Perfusion Strategies for Cytoreductive Surgery With Heated Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma.

Cytoreductive surgery (CRS) with heated intraoperative intraperitoneal chemotherapy (HIPEC) has been shown to improve survival for patients with malignant peritoneal mesothelioma (MPM). Presently, there is no standardized HIPEC protocol with respect to chemotherapeutic agent, dose, administration temperature, or duration and limited literature comparing outcomes in different regimens. In this study, we analyze common practices and outcomes of published HIPEC regimens to gain insight into current practice to inform future directions of study. We conducted a literature search for investigational studies of CRS and HIPEC for MPM treatment in adults and identified 35 such articles. These studies were analyzed for institution type and location, drug regimens, perfusion temperatures and time, and study outcomes including median survival, complication rates, and perioperative mortality rates. On review, there is significant heterogeneity in HIPEC regimens and outcome reporting metrics, suggesting a need for multi-institutional standardized study protocols to better determine the safest and most efficacious treatment regimen.

Reasons for Surgical Attrition Among Nonmetastatic Upper Gastrointestinal Cancer Patients: A Single Institutional Experience.

INTRODUCTION: Upper gastrointestinal (UGI) cancers require multidisciplinary treatment, but surgery provides the only potentially curative option. We sought to understand reasons for attrition before surgery within our regional hospital network. METHODS: We performed chart reviews of patients (age 18-80) with stage I-III UGI cancers (gastroesophageal junction, gastric, and hepatopancreatobiliary adenocarcinomas) in our multihospital cancer registry from 2015 to 2021. Our primary outcome was reasons for surgical attrition. Univariable analysis identified factors related to surgical attrition and the Kaplan-Meier method estimated overall survival based on surgery receipt. RESULTS: Seven hundred and ninety-two patients were included in our analysis, of whom 107 (13.5%) did not undergo curative surgery. Reasons for not undergoing surgery included medical comorbidities (30.8%), patient preference/nonmedical barriers (24.3%, which included: not interested without further explanation, worried about complications, nonadherence to appointments, insurance issues, did not wish for blood transfusion, lack of social support, preferring home care, and worried about recurrence), psychosocial (5.6%), progression while on neoadjuvant therapy or waiting for transplant (15.0% and 7.5%), poor performance status (3.7%), side effects of neoadjuvant therapy (3.7%), and death unrelated to treatment or unknown cause (9.4%). Nonsurgical management was not associated with race, socioeconomic status, or distance traveled for care. Survival was greatly improved for patients who underwent surgery (158 vs. 63 weeks, p < 0.05). CONCLUSION: Nearly one in seven patients (18-80 years old) with UGI cancers evaluated at our academic cancer center did not undergo surgical resection. Reasons for surgical attrition included potentially modifiable issues, and addressing these barriers could help overcome inequities in cancer treatment and survival.

The effect of surgical timing in nonmetastatic melanoma.

BACKGROUND AND OBJECTIVES: There is no consensus guidelines on the best timing to perform Sentinel lymph node biopsy (SLNB) in high-risk melanoma patients. We aimed to understand the impact of surgical timing on nodal upstaging in patients with cutaneous melanoma. METHODS: We queried the National Cancer Database from 2004 to 2018 for patients with T2-T4, N0, M0 melanomas, who underwent melanoma excision and nodal surgery. We included patients who underwent surgery within 2-19 weeks postdiagnosis. We aimed to determine the association of surgical delay (weeks) with nodal positivity. RESULTS: A total of 53 355 patients were included, of whom 20.9% had positive lymph nodes. Patients underwent surgery at a median of 5 (4-7) weeks after diagnosis. The rate of positive nodes increased with increased weeks to surgery (line of best-fit slope = 0.38). Multivariable regression analysis identified an association between time to surgery and nodal positivity (2.4% increased risk per week, p < 0.05). Our analysis showed significantly increased likelihood of nodal positivity beginning 9 weeks after diagnosis (odds ratio [OR] = 1.3, p < 0.05). Furthermore, patients with T2-3 tumors had a significant increase in nodal positivity with increased time to surgery (OR = 1.03 per week, p < 0.001). However, no significant trend in nodal positivity was identified for patients with T4 melanomas (OR = 1.01 per week, p = 0.596). CONCLUSION: Surgery within 9 weeks of melanoma diagnosis was not associated with increased likelihood of nodal positivity. These data can guide clinical conversations regarding the importance of surgical timing for melanoma.

Knockdown of GADD34 in neonatal mutant SOD1 mice ameliorates ALS.

Mutations in Cu/Zn superoxide dismutase (SOD1) cause ~20% of familial ALS (FALS), which comprises 10% of total ALS cases. In mutant SOD1- (mtSOD1-) induced ALS, misfolded aggregates of SOD1 lead to activation of the unfolded protein response/integrated stress response (UPR/ISR). Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), a kinase that phosphorylates eukaryotic translation initiator factor 2α (p-eIF2α), coordinates the response by causing a global suppression of protein synthesis. Growth arrest and DNA damage 34 (GADD34) dephosphorylates p-eIF2α, allowing protein synthesis to return to normal. If the UPR/ISR is overwhelmed by the amount of misfolded protein, CCAAT/enhancer-binding homologous protein (CHOP) is activated leading to apoptosis. In the current study we investigated the effect of knocking down CHOP and GADD34 on disease of G93A and G85R mtSOD1 mice. Although a CHOP antisense oligonucleotide had no effect on survival, an intravenous injection of GADD34 shRNA encoded in adeno-associated virus 9 (AAV9) into neonatal G93A as well as neonatal G85R mtSOD1 mice led to a significantly increased survival. G85R mtSOD1 mice had a reduction in SOD1 aggregates/load, astrocytosis, and microgliosis. In contrast, there was no change in disease phenotype when GADD34 shRNA was delivered to older G93A mtSOD1 mice. Our current study shows that GADD34 shRNA is effective in ameliorating disease when administered to neonatal mtSOD1 mice. Targeting the UPR/ISR may be beneficial in mtSOD1-induced ALS as well as other neurodegenerative diseases in which misfolded proteins and ER stress have been implicated.

Single chain variable fragment antibodies directed against SOD1 ameliorate disease in mutant SOD1 transgenic mice.

Mutations in Cu/Zn superoxide dismutase (SOD1) are the cause of ~20% of cases of familial ALS (FALS), which comprise ~10% of the overall total number of cases of ALS. Mutant (mt) SOD1 is thought to cause FALS through a gain and not loss in function, perhaps as a result of the mutant protein's misfolding and aggregation. Previously we used a phage display library to raise single chain variable fragment antibodies (scFvs) against SOD1, which were found to decrease aggregation of mtSOD1 and toxicity in vitro. In the present study, we show that two scFvs directed against SOD1 ameliorate disease in G93A mtSOD1 transgenic mice and also decrease motor neuron loss, microgliosis, astrocytosis, as well as SOD1 burden and aggregation. The results suggest that the use of antibodies or antibody mimetics directed against SOD1 may be a useful therapeutic direction in mtSOD1-induced FALS. Since studies suggest that wild type SOD1 may be misfolded similar to that seen with mtSOD1, this therapeutic direction may be effective in sporadic as well as FALS.