Germline CDH1 Variants and Lifetime Cancer Risk.

Importance: Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants. Objective: To describe gastric and breast cancer risk estimates for individuals with CDH1 variants. Design, Setting, and Participants: Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022. Main Outcomes and Measures: Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years. Results: A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%). Conclusions and Relevance: Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

Transthoracic Anastomotic Leak After Esophagectomy: Current Trends.

INTRODUCTION: Leaks from intrathoracic esophagogastric anastomosis are thought to be associated with higher rates of morbidity and mortality than leaks from cervical anastomosis. We challenge this assumption and hypothesize that there is no significant difference in mortality based on the location of the esophagogastric anastomosis. METHODS: A systematic literature search was conducted using PubMed and Embase databases on all studies published from January 2000 to June 2015, comparing transthoracic (TTE) and transhiatal (THE) esophagectomies. Studies using jejunal or colonic interposition were excluded. Outcomes analyzed were leak rate, leak-associated mortality, overall 30-day mortality, and overall morbidity. Meta-analyses were performed using Mantel-Haenszel statistical analyses on studies reporting leak rates of both approaches. Nominal data are presented as frequency and interquartile range (IQR); measures of the association between treatments and outcomes are presented as odds ratio (OR) with 95 % confidence interval. RESULTS: Twenty-one studies (3 randomized controlled trials) were analyzed comprising of 7167 patients (54 % TTE). TTE approach yields a lower anastomotic leak rate (9.8 %; IQR 6.0-12.2 %) than THE (12 %; IQR 11.6-22.1 %; OR 0.56 [0.34-0.92]), without any significant difference in leak associated mortality (7.1 % TTE vs. 4.6 % THE: OR 1.83 [0.39-8.52]). There was no difference in overall 30-day mortality (3.9 % TTE vs. 4.3 % THE; OR 0.86 [0.66-1.13]) and morbidity (59.0 % TTE vs. 66.6 % THE; OR 0.76 [0.37-1.59]). DISCUSSION: Based on meta-analysis, TTE is associated with a lower leak rate and does not result in higher morbidity or mortality than THE. The previously assumed higher rate of transthoracic anastomotic leak-associated mortality is overstated, thus supporting surgeon discretion and other factors to influence the choice of thoracic versus cervical anastomosis.

Laparoscopic Spleen-Preserving Total Pancreatectomy for a Main-Duct Intraductal Papillary Mucinous Neoplasm.

INTRODUCTION: Main-duct intraductal papillary mucinous neoplasms of the pancreas (M-IPMN) are potentially malignant cystic neoplasms that can degenerate into invasive malignancy in 43 % of cases.1 Although laparoscopic pancreaticoduodenectomy and distal pancreatectomy have been previously described for the management of pancreatic neoplasms, laparoscopic total pancreatectomy is rarely described. We present a video demonstrating a laparoscopic spleen-preserving total pancreatectomy in a patient with M-IPMN. CASE PRESENTATION: A healthy 66-year-old male was diagnosed with recurrent pancreatitis. A computed tomography of the abdomen demonstrated a diffusely dilated pancreatic duct (10 mm) and a 5 mm mural nodule in the neck of the pancreas. Endoscopic retrograde cholangiopancreatography demonstrated a 'fish mouth' appearance at the major papilla, with a villous mass (15 mm) in the pancreatic head. Biopsy was consistent with M-IPMN, and tumor markers were normal. RESULTS: A spleen-preserving laparoscopic total pancreatectomy was performed over a period of 270 min, with 150 cc of blood loss without complications. The patient was admitted to the intensive care unit for continuous insulin infusion. On postoperative day (POD) 1, his nasogastric tube was discontinued, transitioned to subcutaneous insulin injections, and transferred to the floor. He tolerated a diabetic diet on POD 4. His surgical drain had minimal output with no evidence of a bile leak, and was discontinued on POD 5. The patient's hospital course was uncomplicated and he was discharged home on POD 7. Pathology demonstrated IPMN with moderate dysplasia. CONCLUSION: Laparoscopic total pancreatectomy can be safely performed in patients with M-IPMN. This video presentation describes the technique we used for this procedure.

Does the cost of robotic cholecystectomy translate to a financial burden?

INTRODUCTION: Robotic application to cholecystectomy has dramatically increased, though its impact on cost of care and reimbursement has not been elucidated. We undertook this study to evaluate and compare cost of care and reimbursement with robotic versus laparoscopic cholecystectomy. METHODS AND PROCEDURES: The charges and reimbursement of all robotic and laparoscopic cholecystectomies at one hospital undertaken from June 2012 to June 2013 were determined. Operative duration is defined as time into and time out of the operating room. Data are presented as median data. Comparisons were undertaken using the Mann-Whitney U-test with significance accepted at p ≤ 0.05. RESULTS: Robotic cholecystectomy took longer (47 min longer) and had greater charges ($8,182.57 greater) than laparoscopic cholecystectomy (p < 0.05 for each). However, revenue, earnings before depreciation, interest, and taxes (EBDIT), and Net Income were not impacted by approach. CONCLUSIONS: Relative to laparoscopic cholecystectomy, robotic cholecystectomy takes longer and has greater charges. Revenue, EBDIT, and Net Income are similar after either approach; this indicates that costs with either approach are similar. Notably, this is possible because much of hospital-based costs are determined by cost allocation and not cost accounting. Thus, the cost of longer operations and costs inherent to the robotic approach for cholecystectomy do not translate to a perceived financial burden.

Pancreaticoduodenectomy in Florida: do 20-year trends document the salutary benefits of centralization of care?

BACKGROUND: Concentration of care has been promoted as fostering superior outcomes. This study was undertaken to determine if the concentration of care is occurring in Florida for a pancreaticoduodenectomy, and if so, is it having a salutary effect. METHODS: The data for a pancreaticoduodenectomy were obtained from the Florida Agency for Health Care Administration for three 3-year periods:1992-1994, 2001-2003, 2010-2012; data were sorted by surgeon volume of pancreaticoduodenectomy during these periods and correlated with post-operative length of stay (LOS), in-hospital mortality and hospital charges (adjusted to 2012 dollars). RESULTS: Relative to 1992-1994, in 2010-2012 46% fewer surgeons performed 115% more pancreaticoduodenectomies with significant reductions in LOS and in-hospital mortality, and higher charges (P < 0.001 for each). From 1992-1994 to 2010-2012 there was an 18-fold increase in the number of pancreaticoduodenectomies by surgeons completing ≥ 12 per year (n = 45 to n = 806, respectively). During 2010-2012, the more frequently surgeons performed a pancreaticoduodenectomy, the shorter LOS, the lower in-hospital mortality, the greater the likelihood of discharge home and the lower the hospital charges (P < 0.03 for each). CONCLUSIONS: Over the last 20 years, the concentration of care has occurred in Florida with substantially fewer surgeons undertaking many more pancreaticoduodenectomies with dramatic improvements in LOS and in-hospital mortality, albeit with increased hospital charges.

Liver resection versus ablation in geriatric populations - Does one method impart improved in-hospital mortality?

Objectives: This study aimed to compare surgical resection versus ablation for managing liver malignancies in patients 65 and older. Material and Methods: Cases with liver tumors were extracted from the NSQIP database for patients aged ≥65 years. Following propensity score matching, multivariate Cox regression was used for 30-day morbidity and mortality for liver resection and ablation. Results: Following a propensity score matching, 1048 patients were 1:1 matched for comorbid conditions. Patients stayed in the hospital three days longer after resection (p<0.001). Mortality was lower after ablation (p= 0.013). This difference was more prominent in patients with primary liver tumors (p= 0.008). Group A had a 10-fold lower risk of developing an abdominal abscess, a fourfold decrease in hospital-associated pneumonia (p= 0.001) and reintubation, a 10-fold reduction in bleeding requiring transfusion (p<0.001), and a three-fold decrease in risk of developing sepsis (p<0.001). Conclusion: Despite being a generally sicker patient population with worse underlying liver function, ablative techniques were associated with a lower risk of adverse outcomes when compared to more aggressive resection of primary malignant tumors of the liver.

Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial protocol.

Background: Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors. Methods: Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP. Discussion: Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy. Trial Registration: ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.

Dissatisfaction after laparoscopic Heller myotomy: The truth is easy to swallow.

BACKGROUND: Although laparoscopic Heller myotomy has been shown to well palliate symptoms of achalasia, we have observed a small subset of patients who are "Dissatisfied". This study was undertaken to identify the causes of their dissatisfaction. STUDY DESIGN: Patients undergoing laparoscopic Heller myotomy from 1992 to 2015 were prospectively followed. Using a Likert scale, patients rated their symptom frequency/severity before and after the procedure. Patients graded their experience from "Very Satisfying" to "Very Unsatisfying." RESULTS: 647 patients underwent laparoscopic Heller myotomy. Fifty (8%) patients, median age 57 years and BMI 24 kg/m2 reported dissatisfaction at follow-up subsequent to myotomy. "Dissatisfied" patients were more likely to have undergone prior abdominal operations (p = 0.01) or previous myotomies (p = 0.02). "Dissatisfied" patients had a greater incidence of diverticulectomy (p = 0.03) and had longer postoperative LOS (p = 0.01). Symptom frequency/severity persisted after myotomy for dissatisfied patients (p > 0.05). CONCLUSION: Dissatisfaction after laparoscopic Heller myotomy is directly related to persistent/recurrent symptoms. Previous abdominal operations/myotomies, diverticulectomies, and longer LOS are predictors of dissatisfaction. With this understanding, we can identify patients who might be more prone to dissatisfaction.

Regional differences for pancreaticoduodenectomy in Florida: Location matters.

INTRODUCTION: Regionalization of care raises potential for differences in cost of care and outcome. This study was undertaken to determine if costs and outcome after pancreaticoduodenectomy vary by region in Florida, and whether costs and outcome are related. METHODS: Inpatient data for pancreaticoduodenectomy in Florida during 2010-2012 were obtained from the Florida Agency for Health Care Administration. Seven geographically different regions were designated based on "cost of living index" and "urban to rural population ratio". Hospital costs, LOS, in-hospital mortality, and the frequency with which surgeons performed pancreaticoduodenectomy were evaluated for these regions. RESULTS: Median hospital costs for pancreaticoduodenectomy by region ranged from $101,436-$214,971. Median hospital costs by region correlated positively with LOS (p < 0.0001) and in-hospital mortality (p < 0.0001), and negatively with the frequency of pancreaticoduodenectomies performed by high-volume surgeons (p < 0.0001). CONCLUSIONS: There are regional differences for hospital costs and outcome with pancreaticoduodenectomy in Florida. Regions with lower costs had more pancreaticoduodenectomies performed by high-volume surgeons, shorter LOS, and lower in-hospital mortality rates. Regional differences in cost and quality-of-care need to be studied and abrogated to provide uniform optimal care.

Molecular profiles in foregut oncology.

Oncology is and will continue to evolve resulting from a better understanding of the biology and intrinsic genetic profile of each cancer. Tumor biomarkers and targeted therapies are the new face of precision medicine, so it is essential for all physicians caring for cancer patients to understand and assist patients in understanding the role and importance of such markers and strategies to target them. This review was initiated in an attempt to identify, characterize, and discuss literature supporting clinically relevant molecular markers and interventions. The efficacy of targeting specific markers will be examined with data from clinical trials focusing on treatments for esophageal, gastric, liver, gallbladder, biliary tract, and pancreatic cancers.

Financial Benefits of a Hepatopancreaticobiliary Program.

Financial implications of developing a hepatopancreaticobiliary (HPB) center have not been considered. We undertook this study to determine hospital income associated with a new HPB center and to gauge the opportunity cost associated with such a center. Operations included were based on the HPB fellowship curriculum and the six most commonly undertaken general surgery operations. The income with "core" HPB operations (n = 93) and the six most frequently undertaken general surgery operations (n = 583) at one hospital from June 2012 to June 2013 were determined. Patients were not screened based on the ability to pay. Data are reported as mean ± standard deviation. Per operation, hospital income with HPB operations and general surgery operations were $15,583.20 ± $45,909.41 and $5,162.22 ± $33,679.10 (P < 0.005), respectively. Accordingly, net incomes of $1,449,238.04 (n = 93) and $3,009,572.78 (n = 583) were observed. Although general surgery operations are ubiquitous, HPB centers are uncommonly pursued at most hospitals, in part due to the patient volumes necessary to meet the expertise required. A "core" HPB operation produces triple the net income of a general surgery operation. Accordingly, significant financial benefit is achievable with the development of an HPB center when adequate volume is realized.