Histotripsy: A Method for Mechanical Tissue Ablation with Ultrasound.

Histotripsy is a relatively new therapeutic ultrasound technology to mechanically liquefy tissue into subcellular debris using high-amplitude focused ultrasound pulses. In contrast to conventional high-intensity focused ultrasound thermal therapy, histotripsy has specific clinical advantages: the capacity for real-time monitoring using ultrasound imaging, diminished heat sink effects resulting in lesions with sharp margins, effective removal of the treated tissue, a tissue-selective feature to preserve crucial structures, and immunostimulation. The technology is being evaluated in small and large animal models for treating cancer, thrombosis, hematomas, abscesses, and biofilms; enhancing tumor-specific immune response; and neurological applications. Histotripsy has been recently approved by the US Food and Drug Administration to treat liver tumors, with clinical trials undertaken for benign prostatic hyperplasia and renal tumors. This review outlines the physical principles of various types of histotripsy; presents major parameters of the technology and corresponding hardware and software, imaging methods, and bioeffects; and discusses the most promising preclinical and clinical applications.

Insights from in vivo preclinical cancer studies with histotripsy.

Histotripsy is the first noninvasive, non-ionizing, and non-thermal ablation technique that mechanically fractionates target tissue into acellular homogenate via controlled acoustic cavitation. Histotripsy has been evaluated for various preclinical applications requiring noninvasive tissue removal including cancer, brain surgery, blood clot and hematoma liquefaction, and correction of neonatal congenital heart defects. Promising preclinical results including local tumor suppression, improved survival outcomes, local and systemic anti-tumor immune responses, and histotripsy-induced abscopal effects have been reported in various animal tumor models. Histotripsy is also being investigated in veterinary patients with spontaneously arising tumors. Research is underway to combine histotripsy with immunotherapy and chemotherapy to improve therapeutic outcomes. In addition to preclinical cancer research, human clinical trials are ongoing for the treatment of liver tumors and renal tumors. Histotripsy has been recently approved by the FDA for noninvasive treatment of liver tumors. This review highlights key learnings from in vivo shock-scattering histotripsy, intrinsic threshold histotripsy, and boiling histotripsy cancer studies treating cancers of different anatomic locations and discusses the major considerations in planning in vivo histotripsy studies regarding instrumentation, tumor model, study design, treatment dose, and post-treatment tumor monitoring.

Magic bubbles: utilizing histotripsy to modulate the tumor microenvironment and improve systemic anti-tumor immune responses.

Focused Ultrasound (FUS) is emerging as a promising primary and adjunct therapy for the treatment of cancer. This includes histotripsy, which is a noninvasive, non-ionizing, non-thermal ultrasound guided ablation modality. As histotripsy has progressed from bench-to-bedside, it has become evident that this therapy has benefits beyond local tumor ablation. Specifically, histotripsy has the potential to shift the local tumor microenvironment from immunologically 'cold' to 'hot'. This is associated with the production of damage associated molecular patterns, the release of a selection of proinflammatory mediators, and the induction of inflammatory forms of cell death in cells just outside of the treatment zone. In addition to the induction of this innate immune response, histotripsy can also improve engagement of the adaptive immune system and promote systemic anti-tumor immunity targeting distal tumors and metastatic lesions. These tantalizing observations suggest that, in settings of widely metastatic disease burden, selective histotripsy of a limited number of accessible tumors could be a means of maximizing responsiveness to systemic immunotherapy. More work is certainly needed to optimize treatment strategies that best synergize histotripsy parameters with innate and adaptive immune responses. Likewise, rigorous clinical studies are still necessary to verify the presence and repeatability of these phenomena in human patients. As this technology nears regulatory approval for clinical use, it is our expectation that the insights and immunomodulatory mechanisms summarized in this review will serve as directional guides for rational clinical studies to validate and optimize the potential immunotherapeutic role of histotripsy tumor ablation.

Very Early Recurrence After Curative-Intent Surgery for Gastric Adenocarcinoma.

BACKGROUND: Recurrence after curative-intent surgery can occur in more than 50% of gastric cancer (GC) patients. We sought to identify predictors of very early recurrence (VER) among GC patients who underwent curative-intent surgery. METHODS: A multi-institutional database of GC patients undergoing curative-intent surgery between 2000 and 2020 at 8 major institutions was queried. VER was defined as local or distant tumor recurrence within 6 months from surgery. Univariable Cox proportional hazard models were used to evaluate the predictive value of clinical-pathological features on VER. A regularized Cox regression model was employed to build a predictive model of VER and recurrence within 12 months. The discriminant ability of the Cox regularized models was evaluated by reporting a ROC curve together with the calibration plot, considering 200 runs. RESULTS: Among 1133 patients, 65 (16.0%) patients experienced a VER. Preoperative symptoms (HR 1.198), comorbidities (HR 1.289), tumor grade (HR 1.043), LNR (HR 4.339) and T stage (HR 1.639) were associated with an increased likelihood of VER. Model performance was very good at predicting VER at 6 months (AUC of 0.722) and 12 months (AUC 0.733). Two nomograms to predict 6-month and 12-month VER were built based on the predictive model. A higher nomogram score was associated with worse prognosis. There was good prediction between observed and estimated VER with minimal evidence of overfitting and good performance on internal bootstrapping validation. CONCLUSION: One in 6 patients experienced VER following curative-intent surgery for GC. Nomograms to predict risk of VER performed well on internal validation, and stratified patients into distinct prognostic groups relative to 6- and 12-months recurrence.

Development of a Prognostic Nomogram and Nomogram Software Application Tool to Predict Overall Survival and Disease-Free Survival After Curative-Intent Gastrectomy for Gastric Cancer.

BACKGROUND: We sought to derive and validate a prediction model of survival and recurrence among Western patients undergoing resection of gastric cancer. METHODS: Patients who underwent curative-intent surgery for gastric cancer at seven US institutions and a major Italian center from 2000 to 2020 were included. Variables included in the multivariable Cox models were identified using an automated model selection procedure based on an algorithm. Best models were selected using the Bayesian information criterion (BIC). The performance of the models was internally cross-validated via the bootstrap resampling procedure. Discrimination was evaluated using the Harrell's Concordance Index and accuracy was evaluated using calibration plots. Nomograms were made available as online tools. RESULTS: Overall, 895 patients met inclusion criteria. Age (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.17-1.84), presence of preoperative comorbidities (HR 1.66, 95% CI 1.14-2.41), lymph node ratio (LNR; HR 1.72, 95% CI 1.42-2.01), and lymphovascular invasion (HR 1.81, 95% CI 1.33-2.45) were associated with overall survival (OS; all p < 0.01), whereas tumor location (HR 1.93, 95% CI 1.23-3.02), T category (Tis-T1 vs. T3: HR 0.31, 95% CI 0.14-0.66), LNR (HR 1.82, 95% CI 1.45-2.28), and lymphovascular invasion (HR 1.49; 95% CI 1.01-2.22) were associated with disease-free survival (DFS; all p < 0.05) The models demonstrated good discrimination on internal validation relative to OS (C-index 0.70) and DFS (C-index 0.74). CONCLUSIONS: A web-based nomograms to predict OS and DFS among gastric cancer patients following resection demonstrated good accuracy and discrimination and good performance on internal validation.

Survival benefit with adjuvant radiotherapy after resection of distal cholangiocarcinoma: A propensity-matched National Cancer Database analysis.

BACKGROUND: No convincing evidence for the benefit of adjuvant radiotherapy (RT) following resection of distal cholangiocarcinoma (dCCA) exists, especially for lower-risk (margin- or node-negative) disease. Hence, the association of adjuvant RT on survival after surgical resection of dCCA was compared with no adjuvant RT (noRT). METHODS: Using National Cancer Database data from 2004 to 2016, patients undergoing pancreatoduodenectomy for nonmetastatic dCCA were identified. Patients with neoadjuvant RT and chemotherapy and survival <6 months were excluded. Propensity score matching was used to account for treatment-selection bias. A multivariable Cox proportional hazards model was then used to analyze the association of adjuvant RT with survival. RESULTS: Of 2162 (34%) adjuvant RT and 4155 (66%) noRT patients, 1509 adjuvant RT and 1509 noRT patients remained in the cohort after matching. The rates of node-negative disease (N0), node-positive disease (N+), and unknown node status (Nx) were 39%, 51%, and 10%, respectively. After matching, adjuvant RT was associated with improved survival (median, 29.3 vs 26.8 months; P < .001), which remained after multivariable adjustment (HR, 0.86; 95% CI, 0.80-0.93; P < .001). Multivariable interaction analyses showed this benefit was seen irrespective of nodal status (N0: HR, 0.77; 95% CI, 0.66-0.89; P < .001; N+: HR, 0.79; 95% CI, 0.71-0.89; P < .001) and margin status (R0: HR, 0.58; 95% CI, 0.50-0.67; P < .001; R1: HR, 0.87; 95% CI, 0.78-0.96; P = .007). Stratified analyses by nodal and margin status demonstrated consistent results. CONCLUSIONS: Adjuvant RT after dCCA resection was associated with a survival benefit in patients, even in patients with margin- or node-negative resections. Adjuvant RT should be considered routinely irrespective of margin and nodal status after resection for dCCA. LAY SUMMARY: Adjuvant radiotherapy after resection of distal cholangiocarcinoma was associated with a survival benefit in patients, even in patients with margin-negative or node-negative resections. Adjuvant radiotherapy should be considered routinely irrespective of margin and nodal status after resection of distal cholangiocarcinoma.

Association of Adjuvant Radiotherapy With Survival After Margin-negative Resection of Pancreatic Ductal Adenocarcinoma: A Propensity-matched National Cancer Database (NCDB) Analysis.

INTRODUCTION: There is conflicting evidence for the benefit of adjuvant radiotherapy (RT) after resection of pancreatic ductal adenocarcinoma (PDAC), especially for margin-negative (R0) resections. We aimed to evaluate the association of adjuvant RT with survival after R0 resection of PDAC. METHODS: Using National Cancer Database (NCDB) data from 2004 to 2013, we identified patients with R0 resection of nonmetastatic PDAC. Patients with neoadjuvant radiotherapy and chemotherapy and survival <6 months were excluded. Propensity score matching was used to account for treatment selection bias. A multivariable Cox proportional hazards model was then used to analyze the association of RT with survival. RESULTS: Of 4547 (36%) RT and 7925 (64%) non-RT patients, 3860 RT and 3860 non-RT patients remained in the cohort after matching. Clinicopathologic and demographic variables were well balanced after matching. Lymph node metastases were present in 68% (44% N1, 24% N2). After matching, RT was associated with higher survival (median 25.8 vs 23.9 mo, 5-yr 27% vs 24%, P < 0.001). After multivariable adjustment, RT remained associated with a survival benefit (HR 0.89, 95% CI 0.84-0.94, P < 0.001). Stratified and multivariable interaction analyses showed that this benefit was restricted to patients with node-positive disease: N1 (HR: 0.68, CI95%: 0.62-0.76, P = 0.007) and N2 (HR: 0.59, CI95%: 0.54-0.64, P = 0.04). CONCLUSIONS: In this large retrospective cohort study, adjuvant RT after R0 PDAC resection was associated with a survival benefit in patients with node-positive disease. Adjuvant RT should be considered after R0 resection of PDAC with node-positive disease.

Long-Term Outcomes after Spleen-Preserving Distal Pancreatectomy for Pancreatic Neuroendocrine Tumors: Results from the US Neuroendocrine Study Group.

BACKGROUND: The adoption of spleen-preserving distal pancreatectomy (SPDP) for malignant disease such as pancreatic neuroendocrine tumors (pNETs) has been controversial. The objective of the current study was to assess the impact of SPDP on outcomes of patients with pNETs. METHODS: Patients undergoing a distal pancreatectomy for pNET between 2002 and 2016 were identified in the US Neuroendocrine Tumor Study Group database. Propensity score matching (PSM) was used to compare short- and long-term outcomes of patients undergoing SPDP versus distal pancreatectomy with splenectomy (DPS). RESULTS: Among 621 patients, 103 patients (16.6%) underwent an SPDP. Patients who underwent SPDP were more likely to have lower BMI (median, 27.5 [IQR 24.0-31.2] vs. 28.7 [IQR 25.7-33.6]; p = 0.005) and have undergone minimally invasive surgery (n = 56, 54.4% vs. n = 185, 35.7%; p < 0.001). After PSM, while the median total number of lymph nodes examined among patients who underwent an SPDP was lower compared with DPS (3 [IQR 1-8] vs. 9 [5-13]; p < 0.001), 5-year overall survival (OS) and recurrence-free survival (RFS) were comparable (OS: 96.8 vs. 92.0%, log-rank p = 0.21, RFS: 91.1 vs. 84.7%, log-rank p = 0.93). In addition, patients undergoing SPDP had less intraoperative blood loss (median, 100 mL [IQR 10-250] vs. 150 mL [IQR 100-400]; p = 0.001), lower incidence of serious complications (n = 13, 12.8% vs. n = 28, 27.5%; p = 0.014), and shorter length of stay (median: 5 days [IQR 4-7] vs. 6 days [IQR 5-13]; p = 0.049) compared with patients undergoing DPS. CONCLUSION: SPDP for pNET was associated with acceptable perioperative and long-term outcomes that were comparable to DPS. SPDP should be considered for patients with pNET.

Impact of Insurance Status on Survival in Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: Insurance status predicts access to medical care in the USA. Previous studies have shown uninsured patients with some malignancies have worse outcomes than insured patients. The impact of insurance status on patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is unclear. PATIENTS AND METHODS: A retrospective cohort study of adult patients with resected GEP-NETs was performed using the US Neuroendocrine Tumor Study Group (USNETSG) database (2000-2016). Demographic and clinical factors were compared by insurance status. Patients ≥ 65 years were excluded, as these patients are almost universally covered by Medicare. Kaplan-Meier and log-rank analyses were used for survival analysis. Logistic regression was used to assess factors associated with overall survival (OS). RESULTS: The USNETSG database included 2022 patients. Of those, 1425 were aged 18-64 years at index operation and were included in our analysis. Uninsured patients were more likely to have an emergent operation (7.9% versus 2.5%, p = 0.01) and less likely to receive postoperative somatostatin analog therapy (1.6% versus 9.9%, p = 0.03). OS at 1, 5, and 10 years was significantly higher for insured patients (96.3%, 88.2%, and 73.8%, respectively) than uninsured patients (87.7%, 71.9%, and 44.0%, respectively) (p < 0.01). On Cox multivariate regression analysis controlling for T/M stage, tumor grade, ASA class, and income level, being uninsured was independently associated with worse OS [hazard ratio (HR) 2.69, 95% confidence interval (CI) 1.32-5.48, p = 0.006]. CONCLUSIONS: Insurance status is an independent predictor of survival in patients with GEP-NETs. Our study highlights the importance of access to medical care, disparities related to insurance status, and the need to mitigate these disparities.

A Novel Validated Recurrence Risk Score to Guide a Pragmatic Surveillance Strategy After Resection of Pancreatic Neuroendocrine Tumors: An International Study of 1006 Patients.

OBJECTIVE: Despite heterogeneous biology, similar surveillance schemas are utilized after resection of all pancreatic neuroendocrine tumors (PanNETs). Given concerns regarding excess radiation exposure and financial burden, our aim was to develop a prognostic score for disease recurrence to guide individually tailored surveillance strategies. METHODS: All patients with primary nonfunctioning, nonmetastatic well/moderately differentiated PanNETs who underwent curative-intent resection at 9-institutions from 2000 to 2016 were included (n = 1006). A Recurrence Risk Score (RRS) was developed from a randomly selected derivation cohort comprised of 67% of patients and verified on the validation-cohort comprised of the remaining 33%. RESULTS: On multivariable analysis, patients within the derivation cohort (n = 681) with symptomatic tumors (jaundice, pain, bleeding), tumors >2 cm, Ki67 >3%, and lymph node (LN) (+) disease had increased recurrence. Each factor was assigned a score based on their weighted odds ratio that formed a RRS of 0 to 10: symptomatic = 1, tumor >2 cm = 2, Ki67 3% to 20% = 1, Ki67 >20% = 6, LN (+) = 1. Patients were grouped into low- (RRS = 0-2; n = 247), intermediate-(RRS = 3-5; n = 204), or high (RRS = 6-10; n = 9)-risk groups. At 24 months, 33% of high RRS recurred, whereas only 2% of low and 14% of intermediate RRS recurred. This persisted in the validation cohort (n = 325). CONCLUSIONS: This international, novel, internally validated RRS accurately stratifies recurrence-free survival for patients with resected PanNETs. Given their unique recurrence patterns, surveillance intervals of 12, 6, and 3 months are proposed for low, intermediate, and high RRS patients, respectively, to minimize radiation exposure and optimize cost/resource utilization.

Defining the Role of Lymphadenectomy for Pancreatic Neuroendocrine Tumors: An Eight-Institution Study of 695 Patients from the US Neuroendocrine Tumor Study Group.

BACKGROUND: Preoperative factors that reliably predict lymph node (LN) metastases in pancreatic neuroendocrine tumors (PanNETs) are unclear. The number of LNs needed to accurately stage PanNETs has not been defined. METHODS: Patients who underwent curative-intent resection of non-functional PanNETs at eight institutions from 2000 to 2016 were analyzed. Preoperative factors associated with LN metastases were identified. A procedure-specific target for LN retrieval to accurately stage patients was determined. RESULTS: Of 695 patients who underwent resection, 33% of tumors were proximal (head/uncinate) and 67% were distal (neck/body/tail). Twenty-six percent of patients (n = 158) had LN-positive disease, which was associated with a worse 5-year recurrence-free survival (RFS; 60% vs. 86%; p < 0.001). The increasing number of positive LNs was not associated with worse RFS. Preoperative factors associated with positive LNs included tumor size ≥ 2 cm (odds ratio [OR] 6.6; p < 0.001), proximal location (OR 2.5; p < 0.001), moderate versus well-differentiation (OR 2.1; p = 0.006), and Ki-67 ≥ 3% (OR 3.1; p < 0.001). LN metastases were also present in tumors without these risk factors: < 2 cm (9%), distal location (19%), well-differentiated (23%), and Ki-67 < 3% (16%). Median LN retrieval was 13 for pancreatoduodenectomy (PD), but only 9 for distal pancreatectomy (DP). Given that PD routinely includes a complete regional lymphadenectomy, a minimum number of LNs to accurately stage patients was not identified. However, for DP, removal of less than seven LNs failed to discriminate 5-year RFS between LN-positive and LN-negative patients (less than seven LNs: 72% vs. 83%, p = 0.198; seven or more LNs: 67% vs. 86%; p = 0.002). CONCLUSIONS: Tumor size ≥ 2 cm, proximal location, moderate differentiation, and Ki-67 ≥ 3% are preoperative factors that predict LN positivity in resected non-functional PanNETs. Given the 9-23% incidence of LN metastases in patients without such risk factors, routine regional lymphadenectomy should be considered. PD inherently includes sufficient LN retrieval, while DP should aim to remove seven or more LNs for accurate staging.

Therapeutic index of lymphadenectomy among patients with pancreatic neuroendocrine tumors: A multi-institutional analysis.

BACKGROUND: The benefit derived from lymph node dissection (LND) in patients with pancreatic neuroendocrine tumors (pNETs) based on clinicopathological characteristics remains unclear. METHODS: Patients undergoing surgery for pNET between 1997 and 2016 were identified using a multi-institutional dataset. The therapeutic index of LND relative to patient characteristics was calculated. RESULTS: Among 647 patients, the median number of lymph nodes (LNs) evaluated was 10 (interquartile range: 4-16) and approximately one quarter of patients had lymph node metastasis (LNM) (N = 159, 24.6%). Among patients with LNM, 5-year recurrence-free survival was 56.0%, reflecting a therapeutic index value of 13.8. The therapeutic index was highest among patients with a moderately/poorly-differentiated pNET (21.5), Ki-67 ≥ 3% (20.1), tumor size ≥2.0 cm (20.0), and tumor location at the head of the pancreas (20.0). Patients with ≥8 LNs evaluated had a higher therapeutic index than patients who had 1 to 7 LNs evaluated (≥8: 17.9 vs 1-7: 7.5; difference of index: 11.4). CONCLUSION: LND was mostly beneficial among patients with pNETs >2 cm, Ki-67 ≥ 3%, and lesions located at the pancreatic head as identification of LNM was most common among individuals with these tumor characteristics. Evaluation of ≥8 LNs was associated with a higher likelihood of identifying LNM as well as a higher therapeutic index, and therefore this number of LNs should be considered the goal.

Critical evaluation of the American Joint Commission on Cancer (AJCC) 8th edition staging system for patients with Hepatocellular Carcinoma (HCC): A Surveillance, Epidemiology, End Results (SEER) analysis.

BACKGROUND: Recently, the American Joint Committee on Cancer (AJCC) released its 8th edition changes to the staging system for hepatocellular cancer (HCC). We sought to validate the 8th edition staging system and compare the performance to the 7th edition using a population-based data set. METHODS: Using the Surveillance, Epidemiology and End Results (SEER) database (1998-2013), patients undergoing resection or transplant for non-metastatic HCC were identified. Overall survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Concordance indices (c-indices) were calculated from Cox proportional hazards models to evaluate discriminatory power. RESULTS: The study included 8918 patients resected (63%) or transplanted (37%) for HCC. Nodal staging was performed in 19%, of whom 5% had positive nodes. The c-index for the AJCC 8th edition staging system was 0.60, similar to that for the 7th edition (0.59). Survival was better for solitary tumors >2 cm with vascular invasion than for multifocal tumors <5 cm (median not reached vs 57 months, P < 0.0001), although the staging system groups these tumors together as T2. For multifocal tumors ≤5 cm, those with vascular invasion had worse survival than those without (median 42 vs 50 months, P < 0.001), although the staging system draws no such distinction. CONCLUSION: The AJCC 8th edition staging system for HCC performs similarly to the 7th edition. Future revisions should consider substratification of early HCC, specifically by distinguishing solitary tumors >2 cm from multifocal tumors ≤5 cm, and by considering the prognostic impact of vascular invasion in multifocal tumors ≤5 cm. Future studies should aim to validate these findings.

Validation of the American Joint Commission on Cancer (AJCC) 8th Edition Staging System for Patients with Pancreatic Adenocarcinoma: A Surveillance, Epidemiology and End Results (SEER) Analysis.

BACKGROUND: The 8th edition of the AJCC staging system for pancreatic cancer incorporated several significant changes. This study sought to evaluate this staging system and assess its strengths and weaknesses relative to the 7th edition AJCC staging system. METHODS: Using the Surveillance, Epidemiology and End Results (SEER) database (2004-2013), 8960 patients undergoing surgical resection for non-metastatic pancreatic adenocarcinoma were identified. Overall survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Concordance indices (c-index) were calculated to evaluate the discriminatory power of both staging systems. The Cox proportional hazards model was used to determine the impact of T and N classification on overall survival. RESULTS: The c-index for the AJCC 8th staging system [0.60; 95% confidence interval (CI), 0.59-0.61] was comparable with that for the 7th edition AJCC staging system (0.59; 95% CI, 0.58-0.60). Stratified analyses for each N classification system demonstrated a diminishing impact of T classification on overall survival with increasing nodal involvement. The corresponding c-indices were 0.58 (95% CI, 0.55-0.60) for N0, 0.53 (95% CI, 0.51-0.55) for N1, and 0.53 (95% CI, 0.50-0.56) for N2 classification. CONCLUSION: This is the first large-scale validation of the AJCC 8th edition staging system for pancreatic cancer. The revised system provides discrimination similar to that of the 7th-edition system. However, the 8th-edition system allows for finer stratification of patients with resected tumors according to extent of nodal involvement.

Time to Initiation of Adjuvant Chemotherapy in Pancreas Cancer: A Multi-Institutional Experience.

BACKGROUND: Despite randomized trials addressing adjuvant therapy (AT) for pancreas cancer, the ideal time to initiate therapy remains undefined. Retrospective analyses of the ESPAC-3 trial demonstrated that time to initiation of AT did not impact overall survival (OS). Given the absence of confirmatory data outside of a clinical trial, we sought to determine if AT timing in routine clinical practice is associated with OS differences. METHODS: Perioperative data of pancreatectomies for ductal adenocarcinoma from five institutions (2005-2015) were assessed. Delay in AT was defined as initiation >12 weeks after surgery. Multivariate analysis was performed to identify predictors of mortality. RESULTS: Of 867 patients, 172 (19.8%) experienced omission of AT. Improved OS was observed in patients who received AT compared with patients who did not (24.8 vs. 19.1 months, p < 0.01). Information on time to initiation of AT was available in 488 patients, of whom 407 (83.4%) and 81 (16.6%) received chemotherapy ≤12 and >12 weeks after surgery, respectively. There were no differences in recurrence-free survival or OS (all p > 0.05) between the timely and delayed AT groups. After controlling for perioperative characteristics and tumor pathology, patients who initiated AT ≤ 12 or > 12 weeks after surgery had a 50% lower odds of mortality than patients who only underwent resection (p < 0.01). CONCLUSIONS: In a multi-institutional experience of resected pancreas cancer, delayed initiation of AT was not associated with poorer survival. Patients who do not receive AT within 12 weeks after surgery are still appropriate candidates for multimodal therapy and its associated survival benefit.

The diagnosis of pancreatic mucinous cystic neoplasm and associated adenocarcinoma in males: An eight-institution study of 349 patients over 15 years.

BACKGROUND: Per WHO, 2000 classification, pancreatic mucinous cystic neoplasms (MCN) are defined by presence of ovarian stroma, and are primarily located in the pancreatic body/tail of females. The incidence of MCN and associated malignancy in males, since, standardization of MCN diagnostic-criteria is unknown. METHODS: MCN resections from 2000 to 2014 at eight institutions of the Central-Pancreas-Consortium were included, and divided into early (2000-2007) and late (2008-2014) time-periods. Primary aim was to characterize MCN and associated adenocarcinoma/high-grade-dysplasia (AC/HGD) in males versus females over time. RESULTS: Of 1667 resections for pancreatic cystic lesions, 349 pts (21%) had MCNs: 310 (89%) female, 39 (11%) male. Patients were equally divided between early (n = 173) and late (n = 176) time-periods. MCN in male-patients decreased over time (early: 15%, late: 7%; P = 0.036), as did pancreatic head/neck location (early: 22%, late: 11%; P = 0.01). MCN-associated AC/HGD was more frequent in males versus females (39 vs. 12%; P < 0.001). The overall rate of MCN-associated AC/HGD remained stable (early: 17%, late: 13%; P = 0.4), and was identical in males (39%) over both time-periods. Males with AC/HGD had more LN-positive disease versus females (57 vs. 22%; P = 0.039). CONCLUSIONS: As the diagnostic-criteria of MCN have standardized over time, MCN diagnosis has decreased in males and head/neck location. Despite this, MCN-associated adenocarcinoma/high-grade dysplasia has been stable and remains high in males. Any male with suspected MCN, regardless of location, should undergo resection.

A Multi-institutional Comparison of Perioperative Outcomes of Robotic and Open Pancreaticoduodenectomy.

OBJECTIVES: Limited data exist comparing robotic and open approaches to pancreaticoduodenectomy (PD). We performed a multicenter comparison of perioperative outcomes of robotic PD (RPD) and open PD (OPD). METHODS: Perioperative data for patients who underwent postlearning curve PD at 8 centers (8/2011-1/2015) were assessed. Univariate analyses of clinicopathologic and treatment factors were performed, and multivariable models were constructed to determine associations of operative approach (RPD or OPD) with perioperative outcomes. RESULTS: Of the 1028 patients, 211 (20.5%) underwent RPD (4.7% conversions) and 817 (79.5%) underwent OPD. As compared with OPD, RPD patients had higher body mass index, rates of prior abdominal surgery, and softer pancreatic remnants, whereas OPD patients had a higher percentage of pancreatic ductal adenocarcinoma cases, and greater proportion of nondilated (<3 mm) pancreatic ducts. On multivariable analysis, as compared with OPD, RPD was associated with longer operative times [mean difference = 75.4 minutes, 95% confidence interval (CI) 17.5-133.3, P = 0.01], reduced blood loss (mean difference = -181 mL, 95% CI -355-(-7.7), P = 0.04) and reductions in major complications (odds ratio = 0.64, 95% CI 0.47-0.85, P = 0.003). No associations were demonstrated between operative approach and 90-day mortality, clinically relevant postoperative pancreatic fistula and wound infection, length of stay, or 90-day readmission. In the subset of 522 (51%) pancreatic ductal adenocarcinomas, operative approach was not a significant independent predictor of margin status or suboptimal lymphadenectomy (<12 lymph nodes harvested). CONCLUSIONS: Postlearning curve RPD can be performed with similar perioperative outcomes achieved with OPD. Further studies of cost, quality of life, and long-term oncologic outcomes are needed.

Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice.

Adoptive cell transfer (ACT) melanoma immunotherapy typically employs acutely activated effector CD8+ T cells for their ability to rapidly recognize and clear antigen. We have previously observed that effector CD8+ T cells are highly susceptible to melanoma-induced suppression, whereas memory CD8+ T cells are not. Although memory T cells have been presumed to be potentially advantageous for ACT, the kinetics of local and systemic T cell responses after effector and memory ACT have not been compared. B16F10 melanoma cells stably transfected to express very low levels of the lymphocytic choriomeningitis virus (LCMV) peptide GP33 (B16GP33) were inoculated into syngeneic C57BL/6 mice. Equal numbers of bona fide naïve, effector, or memory phenotype GP33-specific CD8+ T cells were adoptively transferred into mice 1 day after B16GP33 inoculation. The efficacy of ACT immunotherapy was kinetically assessed using serial tumor measurements and flow cytometric analyses of local and systemic CD8+ T cell responses. Control of B16GP33 tumor growth, persistence of adoptively transferred CD8+ cells, intratumoral infiltration of CD8+ T cells, and systemic CD8+ T cell responsiveness to GP33 were strongest after ACT of memory CD8+ T cells. Following surgical tumor resection and melanoma tumor challenge, only mice receiving memory T cell-based ACT immunotherapy exhibited durable tumor-specific immunity. These findings demonstrate how the use of non-expanded memory CD8+ T cells may enhance ACT immunotherapeutic efficacy.