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Postoperative pancreatic fistula is a common complication of pancreatic surgery. In this trial, patients undergoing pancreatic resection who received pasireotide, a somatostatin analogue, had a decreased occurrence of postoperative pancreatic fistula, leak, or abscess. Although mortality after pancreatectomy has decreased to approximately 2% at high-volume centers, the operative morbidity after these procedures has remained between 30% and 50%. 1 , 2 Postoperative pancreatic fistula, leak, and abscess are complications that result from leakage of pancreatic exocrine secretions at the anastomosis or closure of the pancreatic remnant. Postoperative pancreatic fistula is the most common major complication after pancreatectomy, with reported rates between 10% and 28%. Studies suggest that patients in whom postoperative pancreatic fistula develops have a risk of death that is approximately doubled. 3 , 4 Because of the magnitude of this problem, numerous studies have investigated methods . . .

BackgroundThe impact of primary tumor location on overall survival (OS), recurrence-free survival (RFS), and long-term outcomes has not been well established in patients undergoing potentially curative resection of colorectal liver metastases (CRLM).MethodsA single-institution database was queried for initial resections for CRLM 1992–2004. Primary tumor location determined by chart review (right = cecum to transverse; left = splenic flexure to sigmoid). Rectal cancer (distal 16 cm), multiple primaries, and unknown location were excluded. Kaplan–Meier and Cox regression methods were used. Cure was defined as actual 10-year survival with either no recurrence or resected recurrence with at least 3 years of disease-free follow-up.ResultsA total of 907 patients were included with a median follow-up of 11 years; 578 patients (64%) had left-sided and 329 (36%) right-sided primaries. Median OS for patients with a left-sided primary was 5.2 years (95% confidence interval [CI] 4.6–6.0) versus 3.6 years (95% CI 3.2–4.2) for right-sided (p = 0.004). On multivariable analysis, the hazard ratio for right-sided tumors was 1.22 (95% CI 1.02–1.45, p = 0.028) after adjusting for common clinicopathologic factors. Median RFS was marginally different stratified by primary location (1.3 vs. 1.7 years; p = 0.065). On multivariable analysis, location of primary was not significantly associated with RFS (p = 0.105). Observed cure rates were 22% for left-sided and 20% for right-sided tumors.ConclusionsAmong patients undergoing resection of CRLM, left-sided primary tumors were associated with improved median OS. However, long-term survival and recurrence-free survival were not significantly different stratified by primary location. Patients with left-sided primary tumors displayed a prolonged clinical course suggestive of more indolent biology.

Background To assess long-term oncologic outcomes of robotic-assisted liver resection (RLR) for colorectal cancer (CRC) metastases as compared to a propensity-matched cohort of laparoscopic liver resections (LLR). Although safety and short-term outcomes of RLR have been described and previously compared to LLR, long-term and oncologic data are lacking. Methods A retrospective study was performed of all patients who underwent RLR and LLR for CRC metastases at six high-volume centers in the USA and Europe between 2002 and 2017. Propensity matching was used to match baseline characteristics between the two groups. Data were analyzed with a focus on postoperative and oncologic outcomes, as well as long-term recurrence and survival. Results RLR was performed in 115 patients, and 514 patients underwent LLR. Following propensity matching 115 patients in each cohort were compared. Perioperative outcomes including mortality, morbidity, reoperation, readmission, intensive care requirement, length-of-stay and margin status were not statistically different. Both prematching and postmatching analyses demonstrated similar overall survival (OS) and disease-free survival (DFS) between RLR and LLR at 5 years (61 vs. 60% OS, p  = 0.87, and 38 vs. 31% DFS, p  = 0.25, prematching; 61 vs. 60% OS, p  = 0.78, and 38 vs. 44% DFS, p  = 0.62, postmatching). Conclusions Propensity score matching with a large, multicenter database demonstrates that RLR for colorectal metastases is feasible and safe, with perioperative and long-term oncologic outcomes and survival that are largely comparable to LLR.

Colorectal cancer (CRC) is a major cause of human death. Mortality is primarily due to metastatic organ colonization, with the liver being the main organ affected. We modeled metastatic CRC (mCRC) liver colonization using patient-derived primary and metastatic tumor xenografts (PDX). Such PDX modeling predicted patient survival outcomes. In vivo selection of multiple PDXs for enhanced metastatic colonization capacity upregulated the gluconeogenic enzyme PCK1, which enhanced liver metastatic growth by driving pyrimidine nucleotide biosynthesis under hypoxia. Consistently, highly metastatic tumors upregulated multiple pyrimidine biosynthesis intermediary metabolites. Therapeutic inhibition of the pyrimidine biosynthetic enzyme DHODH with leflunomide substantially impaired CRC liver metastatic colonization and hypoxic growth. Our findings provide a potential mechanistic basis for the epidemiologic association of anti-gluconeogenic drugs with improved CRC metastasis outcomes, reveal the exploitation of a gluconeogenesis enzyme for pyrimidine biosynthesis under hypoxia, and implicate DHODH and PCK1 as metabolic therapeutic targets in CRC metastatic progression. Colorectal cancer, also known as bowel cancer, is the second most deadly cancer in the United States, where it affects over 140,000 people each year. This cancer often spreads to the liver, in a process known as metastasis. To do this, the colorectal cancer cells must survive the low oxygen levels found in the blood that carries them from the gut to the liver, and in the liver itself. The majority of colorectal cancer cells that arrive in the liver die, but some survive leading to secondary tumors. To investigate how the colorectal cancer cells that survive and metastasize to the liver accomplish this feat, Yamaguchi, Weinberg, Nguyen et al. took colorectal tumors from patients and introduced them into mice. This showed that tumors from patients with the worst outcomes tended to metastasize more efficiently in mice. Next, Yamaguchi et al. looked to see which genes were active in the colorectal cancer cells that were able to metastasize and compared them to those that were active in the cells that could not. This analysis revealed that the gene coding for a protein called PCK1 was more active in the cells that could metastasize. In healthy cells, PCK1 promotes the generation of the sugar glucose, and Yamaguchi et al. observed that, in a low oxygen environment, higher levels of PCK1 allowed colorectal cancer cells to proliferate faster. Unexpectedly, this was due to PCK1 increasing the production of a molecule needed to make nucleotides, which are the building blocks for DNA and RNA. Consistent with this, metastasizing colorectal cancer cells generated more nucleotide precursors, and inhibiting the enzyme involved in nucleotide synthesis (DHODH) with an arthritis drug called leflunomide stopped colorectal cancer cells from spreading. Metastasizing colorectal cancer cells depend on PCK1 and the nucleotide-synthesizing enzyme to grow, so therapies that target these proteins may help more patients to survive this kind of cancer. The findings also suggest that the arthritis drug leflunomide should be explored further as a potential drug for the treatment of colorectal cancer.

BackgroundPancreatic cancer is a highly lethal cancer with no established a priori markers of survival. Existing nomograms rely mainly on post-resection data and are of limited utility in directing surgical management. This study investigated the use of quantitative computed tomography (CT) features to preoperatively assess survival for pancreatic ductal adenocarcinoma (PDAC) patients.MethodsA prospectively maintained database identified consecutive chemotherapy-naive patients with CT angiography and resected PDAC between 2009 and 2012. Variation in CT enhancement patterns was extracted from the tumor region using texture analysis, a quantitative image analysis tool previously described in the literature. Two continuous survival models were constructed, with 70% of the data (training set) using Cox regression, first based only on preoperative serum cancer antigen (CA) 19-9 levels and image features (model A), and then on CA19-9, image features, and the Brennan score (composite pathology score; model B). The remaining 30% of the data (test set) were reserved for independent validation.ResultsA total of 161 patients were included in the analysis. Training and test sets contained 113 and 48 patients, respectively. Quantitative image features combined with CA19-9 achieved a c-index of 0.69 [integrated Brier score (IBS) 0.224] on the test data, while combining CA19-9, imaging, and the Brennan score achieved a c-index of 0.74 (IBS 0.200) on the test data.ConclusionWe present two continuous survival prediction models for resected PDAC patients. Quantitative analysis of CT texture features is associated with overall survival. Further work includes applying the model to an external dataset to increase the sample size for training and to determine its applicability.

ObjectiveRobotic liver surgery (RLS) has emerged as a feasible alternative to laparoscopic or open resections with comparable perioperative outcomes. Little is known about the oncologic adequacy of RLS. The purpose of this study was to investigate the long-term oncologic outcomes for patients undergoing RLS for primary hepatobiliary malignancies.MethodsWe performed an international, multicenter, retrospective study of patients who underwent RLS for hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), or gallbladder cancer (GBC) between 2006 and 2016. Age, gender, histology, resection margin status, extent of surgical resection, disease-free survival (DFS), and overall survival (OS) were retrospectively collected and analyzed.ResultsOf the 61 included patients, 34 (56%) had RLS performed for HCC, 16 (26%) for CC, and 11 (18%) for GBC. The majority of resections were nonanatomical or segmental resections (39.3%), followed by central hepatectomy (18%), left-lateral sectionectomy (14.8%), left hepatectomy (13.1%), right hepatectomy (13.1%), and right posterior segmentectomy (1.6%). R0 resection was achieved in 94% of HCC, 68% of CC, and 81.8% of GBC patients. Median hospital stay was 5 days, and conversion to open surgery was needed in seven patients (11.5%). Grade III–IV Dindo–Clavien complications occurred in seven patients with no perioperative mortality. Median follow-up was 75 months (95% confidence interval 36–113), and 5-year OS and DFS were 56 and 38%, respectively. When stratified by tumor type, 3-year OS was 90% for HCC, 65% for GBC, and 49% for CC (p = 0.01).ConclusionsRLS can be performed for primary hepatobiliary malignancies with long-term oncologic outcomes comparable to published open and laparoscopic data.

Objective To analyze the natural history of small asymptomatic pancreatic neuroendocrine tumors (PanNET) and to present a matched comparison between groups who underwent either initial observation or resection. Management approach for small PanNET is uncertain. Methods Incidentally discovered, sporadic, small (<3 cm), stage I–II PanNET were analyzed retrospectively between 1993 and 2013. Diagnosis was determined either by pathology or imaging characteristics. Intention-to-treat analysis was applied. Results A total of 464 patients were reviewed. Observation was recommended for 104 patients (observation group), and these patients were matched to 77 patients in the resection group based on tumor size at initial imaging. The observation group was significantly older (median 63 vs. 59 years, p  = 0.04) and tended towards shorter follow-up (44 vs. 57 months, p  = 0.06). Within the observation group, 26 of the 104 patients (25 %) underwent subsequent tumor resection after a median observation interval of 30 months (range 7–135). At the time of last follow-up of the observation group, the median tumor size had not changed (1.2 cm, p  = 0.7), and no patient had developed evidence of metastases. Within the resection group, low-grade (G1) pathology was recorded in 72 (95 %) tumors and 5 (6 %) developed a recurrence, which occurred after a median of 5.1 (range 2.9–8.1) years. No patient in either group died from disease. Death from other causes occurred in 11 of 181 (6 %) patients. Conclusions In this study, no patient who was initially observed developed metastases or died from disease after a median follow-up of 44 months. Observation for stable, small, incidentally discovered PanNET is reasonable in selected patients.

Objective(s) The technical complexity of laparoscopic liver resection (LLR) poses unique challenges distinct from open surgery. An objective scoring system was developed that preoperatively quantifies the difficulty of LRR to help guide surgeon decision-making regarding the feasibility and safety of minimally invasive approaches. The aim of this multiinstitutional study was to externally validate this scoring system. Methods Patients who underwent LLR at two institutions were reviewed. LLR difficulty score (LDS) was calculated based on patient, tumor, and anatomic characteristics by two independent, blinded hepatobiliary surgeons. Surrogates of case complexity (e.g., conversion rate, operative time) were used for validation of this index. Results From 2006 to 2016, 444 LLR were scored as low ( n  = 94), intermediate ( n  = 98), and high difficulty ( n  = 152) with respective conversion rates of 5.3%, 15.7%, and 25%. Cases of higher LDS correlated with larger mean blood loss (203 ml vs. 331 ml vs. 635 ml). Mean operative and Pringle maneuver used were associated with increasing LDS (155 min vs. 202 min vs. 315 min and 14.4% vs. 29.7% vs. 45.1% respectively). These operative surrogates of difficulty correlated significantly with the LDS (all p  < 0.0001). Conclusions This comprehensive external validation of the LDS is robust and applicable in diverse patient populations. This LDS serves as a useful objective predictor of technical difficulty for LLR to help surgeons in selecting patients according to their individual operative experience and is valuable for preoperative risk estimation and stratification in randomized trials.

Accurate survival estimates are important for cancer control planning. Although observed survival estimates are unavailable for many countries, where they are available, wide variations are reported. Understanding the impact of specific treatment and imaging modalities can help decision makers to effectively allocate resources to improve cancer survival in their local context. We developed a microsimulation model of stage-specific cancer survival in 200 countries and territories for 11 cancers (oesophagus, stomach, colon, rectum, anus, liver, pancreas, lung, breast, cervix uteri, and prostate) comprising 60% of global diagnosed cancer cases. The model accounts for country-specific availability of treatment (chemotherapy, surgery, radiotherapy, and targeted therapy) and imaging modalities (ultrasound, x-ray, CT, MRI, PET, single-photon emission CT), as well as quality of care. We calibrated the model to reported survival estimates from CONCORD-3 (which reports global trends in cancer survival in 2000–14). We estimated 5-year net survival for diagnosed cancers in each country or territory and estimated potential survival gains from increasing the availability of individual treatment and imaging modalities, and more comprehensive packages of scale-up of these interventions. We report the mean and 95% uncertainty intervals (UIs) for all outcomes, calculated as the 2·5 and 97·5 percentiles of the simulation results. The estimated global 5-year net survival for all 11 cancers combined is 42·6% (95% uncertainty interval 40·3–44·3), with survival in high-income countries being an average of 12 times (range 4–17) higher than that in low-income countries. Expanding availability of surgery or radiotherapy or improving quality of care would yield the largest survival gains in low-income (2·5–3·4 percentage point increase in survival) and lower-middle-income countries (2·4–6·1 percentage point increase), whereas upper-middle-income and high-income countries are more likely to benefit from improved availability of targeted therapy (0·7 percentage point increase for upper-middle income and 0·4 percentage point increase for high income). Investing in medical imaging will also be necessary to achieve substantial survival gains, with traditional modalities estimated to provide the largest gains in low-income settings, while MRI and PET would yield the largest gains in higher-income countries. Simultaneous expansion of treatment, imaging, and quality of care could improve 5-year net survival by more than ten times in low-income countries (3·8% [95% UI 0·5–9·2] to 45·2% [40·2–52·1]) and could more than double 5-year net survival in lower-middle-income countries (20·1% [7·2–31·7] to 47·1% [42·8–50·8]). Scaling up both treatment and imaging availability could yield synergistic survival gains for patients with cancer. Expanding traditional modalities in lower-income settings might be a feasible pathway to improve survival before scaling up more modern technologies. Harvard T H Chan School of Public Health.

Background Resection of hepatocellular carcinoma (HCC) offers a chance of cure, but recurrence is common and survival is often limited. The clinical and pathological characteristics of long-term survivors have not been well studied. Methods We retrospectively reviewed 212 patients who underwent partial hepatectomy for HCC with curative intent from 1992 to 2006. Fifty patients who survived beyond 10 years were compared with 109 patients who died of recurrence within 10 years. Results Multivariate analysis showed that tumors <5 cm (odds ratio [OR] 2.3, p  = 0.04), solitary tumors (OR 3.2, p  = 0.01), and absence of vascular invasion (OR 2.3, p  = 0.04) were independently associated with actual 10-year survival. However, more than 20% of long-term survivors also possessed established poor prognostic factors, including α-fetoprotein >1000 ng/mL, unfavorable serum inflammatory indices, tumor size >10 cm, microvascular invasion, poor tumor differentiation, cirrhosis, and metabolic syndrome. None of the 10-year survivors had an R1 resection. While 77% of the short-term survivors developed recurrence within 2 years, 42% of the 10-year survivors developed recurrence during their decade of follow-up, although most of the recurrences among 10-year survivors were intrahepatic and amenable to further treatment. Among patients who survived beyond 10 years, 42% remained alive without recurrence. Conclusions In this largest Western series of actual 10-year survivors after HCC resection, almost one in four patients survived over a decade, even though nearly half of this subset had developed recurrence. While many well-known variables were associated with a poor outcome, only a positive microscopic margin precluded long-term survival.