Prophylactic Cholecystectomy is Safe in Patients Undergoing Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: While cholecystectomy is one of the most common operations performed in the United States, there is a continued debate regarding its prophylactic role in elective surgery. Particularly among patients with peritoneal carcinomatosis who undergo cytoreduction surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), further abdominal operations may pose increasing morbidity due to intraabdominal adhesions and potential recurrence. This bi-institutional retrospective study aims to assess postoperative morbidity associated with prophylactic cholecystectomy at the time of CRS-HIPEC. METHODS: We performed a bi-institutional retrospective analysis of 578 patients who underwent CRS-HIPEC from 2011 to 2021. Postoperative outcomes among patients who underwent prophylactic cholecystectomy at the time of CRS-HIPEC were compared to patients who did not, particularly rate of bile leak, hospital length of stay, rate of Clavien-Dindo classification morbidity grade III or greater, and number of hospital re-admissions within 30 days. RESULTS: Of the 535 patients available for analysis, 206 patients (38.3%) underwent a prophylactic cholecystectomy. Of the 3 bile leaks (1.5%) that occurred among patients who underwent prophylactic cholecystectomy, all 3 occurred in patients who underwent a concomitant liver resection. There were no significant differences in hospital length of stay, postoperative morbidity, and number of hospital re-admissions among patients who underwent prophylactic cholecystectomy compared to those who did not. CONCLUSION: Prophylactic cholecystectomy in patients undergoing CRS-HIPEC is not associated with increased morbidity or increased bile leak risk compared to historical data. While the benefits of prophylactic cholecystectomy are not yet elucidated, it may be considered to avoid potential future morbid operations for biliary disease.

Actual 5-Year Survival After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Patients with Peritoneal Carcinomatosis of Colorectal Origin.

BACKGROUND: Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) improves survival compared with chemotherapy alone in patients with peritoneal carcinomatosis (PC) of colorectal (CRC) origin, however, long-term survival data are lacking. We report the actual survival of patients who underwent CRS/HIPEC for PC of CRC origin with a minimum potential 5-year follow-up period to identify factors that preclude long-term survival. METHODS: We performed a retrospective analysis of a prospective database, analyzing patients undergoing CRS/HIPEC for PC of CRC origin from 2007 to 2017. Patients with aborted CRS/HIPEC, postoperative follow-up <90 days, or non-CRC histology were excluded. Overall survival (OS) and disease-free survival (DFS) were measured from date of surgery. Surviving patients with <60 months of follow-up were censored at date of last follow-up. RESULTS: A total of 103 patients met inclusion criteria and were analyzed. CC score 0-1 was achieved in 89.3% of patients, and median peritoneal cancer index (PCI) was 9 (interquartile range [IQR] 5-17). Ninety-day mortality was 2.9%. The median follow-up of survivors was 88 months. Five-year OS was 36%, and median OS was 42.5 months. Factors independently associated with poor survival included high PCI (PCI = 14-20, hazard ratio [HR] 3.1, p = 0.007, and PCI > 20, HR 5.3, p ≤ 0.001) and incomplete CRS (CC score-2, HR 2.96, p = 0.02). Patients with low PCI (0-6) had 5-year OS 60.7%. CONCLUSIONS: Actual 5-year OS was 36% and median OS was 42.5 months. Our study demonstrates that patients with PC from CRC origin with low PCI who undergo complete surgical resection can achieve favorable long-term survival.

Preoperative Frailty and Malnutrition in Surgical Oncology Patients Predicts Higher Postoperative Adverse Events and Worse Survival: Results of a Blinded, Prospective Trial.

BACKGROUND: Frailty, a multidimensional state leading to reduced physiologic reserve, is associated with worse postoperative outcomes. Despite the availability of various frailty tools, surgeons often make subjective assessments of patients' ability to tolerate surgery. The Risk Analysis Index (RAI) is a validated preoperative frailty assessment tool that has not been studied in cancer patients with plans for curative-intent surgery. METHODS: In this prospective, surgeon-blinded study, patients who had abdominal malignancy with plans for resection underwent preoperative frailty assessment with the RAI and nutrition assessment by measurement of albumin, prealbumin, and C-reactive protein (CRP). Postoperative outcomes and survival were assessed. RESULTS: The study included 220 patients, 158 (72%) of whom were considered frail (RAI ≥21). Frail patients were more likely to be readmitted within 30 and 90 days, (16% vs. 3% [P = 0.006] and 16% vs. 5% [P = 0.025], respectively). Patients with abnormal CRP, prealbumin, and albumin experienced higher rates of unplanned intensive care unit admission (CRP [27% vs. 8%; P < 0.001], albumin [30% vs. 10%; P < 0.001], prealbumin [29% vs. 9%; P < 0.001]) and increased postoperative mortality at 90 and 180 days. Survival was similar for frail and non-frail patients. In the multivariate analysis, frailty remained an independent risk factor for readmission (hazard ratio, 5.58; 95% confidence interval, 1.39-22.15; P = 0.015). In the post hoc analysis using the pre-cancer RAI score, the postoperative outcomes did not differ between the frail and non-frail patients. CONCLUSION: In conjunction with preoperative markers of nutrition, the RAI may be used to identify patients who may benefit from additional preoperative risk stratification and increased postoperative follow-up evaluation.

Surgical management of pancreatic ductal adenocarcinoma: a narrative review.

Background and Objective: Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related death in the United States and is projected to become the second-leading cause of cancer-related death by 2030. Despite advances in systemic and radiation therapy, for patients with surgically resectable PDAC, complete surgical resection is the only potentially curative treatment option. The conduct of a safe, technically excellent pancreatectomy is essential to achieve optimal perioperative outcomes and long-term survival. In this narrative review, evidence from large, well-executed studies and clinical trials examining the technical aspects of pancreatectomy is reviewed. Methods: A search was conducted in PubMed, Medline, and Cochrane Review databases to identify English-language randomized clinical trials, meta-analyses, and systematic reviews assessing surgical aspects of pancreatectomy for PDAC published between 2010 to 2023. Key Content and Findings: We identified retrospective and prospective studies evaluating the technical aspects of surgery for PDAC. In this review, we evaluate data on surgical techniques of pancreatectomy for PDAC, including the role of minimally invasive techniques, extent of lymphadenectomy, reconstruction options after pancreatoduodenectomy, and the role of surgical drainage. Conclusions: Surgical resection has a critical role in the treatment of operable PDAC. While pancreatic cancer surgery is an active area of research, conducting a technically excellent surgical resection maintains paramount importance for both oncological and perioperative outcomes. In this review, we summarize the latest evidence on surgical technique for operable PDAC.

Actual and perceived gender differences in virtual tumor board participation.

Introduction: Participant characteristics are known to affect group discourse and discussion outcomes. In medicine, many decisions are made by group consensus, therefore an understanding of these factors is highly relevant. We aimed to measure the effects of participant characteristics on tumor board discussions. Methods: We performed a prospective, multi-institution, quantitative study of multi-disciplinary virtual tumor board meetings. Participant characteristics included age, gender, and clinical discipline. Outcomes of interest were speech events, duration, and discourse style. Participant impressions was assessed by a post-hoc survey. Results: A total of 361 cases were discussed across 32 virtual meetings. Of the 283 attendees, 66.4 % were women, and all moderators were men. Women comprised 43 % of the 54 speakers, thus speaking less than male attendees (p < 0.001). No significant differences were detected in the duration or style of speech between men and women. Women participants commented more frequently on cases where the clinical attending was a woman (4.09 comments by women vs. 2.99 comments by men, p < 0.001), and less frequently when the attending was a man (2.48 comments by women vs. 3.20 comments by men, p < 0.001). On post hoc survey, men responded that they introduced ideas, guided discussions, and succeeded in influencing decisions significantly more than women reported that they did. Conclusion: Women physicians were underrepresented in tumor boards as moderators, speakers, and attendings of record. Women physicians commented less on men physicians' patients. Women felt less impactful than their men counterparts, despite having the same duration and style of speech. Prompted participation, moderator feedback, talking points, and limiting the number of cases can be used to balance representation in discussions.

Perineural Invasion of Pancreatic Ductal Adenocarcinoma is Associated with Early Recurrence after Neoadjuvant Therapy Followed by Resection.

BACKGROUND: Neoadjuvant therapy (NAT) is increasingly utilized in the treatment of pancreatic ductal adenocarcinoma (PDAC). However, there are limited data on risk factors and patterns of recurrence after surgical resection. This study aimed to analyze timing and recurrence patterns of PDAC after NAT followed by curative resection. METHODS: The medical charts of patients with PDAC treated with NAT followed by curative-intent surgical resection at a single health system from January 1, 2012 to January 1, 2020 were retrospectively reviewed. Early recurrence was defined as recurrence within 12 months of surgical resection. RESULTS: 91 patients were included and median follow up was 20.1 months. Recurrence occurred in 50 (55%) patients, with median recurrence free survival (RFS) of 11.9 months. Overall, 18 (36%) patients had local and 32 (64%) had distant recurrences. Median RFS and overall survival (OS) between local and distant recurrence were similar. Perineural invasion (PNI) and the presence of a T2 + tumor was significantly higher in recurrence group than in no recurrence group. PNI was a significant risk factor for early recurrence. CONCLUSION: After NAT and surgical resection of PDAC, disease recurrence was common, with distant metastasis being the most common. PNI was significantly higher in the recurrence group.

A possible role for ketorolac in the management of increased biliary drain output.

Percutaneous transhepatic biliary drainage is used to achieve biliary decompression in jaundiced patients with biliary obstruction. High drain output >2000 mL/day is rare, and can cause dehydration and electrolyte derangements, without effective treatments. We present the first patient, to our knowledge, who reacted to the use of the analgesic ketorolac with progressive reduction in biliary output, in the setting of malignant biliary obstruction from duodenal adenocarcinoma.

How Effective is the Use of Molecular Testing in Preoperative Decision Making for Management of Indeterminate Thyroid Nodules?

INTRODUCTION: We performed Thyroseq v2 molecular testing on indeterminate thyroid nodules and evaluated whether they underwent a management change from the standard of thyroid lobectomy. METHODS: We conducted a retrospective analysis of all indeterminate thyroid nodules that underwent Thyroseq v2 molecular testing from 2014 to 2019 at a large academic center. Pathology was reviewed by thyroid cytopathologists. Thyroseq results were reported benign (malignancy probability less than 10%) or suspicious (malignancy probability greater than 30%). The primary endpoint was a management change from a diagnostic lobectomy. RESULTS: A total of 142 nodules were included: 113 (80%) Bethesda III and 29 (20%) Bethesda IV. Seventy-three nodules underwent surgical management and 69 did not. We noted a change in management in 64% (91/142) of nodules. Patients who underwent a change in management to no surgery had a significantly higher rate of benign Thyroseq result than those without a change (75.8% vs. 49.0%, p = 0.001). On logistic regression analysis, a benign Thyroseq result was a positive independent predictor of a change to no surgery (OR 3.87, 95% CI 1.69-8.89). Nodule size, multiple nodules, compressive symptoms, and history of hypothyroidism were not significant. Of the 91 patients who underwent a management change, 71% (65/91) did not undergo surgery. On follow-up (average 985 ± 615 days), 12% (8/65) of those nodules were growing or developed suspicious features requiring surgery. CONCLUSIONS: Molecular testing helped avoid surgery in almost half our population with indeterminate thyroid nodules, and benign results may help avoid surgery in asymptomatic patients with indeterminate thyroid nodules.

Venous leg ulcers: potential algorithms of care.

Management of VLUs can be challenging, depending on wound complexity, and may require the use of several treatment modalities to achieve complete wound closure or significant wound area reduction. This review presents a systematic approach to management of VLUs based on previous literature and the authors' clinical experience, with consideration given to wound size, etiology, and responses to prior treatment. Techniques described include debridement (autolytic, enzymatic, sharp/surgical), compression therapy, physical therapy, medical adjuncts, and cellular- and tissue-based therapy. The algorithm of care for VLUs is multimodal. Appropriate diagnostic studies must be performed, including venous duplex and appropriate pathophysiology to confirm the diagnosis of VLU. After the correct diagnosis is confirmed, appropriate treatment may commence. All patients should undergo appropriate wound debridement; the exact modality used is dependent on wound characteristics. Patients must also adhere to consistent compression therapy. Any underlying venous disease that is amenable to surgical intervention should be addressed. Treatment with a medical adjunct and physical therapy are recommended. For patients who do not achieve significant wound area reduction, the addition of CTP is recommended. Use of these methods should result in substantial wound area reduction and/or wound closure.

The Evidence for Antimicrobial and Hard to Infect Regenerative Matrices.

Preparation of the wound bed is a key step in the use of cell- and tissue-based therapy (CTP). In particular, good pre-application debridement is an essential component of CTP. However, there are many situations in which the wound bed is not adequately debrided, including trauma, burn, and in cases of chronic wounds with significant biofilm. In the setting of inadequate wound bed preparation, the use of a CTP that has either added or intrinsic antimicrobial properties is attractive. Some CTPs include added antimicrobial agents such as PHMB or silver, while others have intrinsic antimicrobial components, such as Omega 3 fatty acids. In addition, some wound-covering dressings are completely synthetic, and therefore simply do not become infected. A full understanding of the basic science and clinical data supporting the use of these therapies is important for the advanced wound care practitioner.

The Role of Intermittent Pneumatic Compression in the Treatment of Lower Extremity Chronic Wounds.

Intermittent pneumatic compression devices (IPC) are often used as noninvasive adjuncts in patients with lymphedema, and more recently with venous stasis disease, to promote flow and reduce the adverse effects of interstitial edema associated with both disorders. We will be focusing on lower extremity wounds associated with venous and/or lymphatic disease, the combination often referred to as "lymphophlebitic" disease, and the treatment effect of IPC on this disease process and its sequelae. The function and purpose of pneumatic compression is closely examined along with a variety of pneumatic compression devices that currently exist in the market. A thorough review of the literature was conducted to evaluate the utility of intermittent pneumatic compression in the treatment of lower extremity venous stasis ulcers. Additionally, the author describes personal experience with the use of pneumatic compression on 10 patients with venous stasis ulcers at a single center. There is significant data supporting the use of IPC in patients with lymphophlebitic disease. Overall, ideal patient selection may be crucial. Previous data has shown that patients with high body mass index (>33 kg/m2) and poor functional status (walking less than 200m a day) are related to poor ulcer healing. Therefore, a study that looks primarily at this group (as our small quality assurance [QA] project did) may show increased benefit in this population. It is clear that IPC is of benefit to some patient cohorts with lymphophlebitic disease. This advanced therapy would help patients who have failure of their calf muscle pump and an inability to improve it through other means. However, it is only part of an algorithm that includes: direct wound bed management, moisture control, possible primary venous disease intervention, physical therapy, weight loss, and improved nutrition.

Generation of IL-3-Secreting CD4+ T Cells by Microbial Challenge at Skin and Mucosal Barriers.

During Ag priming, naive CD4+ T cells differentiate into subsets with distinct patterns of cytokine expression that dictate to a major extent their functional roles in immune responses. We identified a subset of CD4+ T cells defined by secretion of IL-3 that was induced by Ag stimulation under conditions different from those associated with previously defined functional subsets. Using mouse models of bacterial and viral infections, we showed that IL-3-secreting CD4+ T cells were generated by infection at the skin and mucosa but not by infections introduced directly into the blood. Most IL-3-producing T cells coexpressed GM-CSF and other cytokines that define multifunctionality. Generation of IL-3-secreting T cells in vitro was dependent on IL-1 family cytokines and was inhibited by cytokines that induce canonical Th1 or Th2 cells. Our results identify IL-3-secreting CD4+ T cells as a potential functional subset that arises during priming of naive T cells in specific tissue locations.

HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates.

A single-cycle herpes simplex virus (HSV) deleted in glycoprotein D (ΔgD-2) elicited high titer HSV-specific antibodies (Abs) that (i) were rapidly transported into the vaginal mucosa; (ii) elicited antibody-dependent cell-mediated cytotoxicity but little neutralization; (iii) provided complete protection against lethal intravaginal challenge; and (iv) prevented establishment of latency in mice. However, clinical isolates may differ antigenically and impact vaccine efficacy. To determine the breadth and further define mechanisms of protection of this vaccine candidate, we tested ΔgD-2 against a panel of clinical isolates in a murine skin challenge model. The isolates were genetically diverse, as evidenced by genomic sequencing and in vivo virulence. Prime and boost immunization (s.c.) with live but not heat- or UV-inactivated ΔgD-2 completely protected mice from challenge with the most virulent HSV-1 and HSV-2 isolates. Furthermore, mice were completely protected against 100 times the lethal dose that typically kills 90% of animals (LD90) of a South African isolate (SD90), and no latent virus was detected in dorsal root ganglia. Immunization was associated with rapid recruitment of HSV-specific FcγRIII- and FcγRIV-activating IgG2 Abs into the skin, resolution of local cytokine and cellular inflammatory responses, and viral clearance by day 5 after challenge. Rapid clearance and the absence of latent virus suggest that ΔgD-2 elicits sterilizing immunity.

The Vaginal Acquisition and Dissemination of HIV-1 Infection in a Novel Transgenic Mouse Model Is Facilitated by Coinfection with Herpes Simplex Virus 2 and Is Inhibited by Microbicide Treatment.

UNLABELLED: Epidemiological studies have demonstrated that herpes simplex virus 2 (HSV-2) infection significantly increases the risk of HIV-1 acquisition, thereby contributing to the expanding HIV-1 epidemic. To investigate whether HSV-2 infection directly facilitates mucosal HIV-1 acquisition, we used our transgenic hCD4/R5/cT1 mouse model which circumvents major entry and transcription blocks preventing murine HIV-1 infection by targeting transgenic expression of human CD4, CCR5, and cyclin T1 genes to CD4(+) T cells and myeloid-committed cells. Productive infection of mucosal leukocytes, predominantly CD4(+) T cells, was detected in all hCD4/R5/cT1 mice intravaginally challenged with an HIV-1 infectious molecular clone, HIV-Du151.2env-NLuc, which expresses an env gene (C.Du151.2) cloned from an acute heterosexually infected woman and a NanoLuc luciferase reporter gene. Lower genital tract HIV-1 infection after HIV-Du151.2env-NLuc intravaginal challenge was increased ~4-fold in hCD4/R5/cT1 mice coinfected with HSV-2. Furthermore, HIV-1 dissemination to draining lymph nodes was detected only in HSV-2-coinfected mice. HSV-2 infection stimulated local infiltration and activation of CD4(+) T cells and dendritic cells, likely contributing to the enhanced HIV-1 infection and dissemination in HSV-2-coinfected mice. We then used this model to demonstrate that a novel gel containing tenofovir disoproxil fumarate (TDF), the more potent prodrug of tenofovir (TFV), but not the TFV microbicide gel utilized in the recent CAPRISA 004, VOICE (Vaginal and Oral Interventions to Control the Epidemic), and FACTS 001 clinical trials, was effective as preexposure prophylaxis (PrEP) to completely prevent vaginal HIV-1 infection in almost half of HSV-2-coinfected mice. These results also support utilization of hCD4/R5/cT1 mice as a highly reproducible immunocompetent preclinical model to evaluate HIV-1 acquisition across the female genital tract. IMPORTANCE: Multiple epidemiological studies have reported that genital herpes simplex virus 2 (HSV-2) infection increases the risk of HIV-1 sexual acquisition by severalfold. Understanding the underlying mechanisms by which HSV-2 facilitates HIV-1 infection and optimizing the efficacy of therapies to inhibit HIV-1 infection during HSV-2 coinfection should contribute to reducing HIV-1 transmission. Using our novel transgenic hCD4/R5/cT1 mouse model infectible with HIV-1, we demonstrated that HSV-2 infection enhances vaginal transmission and dissemination of HIV-1 infection while stimulating recruitment and activation of CD4(+) T cells and dendritic cells in the lower genital tract. HIV acquisition by hCD4/R5/cT1 mice vaginally coinfected with HSV-2 could be completely prevented in almost half the mice by preexposure prophylaxis (PrEP) with a novel gel containing tenofovir disoproxil fumarate (TDF), the tenofovir prodrug, but not with the tenofovir microbicide gel utilized in CAPRISA-004, VOICE, and FACTS-001 clinical trials. The hCD4/R5/cT1 mice represent a new preclinical mouse model to evaluate vaginal HIV-1 acquisition.

Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease.

Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD(-/+gD-1)). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD(-/+gD1) provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD(-/+gD1) elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.