose tissues are normally present during fetal development, with regression over time. Brown adipose tissues are thermogenic and usually located in the neck, mediastinum, and retroperitoneum. Here, we report a case of a unilateral pheochromocytoma surrounded by brown fat. The abnormal stimulation of brown fat noted on positive emission tomography scan (PET) resolved after the pheochromocytoma was resected.

Successful use of resuscitative endovascular balloon occlusion of the aorta in the treatment of ruptured 8.5-cm splenic artery aneurysm.

Spontaneous rupture of splenic artery aneurysm is a rare cause of acute abdomen with hemorrhagic shock that is a life-threatening surgical emergency. We report a case of a spontaneous rupture of an 8.5-cm splenic artery aneurysm managed using resuscitative endovascular balloon occlusion of the aorta (ER-REBOA Catheter; Prytime Medical Inc, Boerne, Tex) for proximal control of the aorta before laparotomy. This is a minimally invasive technique that can be used as an adjunct to massive transfusion resuscitation and laparotomy for life-threatening intraperitoneal hemorrhage.

Anal Melanoma in an Elderly Woman Masquerading as Hemorrhoid.

Anal melanoma is a rare and aggressive neoplasm of the anal canal seen in the elderly population in the six or seventh decade of their lives. Presentation is usually nonspecific and diagnosis is often delayed or missed initially. The management is surgical and prognosis is poor. Here we present a case of anal melanoma in an elderly patient masquerading as hemorrhoid.