International Expert Consensus on Defining Textbook Oncologic Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastasis.

BACKGROUND: Textbook oncologic outcome (TOO) is a composite metric shown to correlate with improved survival after curative intent oncologic procedures. Despite increasing use among disciplines in surgical oncology, no consensus exists for its definition in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). STUDY DESIGN: An international consensus-based study employed a Delphi methodology to achieve agreement. Fifty-four senior surgeons from the peritoneal surface malignancies field received a questionnaire comprising TOO parameters divided into 3 surgical domains: operative, short-term, and long-term postoperative outcomes. Two online meetings with participants defined the new criteria. Consensus was achieved when 75% of agreement rate was reached. Clinical data of patients who underwent CRS and HIPEC for colorectal peritoneal metastasis between 2010 and 2022 from 1 designated center (Sheba Medical Center) were collected, the consensus definition applied and outcomes analyzed. RESULTS: Thirty-eight surgeons (70%) participated. Expert consensus TOO parameters for colorectal peritoneal metastasis CRS and HIPEC included the absence of unplanned reoperations during 30 days postoperation, absence of severe postoperative complications (Clavien-Dindo ≥III), absence of unplanned readmissions during 30 days postoperation, 90-day postoperative mortality, and absence of contraindications for chemotherapy within 12 weeks from operation, and included the achievement of complete cytoreduction (CC0). The study cohort consisted of 251 patients, and 151 (60%) met TOO criteria. Patients who achieved TOO had significantly better overall survival (median 67.5 months, 95% CI) vs patients who did not achieve TOO (median 44.6 months, 95% CI, p < 0.001) and significantly improved disease-free survival (median, 12 months, 95% CI, vs 9 months, 95% CI, p = 0.01). CONCLUSIONS: Achievement of TOO as defined by consensus statement is associated with improved survival.

Distress, Depression, and the Effect of ZIP Code in Pancreaticobiliary Cancer Patients and Their Significant Others.

BACKGROUND: Distress screening of cancer patients is mandated by the American College of Surgeons Commission on Cancer. Clinical implementation remains limited, particularly in surgical oncology settings in individuals with pancreaticobiliary cancers. STUDY DESIGN: This study evaluated differences in mean distress scores based on the National Comprehensive Cancer Network Distress Thermometer & Problem List for patients with pancreaticobiliary cancers, benign pancreatic conditions, and for their significant others (SOs). The distress screening was conducted at the first office visit and postoperatively in a subset of those who had surgery. Distress Thermometer (DT) scores were dichotomized at ≤5 vs >5 and at ≥7 and correlated with Problem List items. The US ZIP Code database was used to correlate income range, percent poverty, and unemployment in the patient's self-identified ZIP code. Regression models were fitted to identify independent predictors of distress. RESULTS: A total of 547 patients and 184 SOs were evaluated. Thirty percent of patients had DT scores >5, with pancreatic adenocarcinoma patients reporting the highest levels of distress. SOs of pancreatic adenocarcinoma patients reported even greater distress than the patients themselves. As the number of pre-existing medical problems increased; so did DT scores. Distress correlated with physical and emotional problems and worry about insurance coverage and transportation. Higher income level predicted higher DT scores, although poverty predicted lower DT scores. Depression was present in 12% of the patients. Distress improved in those undergoing surgery. CONCLUSIONS: Distress and depression in pancreaticobiliary cancer patients and SOs are prevalent. The findings of this study have multiple actionable implications and require diagnosis, treatment, and referral to supportive care resources.

The FDA-Approved Anthelmintic Pyrvinium Pamoate Inhibits Pancreatic Cancer Cells in Nutrient-Depleted Conditions by Targeting the Mitochondria.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal aggressive cancer, in part due to elements of the microenvironment (hypoxia, hypoglycemia) that cause metabolic network alterations. The FDA-approved antihelminthic pyrvinium pamoate (PP) has previously been shown to cause PDAC cell death, although the mechanism has not been fully determined. We demonstrated that PP effectively inhibited PDAC cell viability with nanomolar IC50 values (9-93 nmol/L) against a panel of PDAC, patient-derived, and murine organoid cell lines. In vivo, we demonstrated that PP inhibited PDAC xenograft tumor growth with both intraperitoneal (IP; P < 0.0001) and oral administration (PO; P = 0.0023) of human-grade drug. Metabolomic and phosphoproteomic data identified that PP potently inhibited PDAC mitochondrial pathways including oxidative phosphorylation and fatty acid metabolism. As PP treatment reduced oxidative phosphorylation (P < 0.001), leading to an increase in glycolysis (P < 0.001), PP was 16.2-fold more effective in hypoglycemic conditions similar to those seen in PDAC tumors. RNA sequencing demonstrated that PP caused a decrease in mitochondrial RNA expression, an effect that was not observed with established mitochondrial inhibitors rotenone and oligomycin. Mechanistically, we determined that PP selectively bound mitochondrial G-quadruplexes and inhibited mitochondrial RNA transcription in a G-quadruplex-dependent manner. This subsequently led to a 90% reduction in mitochondrial encoded gene expression. We are preparing to evaluate the efficacy of PP in PDAC in an IRB-approved window-of-opportunity trial (IND:144822).

Dr. Orvar Swenson and the Pull-Through.

Dr. Orvar Swenson is best remembered for developing the Swenson pull-through, a technique he developed to treat Hirschsprung's disease. After graduating from Harvard Medical School and beginning his residency at Peter Bent Brigham Hospital, Dr. Swenson observed that patients with Hirschsprung's disease and toxic megacolon resumed normal bowel function after placement of transverse colostomies. His observation led to studying the patency of his patients' colons using barium enema contrast studies. At the collapsed portion of the colon, he performed rectal biopsies leading to the discovery that the cause of Hirschsprung's disease is that the collapsed portion of the colon lacks the Auerbach plexus. The Swenson pull-through removes this aganglionic portion of the colon and cures the patient. His career grew from there as he traveled to academic institutions teaching his technique. He is remembered fondly for his contributions to pediatric surgery through the restructuring of pediatric surgery departments, pediatric surgery research, and writing and editing multiple volumes of Pediatric Surgery, the standard textbook for pediatric surgeons. He died peacefully in 2012 at the age of 103 years.

Cytoplasmic HuR Status Predicts Disease-free Survival in Resected Pancreatic Cancer: A Post-hoc Analysis From the International Phase III ESPAC-3 Clinical Trial.

OBJECTIVES: We tested cytoplasmic HuR (cHuR) as a predictive marker for response to chemotherapy by examining tumor samples from the international European Study Group of Pancreatic Cancer-3 trial, in which patients with resected pancreatic ductal adenocarcinoma (PDA) received either gemcitabine (GEM) or 5-fluorouracil (5-FU) adjuvant monotherapy. BACKGROUND: Previous studies have implicated the mRNA-binding protein, HuR (ELAVL1), as a predictive marker for PDA treatment response in the adjuvant setting. These studies were, however, based on small cohorts of patients outside of a clinical trial, or a clinical trial in which patients received multimodality therapy with concomitant radiation. METHODS: Tissue samples from 379 patients with PDA enrolled in the European Study Group of Pancreatic Cancer-3 trial were immunolabeled with an anti-HuR antibody and scored for cHuR expression. Patients were dichotomized into groups of high versus low cHuR expression. RESULTS: There was no association between cHuR expression and prognosis in the overall cohort [disease-free survival (DFS), P = 0.44; overall survival, P = 0.41). Median DFS for patients with high cHuR was significantly greater for patients treated with 5-FU compared to GEM [20.1 months, confidence interval (CI): 8.3-36.4 vs 10.9 months, CI: 7.5-14.2; P = 0.04]. Median DFS was similar between the treatment arms in patients with low cHuR (5-FU, 12.8 months, CI: 10.6-14.6 vs GEM, 12.9 months, CI: 11.2-15.4). CONCLUSIONS: Patients with high cHuR-expressing tumors may benefit from 5-FU-based adjuvant therapy as compared to GEM, whereas those patients with low cHuR appear to have no survival advantage with GEM compared with 5-FU. Further studies are needed to validate HuR as a biomarker in both future monotherapy and multiagent regimens.

Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS).

BACKGROUND: This position statement was developed to expedite a consensus on definition and treatment for borderline resectable pancreatic ductal adenocarcinoma (BRPC) that would have worldwide acceptability. METHODS: An international panel of pancreatic surgeons from well-established, high-volume centers collaborated on a literature review and development of consensus on issues related to borderline resectable pancreatic cancer. RESULTS: The International Study Group of Pancreatic Surgery (ISGPS) supports the National Comprehensive Cancer Network criteria for the definition of BRPC. Current evidence supports operative exploration and resection in the case of involvement of the mesentericoportal venous axis; in addition, a new classification of extrahepatic mesentericoportal venous resections is proposed by the ISGPS. Suspicion of arterial involvement should lead to exploration to confirm the imaging-based findings. Formal arterial resections are not recommended; however, in exceptional circumstances, individual therapeutic approaches may be evaluated under experimental protocols. The ISGPS endorses the recommendations for specimen examination and the definition of an R1 resection (tumor within 1 mm from the margin) used by the British Royal College of Pathologists. Standard preoperative diagnostics for BRPC may include: (1) serum levels of CA19-9, because CA19-9 levels predict survival in large retrospective series; and also (2) the modified Glasgow Prognostic Score and the neutrophil/lymphocyte ratio because of the prognostic relevance of the systemic inflammatory response. Various regimens of neoadjuvant therapy are recommended only in the setting of prospective trials at high-volume centers. CONCLUSION: Current evidence justifies portomesenteric venous resection in patients with BRPC. Basic definitions were identified, that are currently lacking but that are needed to obtain further evidence and improvement for this important patient subgroup. A consensus for each topic is given.

dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: a dual-institutional follow-up with the RTOG 9704 trial.

Deoxycytidine kinase (dCK) and human antigen R (HuR) have been associated with response to gemcitabine in small studies. The present study investigates the prognostic and predictive value of dCK and HuR expression levels for sensitivity to gemcitabine and 5-fluorouracil (5-FU) in a large phase III adjuvant trial with chemoradiation backbone in pancreatic ductal adenocarcinoma (PDA). The dCK and HuR expression levels were determined by immunohistochemistry on a tissue microarray of 165 resected PDAs from the Radiation Therapy Oncology Group (RTOG) 9704 trial. Association with overall survival (OS) and disease-free survival (DFS) status were analyzed using the log-rank test and the Cox proportional hazards model. Experiments with cultured PDA cells were performed to explore mechanisms linking dCK and HuR expression to drug sensitivity. dCK expression levels were associated with improved OS for all patients analyzed from RTOG 9704 (HR: 0.66, 95% CI [0.47-0.93], P = 0.015). In a subset analysis based on treatment arm, the effect was restricted to patients receiving 5-FU (HR: 0.53, 95% CI [0.33-0.85], P = 0.0078). Studies in cultured cells confirmed that dCK expression rendered cells more sensitive to 5-FU. HuR cytoplasmic expression was neither prognostic nor predictive of treatment response. Previous studies along with drug sensitivity and biochemical studies demonstrate that radiation interferes with HuR's regulatory effects on dCK, and could account for the negative findings herein based on the clinical study design (i.e., inclusion of radiation). Finally, we demonstrate that 5-FU can increase HuR function by enhancing HuR translocation from the nucleus to the cytoplasm, similar to the effect of gemcitabine in PDA cells. For the first time, in the pre-treatment tumor samples, dCK and HuR cytoplasmic expression were strongly correlated (chi-square P = 0.015). This dual-institutional follow up study, in a multi-institutional PDA randomized clinical trial, observed that dCK expression levels were prognostic and had predictive value for sensitivity to 5-FU.

The influence of prognostic factors and adjuvant chemoradiation on survival after pancreaticoduodenectomy for ampullary carcinoma.

INTRODUCTION: The prognosis after pancreaticoduodenectomy (PD) for ampullary carcinoma (AC) is superior to that of pancreatic cancer. Decisions regarding adjuvant therapy are influenced by factors such as nodal status, stage, and grade, but the influence of these individual variables on survival is unclear. METHODS: A prospective tumor registry database was queried to identify patients who underwent PD for AC at Thomas Jefferson University between Jan 1997 and Apr 2009. The study was conducted with the approval of the institutional review board. Data were collected through review of hospital and departmental charts. Overall survival (OS) was analyzed using univariate and multivariate Cox proportional hazard models. The proportional hazard assumption was verified for the overall model and individual covariates. RESULTS: A total of 61 patients underwent PD for AC at our institution. There were five perioperative deaths (8.2%). Mean age was 70 years (62% male). Median survival time (MST) was 50 months for all patients. Only primary tumor stage, T1/T2 versus T3/T4 (American Joint Committee on Cancer Staging, version 6), was associated with OS in univariate analyses (p = 0.003). The association of nodal status with OS was borderline-significant (p = 0.08), with the MST being 84 months for node-negative and 17 months for node-positive patients. The remaining covariates were not predictors of OS. In the multivariate analysis, only primary tumor stage (HR, 5.1; p < 0.001) and age (HR, 1.04; p = 0.06), but not nodal status or adjuvant therapy, were associated with overall survival. CONCLUSIONS: Advanced primary tumor stage and age were associated with inferior OS after PD for AC. Adjuvant therapy did not impact survival. Patients with advanced tumor stage should be considered for clinical trials of adjuvant therapy after PD with novel compounds and optimized radiation therapy strategies.

Adjuvant concurrent chemoradiation for node-positive adenocarcinoma of the duodenum.

HYPOTHESIS: Adjuvant chemoradiation improves local control and survival in patients with node-positive duodenal adenocarcinoma treated with pancreaticoduodenectomy. DESIGN: A retrospective review of outcomes, with a planned comparison with historical controls. SETTING: A single, high-volume academic referral center. PATIENTS: All patients with periampullary carcinoma treated with pancreaticoduodenectomy and adjuvant chemoradiotherapy at The Johns Hopkins Hospital between 1994 and 2003. Fourteen cases of node-positive duodenal adenocarcinoma were identified. Median radiation dose was 5000 cGy (range, 4000-5760 cGy). Concurrent fluorouracil-based chemotherapy was given with radiation therapy, followed by maintenance chemotherapy. RESULTS: The median follow-up was 12 months for patients who died and 42 months for those who lived. Death occurred in 7 of 14 patients (50%) during the follow-up period. Median survival for all patients was 41 months, and the 5-year survival rate was 44%. Of the 7 patients who experienced disease recurrence, 6 experienced distant metastasis as first recurrence. One of these 7 patients experienced both local recurrence and distant metastasis. Local control for all patients in the study was 93%, which compares favorably with local control reported in a series of patients treated with surgery alone (67%). Compared with historical controls treated with surgery alone, patients who received adjuvant chemoradiation therapy had an improved median survival (21 months vs 41 months, respectively). Overall 5-year survival, however, was not improved (44% vs 43%, respectively). CONCLUSION: Adjuvant chemoradiation therapy after pancreaticoduodenectomy for node-positive duodenal adenocarcinoma may improve local control and median survival but does not impact 5-year overall survival.

Adjuvant concurrent chemoradiation for adenocarcinoma of the distal common bile duct.

PURPOSE: To examine the effect of adjuvant chemoradiation for adenocarcinoma of the distal common bile duct (DCBD) after pancreaticoduodenectomy (PD) on local control and survival. METHODS AND MATERIALS: A total of 34 cases of adenocarcinoma of the DCBD were treated with PD and adjuvant chemoradiation at Johns Hopkins Hospital between 1994 and 2003. Median radiation dose was 5,040 cGy (range, 4,000-5,400 cGy). Concurrent 5-fluorouracil-based chemotherapy was given with radiation therapy, followed by maintenance chemotherapy. RESULTS: The median follow-up of patients alive at the time of analysis was 41 months. Death occurred in 21 of 34 patients (62%) during the follow-up period, all from progressive, distant metastatic disease. Median overall survival was 36.9 months, with a 5-year survival of 35%. On multivariate analysis, only nodal status significantly predicted survival (p < 0.02). For patients with negative and positive lymph nodes, 5-year survival was 100% and 24%, respectively. Actuarial 5-year local control was 70%. Compared with historical controls who underwent PD alone, patients who underwent surgery and adjuvant chemoradiation had significantly longer survival (36.9 months vs. 22 months; p < 0.05). Overall survival was significantly longer for both lymph node negative and lymph node positive patients (p < 0.05). CONCLUSIONS: Adjuvant chemoradiation after PD for adenocarcinoma of the DCBD may improve local control and overall survival. The predominant mode of failure is distant metastatic disease, highlighting the need for improved systemic therapy.

The case for routine use of adjuvant therapy in pancreatic cancer.

Pancreatic cancer is a devastating disease with a poor prognosis for most patients. Surgical resection remains the cornerstone of treatment, providing the only realistic hope of long-term survival. Even with optimal surgical management, 5-year survival averages 15% to 20% for resectable disease. Progress is being made, however. Currently, the benefits of postoperative therapy for resected pancreatic ductal adenocarcinoma appear clear, and recommendations for such therapy appear to us to be well justified. Additional benefit to patients awaits the development of new agents, molecular targeted drugs, and novel approaches such as immunotherapy.