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In pancreatic ductal adenocarcinoma (PDAC), no recurrent metastasis-specific mutation has been found, suggesting that epigenetic mechanisms, such as DNA methylation, are the major contributors of late-stage disease progression. Here, we performed the first whole-genome bisulfite sequencing (WGBS) on mouse and human PDAC organoid models to identify stage-specific and molecular subtype-specific DNA methylation signatures. With this approach, we identified thousands of differentially methylated regions (DMRs) that can distinguish between the stages and molecular subtypes of PDAC. Stage-specific DMRs are associated with genes related to nervous system development and cell-cell adhesions, and are enriched in promoters and bivalent enhancers. Subtype-specific DMRs showed hypermethylation of GATA6 foregut endoderm transcriptional networks in the squamous subtype and hypermethylation of EMT transcriptional networks in the progenitor subtype. These results indicate that aberrant DNA methylation contributes to both PDAC progression and subtype differentiation, resulting in significant and reoccurring DNA methylation patterns with diagnostic and prognostic potential.

PurposeBreast cancer (BC) is the most common secondary cancer and has poorer survival than primary BC (pBC) after any prior malignancy. For BC survivors, developing a contralateral secondary BC (CSBC) is the most frequent second-cancer event and is currently treated similarly to pBC. Identifying survival differences between pBC and CSBC could influence future counseling and treatments for patients with CSBC.MethodsWomen (≥15 years) diagnosed with pBC from 1991 to 2015 in the California Cancer Registry (n = 377,176) were compared with those with CSBC (n = 15,586) by age group (15-39 years, n = 406; 40-64 years, n = 6814; ≥ 65 years, n = 8366). Multivariable logistic regression models assessed factors associated with CSBC. Multivariable Cox proportional hazards regression models assessed BC-specific survival (BCSS), while accounting for the competing risk of death.ResultsAcross all ages, CSBC patients were more likely to have smaller tumors (T2 vs. T1a; 15-39 yeras: OR 0.25, CI 0.16-0.38; 40-64 years: OR 0.41, CI 0.37-0.45; ≥ 65 years: OR 0.46, CI 0.42-0.51) and lymph node-negative disease (positive vs. negative; 15-39 years: OR 0.86, CI 0.69-1.08; 40-64 years: OR 0.88, CI 0.83-0.93; ≥ 65 years: OR 0.89, CI 0.84-0.94). Additionally, CSBC was associated with worse survival compared with pBC across all ages (15-39 years: HR 2.73, CI 2.30-3.25; 40-64 years: HR 2.13, CI 2.01-2.26; ≥ 65 years: HR 1.52, CI 1.43-1.61).ConclusionBCSS is worse among all women diagnosed with CSBC compared with pBC, with the strongest impact seen in adolescent and young adult women. Worse survival after CSBC, despite associations with smaller tumors and lymph node negativity, suggests that CSBC may need eventual treatment reconsideration.

ObjectivesComorbid psychiatric illness has been associated with worse outcomes after some major surgical procedures. We hypothesized that patients with preexisting mood disorders would have worse postoperative and oncologic outcomes after pancreatic cancer resection.MethodsThis retrospective cohort study analyzed Surveillance, Epidemiology, and End Results patients with resectable pancreatic adenocarcinoma. A preexisting mood disorder was classified if a patient was diagnosed and/or treated with medication approved for depression/anxiety within 6 months before surgery.ResultsOf 1305 patients, 16% had a preexisting mood disorder. Mood disorders had no impact on hospital length of stay (12.9 vs 13.2 days, P = 0.75), 30-day complications (26% vs 22%, P = 0.31), 30-day readmissions (26% vs 21%, P = 0.1), or mortality (30 days: 3% vs 4%, P = 0.35); only an increased 90-day readmissions rate (42% vs 31%, P = 0.001) was observed. No effect on adjuvant chemotherapy receipt (62.5% vs 69.2%, P = 0.06) or survival (24 months, 43% vs 39%, P = 0.44) was observed.ConclusionsPreexisting mood disorders influenced 90-day readmissions after pancreatic resection, but not other postoperative or oncologic outcomes. These findings suggest that affected patients should be expected to have outcomes similar to patients without mood disorders.

BackgroundSecondary cancers account for 16% of all new cancer diagnoses, with breast cancer (BC) the most common secondary cancer. We have shown that secondary BC has unique characteristics and decreased survival compared with primary BC in adolescent and young adults (AYA; 15-39 years old). However, older BC populations are less well studied.MethodsFemales (age ≥ 15 years) diagnosed with primary BC during 1991-2015 (n = 377,167) and enrolled in the California Cancer Registry were compared with those with secondary BC (n = 37,625) by age (15-39, 40-64, ≥ 65 years). We examined BC-specific survival (BCSS) accounting for other causes of death as a competing risk using multivariable Cox proportional hazards regression.ResultsMost secondary BC patients were of older age (15-39, n = 777; 40-64, n = 15,848; ≥ 65, n = 21,000). Compared with primary BC treatment, secondary BCs were more often treated with mastectomy and less often with chemotherapy and/or radiation. BCSS was shorter in secondary BC patients than primary BC patients, but the survival difference between secondary and primary BC diminished with age [15-39 hazard ratio (HR): 2.09, 95% confidence interval (CI) 1.83-2.39; 40-64 HR: 1.51; 95% CI 1.44-1.58; ≥ 65 HR: 1.14; 95% CI 1.10-1.19]. Survival differences were most pronounced in women with hormone receptor positive disease and Hispanic and Asian/Pacific Islanders 40-64 years of age.ConclusionsWhen BC is diagnosed following a prior cancer of any organ site, BCSS is worse than when compared with patients for whom BC is the primary diagnosis, suggesting that we may need to tailor our treatments for women with secondary BC.

BackgroundAlthough malignant bowel obstruction (MBO) often is a terminal event, systemic therapies are advocated for select patients to extend survival. This study aimed to evaluate factors associated with receipt of chemotherapy after MBO and to determine whether chemotherapy after MBO is associated with survival.MethodsThis retrospective cohort study investigated patients 65 years of age or older with metastatic gastrointestinal, gynecologic, or genitourinary cancers who were hospitalized with MBO from 2008 to 2012 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Fine and Gray models were used to identify factors associated with receipt of chemotherapy accounting for the competing risk of death. Cox models identified factors associated with overall survival.ResultsOf the 2983 MBO patients, 39% (n = 1169) were treated with chemotherapy after MBO. No differences in receipt of chemotherapy between the surgical and medical patients were found in the univariable analysis (subdistribution hazard ratio [SHR], 0.96; 95% confidence interval [CI], 0.86-1.07; p = 0.47) or multivariable analysis (SHR, 1.12; 95% CI, 1.00-1.26; p = 0.06). Older age, African American race, medical comorbidities, non-colorectal and non-ovarian cancer diagnoses, sepsis, ascites, and intensive care unit stays were inversely associated with receipt of chemotherapy after MBO (p < 0.05). Chemotherapy with surgery was associated with longer survival than surgery (adjusted hazard ratio [aHR], 2.97; 95% CI, 2.65-3.34; p < 0.01) or medical management without chemotherapy (aHR, 4.56; 95% CI, 4.04-5.14; p < 0.01). Subgroup analyses of biologically diverse cancers (colorectal, pancreatic, and ovarian) showed similar results, with greater survival related to chemotherapy (p < 0.05).ConclusionsChemotherapy plays an integral role in maximizing oncologic outcome for select patients with MBO. The data from this study are critical to optimizing multimodality care for these complex patients.

BackgroundVolume of operative cases may be an important factor associated with improved survival for early-stage pancreatic cancer. Most high-volume pancreatic centers are also academic institutions, which have been associated with additional healthcare costs. We hypothesized that at high-volume centers, the value of the extra survival outweighs the extra cost.Study designThis retrospective cohort study used data from the California Cancer Registry linked to the Office of Statewide Health Planning and Development database from January 1, 2004 through December 31, 2012. Stage I-II pancreatic cancer patients who underwent resection were included. Multivariable analyses estimated overall survival and 30-day costs at low- vs high-volume pancreatic surgery centers. The incremental cost-effectiveness ratio (ICER) and incremental net benefit (INB) were estimated, and statistical uncertainty was characterized using net benefit regression.ResultsOf 2,786 patients, 46.5% were treated at high-volume centers and 53.5% at low-volume centers. There was a 0.45-year (5.4 months) survival benefit (95% CI 0.21-0.69) and a $7,884 extra cost associated with receiving surgery at high-volume centers (95% CI $4,074-$11,694). The ICER was $17,529 for an additional year of survival (95% CI $7,997-$40,616). For decision-makers willing to pay more than $20,000 for an additional year of life, high-volume centers appear cost-effective.ConclusionsAlthough healthcare costs were greater at high-volume centers, patients undergoing pancreatic surgery at high-volume centers experienced a survival benefit (5.4 months). The extra cost of $17,529 per additional year is quite modest for improved survival and is economically attractive by many oncology standards.

PurposeCurrent treatment guidelines for male breast cancer are guided by female-only trials despite data suggesting distinct clinicopathologic differences between sexes. We sought to evaluate whether radiation therapy (RT) after lumpectomy was associated with equivalent survival among men > 70 years of age with stage I, estrogen receptor (ER) positive tumors, as seen in women from the Cancer and Leukemia Group B (CALGB) 9343 trial.MethodsWe performed a retrospective analysis of 752 stage I, ER-positive male breast cancer patients ≥ 70 years who were treated with hormone therapy and surgery, with or without RT, from the National Cancer Database between 2004 and 2014. Patients were categorized based on surgery and RT (lumpectomy alone, lumpectomy with RT, and mastectomy alone). Multivariable Cox proportional hazards regression analysis was used to compare overall survival between treatment groups.ResultsMost patients underwent total mastectomy, with only 32.6% treated with lumpectomy. Of those who underwent lumpectomy, 72.7% received adjuvant RT. In multivariate analysis, there was no statistical difference in overall survival when comparing lumpectomy alone and lumpectomy with RT (aHR 0.72 [95% CI 0.38-1.37], p = 0.31) or when comparing lumpectomy (alone or with RT) and mastectomy (aHR 1.28 [95% CI 0.88-1.87], p = 0.20).ConclusionsIn this national sample of elderly men with ER-positive early-stage disease treated with endocrine therapy, there were no significant differences in overall survival when comparing lumpectomy alone and lumpectomy with RT, or lumpectomy (alone or with RT) and mastectomy. These results suggest that less aggressive treatment may be appropriate for a subset of male breast cancer patients.

Cancer cells are dysregulated and addicted to continuous supply and metabolism of nutritional glucose and amino acids (e.g., arginine) to drive the synthesis of critical macromolecules for uncontrolled growth. Recent studies have revealed that genome-derived microRNA (miRNA or miR)-1291-5p (miR-1291-5p or miR-1291) may modulate the expression of argininosuccinate synthase (ASS1) and glucose transporter protein type 1 (GLUT1). We also developed a novel approach to produce recombinant miR-1291 agents for research, which are distinguished from conventional chemo-engineered miRNA mimics. Herein, we firstly demonstrated that bioengineered miR-1291 agent was selectively processed to high levels of target miR-1291-5p in human pancreatic cancer (PC) cells. After the suppression of ASS1 protein levels, miR-1291 perturbed arginine homeostasis and preferably sensitized ASS1-abundant L3.3 cells to arginine deprivation therapy. In addition, miR-1291 treatment reduced the protein levels of GLUT1 in both AsPC-1 and PANC-1 cells, leading to a lower glucose uptake (deceased > 40%) and glycolysis capacity (reduced approximately 50%). As a result, miR-1291 largely improved cisplatin efficacy in the inhibition of PC cell viability. Our results demonstrated that miR-1291 was effective to sensitize PC cells to arginine deprivation treatment and chemotherapy through targeting ASS1- and GLUT1-mediated arginolysis and glycolysis, respectively, which may provide insights into understanding miRNA signaling underlying cancer cell metabolism and development of new strategies for the treatment of lethal PC. SIGNIFICANCE STATEMENT: Many anticancer drugs in clinical use and under investigation exert pharmacological effects or improve efficacy of coadministered medications by targeting cancer cell metabolism. Using new recombinant miR-1291 agent, we revealed that miR-1291 acts as a metabolism modulator in pancreatic carcinoma cells through the regulation of argininosuccinate synthase- and glucose transporter protein type 1-mediated arginolysis and glycolysis. Consequently, miR-1291 effectively enhanced the efficacy of arginine deprivation (pegylated arginine deiminase) and chemotherapy (cisplatin), offering new insights into development of rational combination therapies.

BackgroundRadiotherapy is used to treat many adolescent and young adult (AYA) and childhood cancer patients and is a risk factor for secondary breast cancer. While premenopausal breast cancer is inherently more aggressive, no studies to date have evaluated the characteristics and breast cancer-specific survival (BCSS) of premenopausal secondary breast cancer after radiotherapy in AYA and childhood cancer survivors.MethodsFemale patients ages 12 to 50 diagnosed with primary breast cancer from 1988 to 2014 (n = 107,751) were obtained from the California Cancer Registry and compared with similar aged patients with secondary breast cancer who were treated with radiotherapy for their primary tumor (n = 1,147) from ages 12 to 39. We examined BCSS using multivariable Cox proportional hazards regression.ResultsThe secondary breast cancer cohort was more likely to be Hispanic or Black, be 35 to 45 years of age, have earlier stage tumors, be higher grade, have no lymph node involvement, and be hormone receptor negative. All women showed worse BCSS for large tumor size, lymph node involvement, and hormone receptor-negative status. BCSS was worse for women with secondary breast cancer both overall (hazard ratio, 1.98; 95% confidence interval, 1.77-2.23) and in all subgroups considered. Associations were most pronounced in Hispanics, Asian/Pacific Islanders, and younger women, as well as those with earlier stage, lymph node-negative, and hormone receptor-positive disease.ConclusionsBCSS is significantly decreased among all survivors of childhood and AYA cancer treated with radiotherapy that develop a secondary breast cancer, including women with good prognostic features.ImpactTherefore, we may need to consider alternative and even more aggressive treatment in what were considered low-risk populations previously.

Tumor-free surgical margins are critical in breast-conserving surgery. In up to 38% of the cases, however, patients undergo a second surgery since malignant cells are found at the margins of the excised resection specimen. Thus, advanced imaging tools are needed to ensure clear margins at the time of surgery. The objective of this study was to evaluate a random forest classifier that makes use of parameters derived from point-scanning label-free fluorescence lifetime imaging (FLIm) measurements of breast specimens as a means to diagnose tumor at the resection margins and to enable an intuitive visualization of a probabilistic classifier on tissue specimen. FLIm data from fresh lumpectomy and mastectomy specimens from 18 patients were used in this study. The supervised training was based on a previously developed registration technique between autofluorescence imaging data and cross-sectional histology slides. A pathologist's histology annotations provide the ground truth to distinguish between adipose, fibrous, and tumor tissue. Current results demonstrate the ability of this approach to classify the tumor with 89% sensitivity and 93% specificity and to rapidly (∼ 20 frames per second) overlay the probabilistic classifier overlaid on excised breast specimens using an intuitive color scheme. Furthermore, we show an iterative imaging refinement that allows surgeons to switch between rapid scans with a customized, low spatial resolution to quickly cover the specimen and slower scans with enhanced resolution (400 μm per point measurement) in suspicious regions where more details are required. In summary, this technique provides high diagnostic prediction accuracy, rapid acquisition, adaptive resolution, nondestructive probing, and facile interpretation of images, thus holding potential for clinical breast imaging based on label-free FLIm.

The role of palliative surgery in the management of acute complications in patients with disseminated malignancy remains controversial given the complexity of assessing acute surgical risk and long-term oncologic outcome. With the emergence of checkpoint blockade immunotherapy, there appears to be an increasing role for historically palliative procedures as a bridge to systemic immunotherapy. This is especially evident in advanced microsatellite instability-high (MSI-H) colorectal cancer where malignant obstruction and fistula formation are more common and where immunotherapy with checkpoint blockade (anti-PD-1/PD-L1, anti-CTLA-4) has a high response rate with potential for favorable oncologic outcomes. We present a series of three patients with MSI-H metastatic colorectal cancer complicated by malignant bowel obstruction and fistula formation, who having progressed on standard chemotherapy, underwent palliative intervention as a bridge to immune checkpoint blockade with durable and clinically meaningful anti-cancer responses. These cases highlight the need to re-evaluate the role of historically palliative operations in the setting of disease progression for immunotherapy-responsive tumors.

Tumor subtype-specific metabolic reprogrammers could serve as targets of therapeutic intervention. Here we show that triple-negative breast cancer (TNBC) exhibits a hyper-activated cholesterol-biosynthesis program that is strongly linked to nuclear receptor RORγ, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of RORγ reduces tumor cholesterol content and synthesis rate while preserving host cholesterol homeostasis. We demonstrate that RORγ functions as an essential activator of the entire cholesterol-biosynthesis program, dominating SREBP2 via its binding to cholesterol-biosynthesis genes and its facilitation of the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces chromatin acetylation at cholesterol-biosynthesis gene loci. RORγ antagonists cause tumor regression in patient-derived xenografts and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our study uncovers a master regulator of the cholesterol-biosynthesis program and an attractive target for TNBC.

BackgroundSurgical guidelines for soft tissue sarcoma (STS) emphasize pretreatment evaluation and reports of the perils of unplanned excision exist. Given the paucity of population-based data on this topic, our objective was to analyze clinical outcomes and costs of planned versus unplanned STS excisions in the Medicare population.MethodsWe analyzed 3913 surgical patients with STS ≥66 y old from 1992 to 2011 using the Surveillance, Epidemiology, and End Results-Medicare datafiles. Planned excisions were classified based on preoperative MRI and/or biopsy, whereas unplanned excisions were classified by excision as the first procedure. Inverse probability of treatment weighting with propensity scores was used to adjust for clinicopathologic differences. Re-excisions, complications, and Medicare payments were compared with multivariate models. Overall survival and disease-specific survival were analyzed using Cox proportional hazards and competing risk models.ResultsBefore the first excision, 24.3% had an MRI and biopsy, 27.3% had an MRI, 11.4% had a biopsy, and 36.9% were unplanned. Re-excision rates were highest for unplanned excisions: 46.3% compared to 18.1%, 36.4%, and 29.7% for other groups (P  0.05). Planned excisions were associated with increased Medicare costs (P

BackgroundCurrent treatment guidelines for male breast cancer are predominantly guided by female-only clinical trials. With scarce research, it is unclear whether breast-conserving therapy (BCT) is equivalent to mastectomy in men. We sought to compare overall survival (OS) among male breast cancer patients who underwent BCT versus mastectomy.MethodsWe performed a retrospective analysis of 8445 stage I-II (T1-2 N0-1 M0) male breast cancer patients from the National Cancer Database (2004-2014). Patients were grouped according to surgical and radiation therapy (RT). BCT was defined as partial mastectomy followed by RT. Multivariable and inverse probability of treatment-weighted (IPTW) Cox proportional hazards models were used to compare OS between treatment groups, controlling for demographic and clinicopathologic characteristics.ResultsMost patients underwent total mastectomy (61.2%), whereas 18.2% underwent BCT, 12.4% underwent total mastectomy with RT, and 8.2% underwent partial mastectomy alone. In multivariable and IPTW models, partial mastectomy alone, total mastectomy alone, and total mastectomy with RT were associated with worse OS compared with BCT (p

PurposeThe study was undertaken to develop and evaluate the potential of an integrin αvβ6-binding peptide (αvβ6-BP) for noninvasive imaging of a diverse range of malignancies with PET.Experimental designThe peptide αvβ6-BP was prepared on solid phase and radiolabeled with 4-[18F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired αvβ6-expressing and αvβ6-null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired αvβ6-expressing and αvβ6-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer.Results[18F]αvβ6-BP displayed excellent affinity and selectivity for the integrin αvβ6 in vitro [IC50(αvβ6) = 1.2 nmol/L vs IC50(αvβ3) >10 μmol/L] in addition to rapid target-specific cell binding and internalization (72.5% ± 0.9% binding and 52.5% ± 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [18F]αvβ6-BP was rapid, primarily via the kidneys. In patients, [18F]αvβ6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [18F]αvβ6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung.ConclusionsThe clinical impact of [18F]αvβ6-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.

Our recent studies have revealed that microRNA-1291 (miR-1291) is downregulated in pancreatic cancer (PC) specimens and restoration of miR-1291 inhibits tumorigenesis of PC cells. This study is to assess the efficacy and underlying mechanism of our bioengineered miR-1291 prodrug monotherapy and combined treatment with chemotherapy. AT-rich interacting domain protein 3B (ARID3B) was verified as a new target for miR-1291, and miR-1291 prodrug was processed to mature miR-1291 in PC cells which surprisingly upregulated ARID3B mRNA and protein levels. Co-administration of miR-1291 with gemcitabine plus nab-paclitaxel (Gem-nP) largely increased the levels of apoptosis, DNA damage and mitotic arrest in PC cells, compared to mono-drug treatment. Consequently, miR-1291 prodrug improved cell sensitivity to Gem-nP. Furthermore, systemic administration of in vivo-jetPEI-formulated miR-1291 prodrug suppressed tumor growth in both PANC-1 xenograft and PC patients derived xenograft (PDX) mouse models to comparable degrees as Gem-nP alone, while combination treatment reduced tumor growth more ubiquitously and to the greatest degrees (70-90%), compared to monotherapy. All treatments were well tolerated in mice. In conclusion, biologic miR-1291 prodrug has therapeutic potential as a monotherapy for PC, and a sensitizing agent to chemotherapy.

PurposeReducing acute care use is an important strategy for improving value in cancer care. However, little information is available to describe and compare population-level hospital use across cancer types. Our aim was to estimate unplanned hospitalization rates and to describe the reasons for hospitalization in a population-based cohort recently diagnosed with cancer.Materials and methodsCalifornia Cancer Registry data linked with administrative inpatient data were used to examine unplanned hospitalization among individuals diagnosed with cancer between 2009 and 2012 (n = 412,850). Hospitalizations for maintenance chemotherapy, radiotherapy, or planned surgery were excluded. Multistate models were used to estimate age-adjusted unplanned hospitalization rates, accounting for survival.ResultsApproximately 67% of hospitalizations in the year after diagnosis were unplanned, 35% of newly diagnosed individuals experienced an unplanned hospitalization, and 67% of unplanned hospitalizations originated in the emergency department (ED). Nonmalignancy principal diagnoses most frequently associated with unplanned hospitalization included infection (15.8%) and complications of a medical device or care (6.5%). Unplanned hospitalization rates were highest for individuals with hepatobiliary or pancreatic cancer (2.08 unplanned hospitalizations per person-year at risk), lung cancer (1.58 unplanned hospitalizations), and brain or CNS cancer (1.47 unplanned hospitalizations), and were lowest among individuals with prostate cancer (0.18 unplanned hospitalizations) and melanoma (0.25 unplanned hospitalizations).ConclusionThe population burden of unplanned hospitalization among individuals newly diagnosed with cancer is substantial. Many unplanned hospitalizations originate in the ED and are associated with potentially preventable admission diagnoses. Efforts to reduce unplanned hospitalization might target subgroups at higher risk and focus on the ED as a source of admission.

BackgroundOutcomes for pancreatic resection have been studied extensively due to the high morbidity and mortality rates, with high-volume centers achieving superior outcomes. Ongoing investigations include healthcare costs, given the national focus on reducing expenditures. Therefore, we sought to evaluate the relationships between pancreatic surgery costs with perioperative outcomes and volume status.MethodsWe performed a retrospective analysis of 27,653 patients who underwent elective pancreatic resections from October 2013 to June 2017 using the Vizient database. Costs were calculated from charges using cost-charge ratios and adjusted for geographic variation. Generalized linear modeling adjusting for demographic, clinical, and operation characteristics was performed to assess the relationships between cost and length of stay, complications, in-hospital mortality, readmissions, and hospital volume. High-volume centers were defined as hospitals performing ≥ 19 operations annually.ResultsThe unadjusted mean cost for pancreatic resection and corresponding hospitalization was $20,352. There were no differences in mean costs for pancreatectomies performed at high- and low-volume centers [- $1175, 95% confidence interval (CI) - $3254 to $904, p = 0.27]. In subgroup analysis comparing adjusted mean costs at high- and low-volume centers, there was no difference among patients without an adverse outcome (- $99, 95% CI - $1612 to 1414, p = 0.90), one or more adverse outcomes (- $1586, 95% CI - $4771 to 1599, p = 0.33), or one or more complications (- $2835, 95% CI - $7588 to 1919, p = 0.24).ConclusionsWhile high-volume hospitals have fewer adverse outcomes, there is no relationship between surgical volume and costs, which suggests that, in itself, surgical volume is not an indicator of improved healthcare efficiency reflected by lower costs. Patient referral to high-volume centers may not reduce overall healthcare expenditures for pancreatic operations.

BackgroundMalignant bowel obstruction (MBO) is often a terminal event in end-stage cancer patients. The decision to intervene surgically is complex, given the risk of harm in patients with a limited lifespan. Therefore, we sought to compare clinically meaningful outcomes in MBO patients treated with surgical versus medical management using population-based data.MethodsWe performed a retrospective analysis of hospitalized patients with MBO from 2006 to 2010 using the California Office of Statewide Health Planning and Development dataset. Hospital-free days (HFDs) at 30-, 90-, and 180-days were calculated accounting for all hospitalization, emergency department visit, and skilled nursing facility lengths of stay. Adjusted regression models were used to compare HFDs, disposition, complications, in-hospital death, and survival for surgical versus medical MBO cohorts, using inverse probability of treatment weighting with propensity scores.ResultsOf 4576 MBO patients, 3421 (74.8%) were treated medically and 1155 (25.2%) were treated surgically. Surgical patients had higher rates of complications (44.0% vs. 21.3%, p

BackgroundSurgical decision-making in patients with advanced cancer requires careful thought and deliberation to balance the high risks with the potential palliative benefits. We sought to compare surgical decision-making and palliative care training among surgeons and medical physicians who commonly treat advanced cancer patients. We hypothesized that surgeons will report less palliative care training compared with medical physicians, and deficits in palliative care training will be associated with more aggressive treatment recommendations in clinical scenarios of advanced cancer patients with symptomatic surgical conditions.Study designPracticing surgeons, medical oncologists, intensivists, and palliative care physicians from a large urban city and its surrounding areas were surveyed with a 32-item questionnaire consisting of a survey addressing palliative care training and 4 clinical vignettes depicting patients with advanced cancer and symptomatic surgical conditions.ResultsOf the 299 physicians surveyed, 102 responded (response rate 34.1%). Surgeons reported fewer hours of palliative care training during residency, fellowship, and continuing medical education combined (median 10, IQR 2-15) compared with medical oncologists (median 30, IQR 20-80) and medical intensivists (median 50 IQR 30-100), P < .05. Additionally, 20% of surgeons reported no history of any palliative care training. Analysis of physician recommendations for treatment of the 4 clinical vignettes showed minimal consensus regardless of physician specialty. Absence of palliative care training was associated with recommending major operative intervention more frequently compared with physicians with ≥40 hours of palliative care training (0.7 ± 0.7 vs 1.6 ± 0.8, P =.01).ConclusionSubstantial deficiencies in palliative care training persist among surgeons and are associated with more aggressive recommendations for treatment for the selected scenarios presented in patients with advanced cancer. These findings highlight the need for greater efforts systemwide in palliative care education among surgeons, including incorporation of a structured palliative care training curriculum in graduate and continuing surgical education.

Background and objectivesAmong patients with disseminated malignancy (DMa), bowel obstruction is common with high operative morbidity. Since preoperative risk stratification is critical, we sought to compare three standard risk indices, the American Society of Anesthesiology (ASA) classification, Charlson comorbidity index (CCI), and modified frailty index (mFI).MethodsWe identified 1928 DMa patients with bowel obstruction who underwent an abdominal operation from 2007 to 2012 American College of Surgeons National Surgical Quality Improvement Program. Multivariate analyses assessed predictors of prolonged length of stay (LOS), 30-day serious morbidity and mortality. Receiver operating characteristics' areas under the curves (AUCs) for risk indices scores and 30-day mortality were assessed.ResultsSerious morbidity and mortality rates were 20.4% and 14.8%. ASA and CCI did not predict serious morbidity or prolonged LOS, but were predictors of mortality. The mFI did not predict prolonged LOS, but did predict serious morbidity and mortality. Subgroup analyses showed similar results. There were no significant differences between ASA, CCI, and mFI AUCs for mortality.ConclusionsASA, CCI, and mFI are limited in their ability to predict postoperative adverse events among DMa patients undergoing surgery for bowel obstruction. These data suggest that a more tailored preoperative risk stratification tool would improve treatment planning.

Background/aimThe predictive value of serum C-reactive protein (CRP) and neutrophil/lymphocyte (N/L) ratio in soft tissue sarcoma (STS) patients receiving neoadjuvant radiotherapy (RT) has not been analyzed.Patients and methodsFrom 2007 to 2015, we identified 98 STS patients from a prospective database. Using multivariate analysis, we analyzed CRP and N/L ratios as predictors of overall survival (OS).ResultsMean age of patients was 59 years, 46% were female, and 55% of tumors were located at the extremity. A total of 15 histologies were represented. Fifty percent received preoperative RT. Except for extremity location, characteristics were similar between the preoperative RT and upfront surgery cohorts, including baseline CRP levels and N/L ratios. Multivariate analysis of upfront surgery revealed histological grade, tumor size, and baseline N/L ratio to be predictors of OS, while for preoperative RT, baseline CRP and N/L ratio were not predictive.ConclusionBaseline CRP and N/L ratio did not predict poor clinical outcome in STS patients receiving neoadjuvant RT.

Re-excision rates for breast cancer lumpectomy procedures are currently nearly 25% due to surgeons relying on inaccurate or incomplete methods of evaluating specimen margins. The objective of this study was to determine if cancer could be automatically detected in breast specimens from mastectomy and lumpectomy procedures by a classification algorithm that incorporated parameters derived from fluorescence lifetime imaging (FLIm). This study generated a database of co-registered histologic sections and FLIm data from breast cancer specimens (N  =  20) and a support vector machine (SVM) classification algorithm able to automatically detect cancerous, fibrous, and adipose breast tissue. Classification accuracies were greater than 97% for automated detection of cancerous, fibrous, and adipose tissue from breast cancer specimens. The classification worked equally well for specimens scanned by hand or with a mechanical stage, demonstrating that the system could be used during surgery or on excised specimens. The ability of this technique to simply discriminate between cancerous and normal breast tissue, in particular to distinguish fibrous breast tissue from tumor, which is notoriously challenging for optical techniques, leads to the conclusion that FLIm has great potential to assess breast cancer margins. Identification of positive margins before waiting for complete histologic analysis could significantly reduce breast cancer re-excision rates.

An important step in establishing the diagnostic potential for emerging optical imaging techniques is accurate registration between imaging data and the corresponding tissue histopathology typically used as gold standard in clinical diagnostics. We present a method to precisely register data acquired with a point-scanning spectroscopic imaging technique from fresh surgical tissue specimen blocks with corresponding histological sections. Using a visible aiming beam to augment point-scanning multispectral time-resolved fluorescence spectroscopy on video images, we evaluate two different markers for the registration with histology: fiducial markers using a 405-nm CW laser and the tissue block's outer shape characteristics. We compare the registration performance with benchmark methods using either the fiducial markers or the outer shape characteristics alone to a hybrid method using both feature types. The hybrid method was found to perform best reaching an average error of 0.78±0.67  mm. This method provides a profound framework to validate diagnostical abilities of optical fiber-based techniques and furthermore enables the application of supervised machine learning techniques to automate tissue characterization.

Purpose Among individuals with advanced cancer, frequent hospitalization increasingly is viewed as a hallmark of poor-quality care. We examined hospitalization rates and individual- and hospital-level predictors of rehospitalization among individuals with advanced cancer in the year after diagnosis. Methods Individuals diagnosed with advanced breast, colorectal, non-small-cell lung, or pancreatic cancer from 2009 to 2012 (N = 25,032) were identified with data from the California Cancer Registry (CCR). After linkage with inpatient discharge data, multistate and log-linear Poisson regression models were used to calculate hospitalization rates and to model rehospitalization in the year after diagnosis, accounting for survival. Results In the year after diagnosis, 71% of individuals with advanced cancer were hospitalized, 16% had three or more hospitalizations, and 64% of hospitalizations originated in the emergency department. Rehospitalization rates were significantly associated with black non-Hispanic (incidence rate ratio [IRR], 1.29; 95% CI, 1.17 to 1.42) and Hispanic (IRR, 1.11; 95% CI, 1.03 to 1.20) race/ethnicity; public insurance (IRR, 1.37; 95% CI, 1.23 to 1.47) and no insurance (IRR, 1.17; 95% CI, 1.02 to 1.35); lower socioeconomic status quintiles (IRRs, 1.09 to 1.29); comorbidities (IRRs, 1.13 to 1.59); and pancreatic (IRR, 2.07; 95% CI, 1.95 to 2.20) and non-small-cell lung (IRR, 1.69; 95% CI, 1.54 to 1.86) cancers versus colorectal cancer. Rehospitalization rates were significantly lower after discharge from a hospital that had an outpatient palliative care program (IRR, 0.90; 95% CI, 0.83 to 0.97) and were higher after discharge from a for-profit hospital (IRR, 1.33; 95% CI, 1.14 to 1.56). Conclusion Individuals with advanced cancer experience a heavy burden of hospitalization in the year after diagnosis. Efforts to reduce hospitalization and provide care congruent with patient preferences might target individuals at higher risk. Future work might explore access to palliative care in the community and related health care use among individuals with advanced cancer.

BackgroundNeoadjuvant radiotherapy (RT) is increasingly advocated for the management of soft tissue sarcoma (STS). Therefore, this study sought to characterize the impact of neoadjuvant RT on rates of R0 resection and overall survival (OS) in extremity STS patients undergoing surgery.MethodsFrom January 2003 to December 2012, the study identified patients with a diagnosis of extremity STS from the National Cancer Database. After exclusion of patients younger than 18 years, not treated by surgery, who had metastases at diagnosis, intraoperative RT, and missing or unknown data, 27,969 patients were identified. Logistic regression and Cox-proportional hazard analysis were used to compare rates of R0 resection among preoperative, postoperative, and no-RT cohorts and to determine predictors of R0 resection and OS.ResultsThe mean age of the patients was 59.5 ± 17.1 years, and 45.9% were female. The median tumor size was 10.5 cm. The data showed that 51% of the patients did not receive RT, 11.8% received preoperative RT, and 37.2% received postoperative RT. The rates of R0 resection were 90.1% for the preoperative RT cohort, 74.9% for the postoperative RT cohort, and 79.9% for the no-RT cohort (P

BackgroundThe modified frailty index (mFI) is an important method to risk-stratify surgical patients and has been validated for general surgery and selected surgical subspecialties. However, there are currently no data assessing the efficacy of the mFI to predict acute morbidity and mortality in patients undergoing surgery for retroperitoneal sarcoma.MethodsUsing the American College of Surgeons' National Surgical Quality Improvement Program from 2007 to 2012, we performed a retrospective analysis of patients with a diagnosis of primary malignant retroperitoneal neoplasm who underwent surgical resection. The mFI was calculated according to standard published methods. Univariate and multivariate statistical analyses including χ2 and logistic regression were used to identify predictors of 30-d overall morbidity, 30-d severe morbidity (Clavien III/IV), and 30-d mortality.ResultsWe identified 846 patients with the diagnosis of primary malignant retroperitoneal neoplasm who underwent surgical resection. The distribution mFI scores was 0 (48.5%) or 1 (36.3%), with only 4.5% of patients presenting with a score ≥3. Rates of 30-d overall morbidity, serious morbidity, and mortality were 22.6%, 12.9%, and 1.2%, respectively. Only selected mFI scores were associated with serious morbidity and overall morbidity on multivariate analysis (P  0.05).ConclusionsOur data demonstrate that the majority of patients undergoing retroperitoneal sarcoma resections have few, if any, comorbidities. The mFI was a limited predictor of overall and serious complications and was not a significant predictor of mortality. Better discriminators of preoperative risk stratification may be needed for this patient population.

BackgroundRecent reports call for reductions in costly and potentially avoidable services such as emergency department (ED) visits. Providing high-quality and safe care for oncology patients remains challenging for ED providers given the diversity of patients seeking care and the unpredictable clinical environment. While ED use by oncology patients is appropriate for acute health concerns, some ED visits may be preventable with well-coordinated care and adequate symptom management.ObjectiveThe aim of this study was to summarize available evidence regarding the incidence, predictors of, and reasons for ED visits among oncology patients.MethodsKeyword/MeSH term searches were conducted using 4 online databases. Inclusion criteria were publication date between April 1, 2003, and December 5, 2014; sample size of 50 or more; and report of the incidence or predictors of ED use among oncology patients.ResultsThe 15 studies that met criteria varied in study aim, design, and time frames for calculating ED utilization rates. The incidence of ED visits among oncology patients ranged from 1% to 83%. The 30-day standardized visit rate incidence ranged from 1% to 12%. Collectively, the studies lack population-based estimates for all cancers combined.ConclusionsThe studies included in this review suggest that rates of ED use among cancer patients exceed those of the general population. However, the extent of ED use by oncology patients and the reasons for ED visits remain understudied.Implications for practiceNurses are involved in the treatment of cancer, patient education, and symptom management. Nurses are well positioned to develop patient-centered treatment and care coordination plans to improve quality of care and reduce ED visits.

BackgroundImproving the quality of cancer care and reducing preventable health system use are goals of increasing importance to health practitioners and policy makers. Emergency department (ED) visits are often cited as a source of preventable health system use, however, few studies have described the incidence of ED use by recently diagnosed cancer patients in population-based samples, and no study has addressed the full spectrum of cancer types.ObjectiveTo describe ED use by recently diagnosed cancer patients.MethodsCalifornia Office of Statewide Health Planning and Development data and the California Cancer Registry were used to describe ED use in the year after a cancer diagnosis (2009-2010). The incidence of ED use was tabulated by cancer type. Logistic regression and recycled predictions were used to examine ED use adjusting for confounding factors.ResultsMost ED visits (68%) occurred within 180 days of diagnosis. The incidence of ED use for all cancer types examined was 17% within 30 days, 35% within 180 days and 44% within 365 days of diagnosis. ED use varied by cancer type (5%-39% within 30 days of diagnosis; 14% -62% within 180 days; and 22%-69% within 365 days). Patterns of ED use by cancer type remained similar after accounting for demographic and socioeconomic factors.LimitationsThose common to administrative and registry datasets. Specifically, we were unable to account for ED visits in relation to cancer treatment dates and comorbid conditions.ConclusionsCancer patients use EDs at higher rates than previously reported, with considerable variability by cancer type. Future research should examine reasons for ED visits by cancer type and identify predictors of ED use, including treatment and comorbid conditions.

PurposeThe aim of this study is to examine predictors of cancer-related financial difficulties and work modifications in a national sample of cancer survivors.MethodsUsing the 2011 Medical Expenditure Panel Survey and Experiences with Cancer Survivorship Supplement, the prevalence of financial difficulties and work modifications was examined. Logistic regression and survey weights were used to model these outcomes as functions of sociodemographic and health covariates separately among survivors in active treatment and survivors under age 65 years.ResultsAmong all survivors, 33.2% reported any financial concern, with 17.9% reporting financial difficulties such as debt or bankruptcy. Among working survivors, 44.0% made any work modification and 15.3% made long-term work modifications (e.g., delayed or early retirement). Among those in active treatment, predictors of financial difficulty included: race/ethnicity other than white, non-Hispanic [OR = 8.0; 95% CI 2.2-28.4]; income

BackgroundThe impact of surgery on end of life care for patients with disseminated malignancy (DMa) is incompletely characterized. The purpose of this study was to evaluate postoperative outcomes impacting quality of care among DMa patients, specifically prolonged length of hospital stay, readmission, and disposition.MethodsThe American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for years 2011-2012. DMa patients were matched to non-DMa patients with comparable clinical characteristics and operation types. Primary hepatic operations were excluded, leaving a final cohort of 17,972 DMa patients. The primary outcomes were analyzed using multivariate Cox regression models.ResultsDMa patients represented 2.1% of all ACS-NSQIP procedures during the study period. The most frequent operations were bowel resections (25.3%). Compared to non-DMa matched controls, DMa patients had higher rates of postoperative overall morbidity (24.4% vs. 18.7%, p

BackgroundRadiation therapy (RT) is a standard component in the multimodality management of localized soft tissue sarcoma (STS). Increasing studies are focusing on biological modifiers that may influence the host's response to RT, including immunologic mechanisms known to change with the aging process. We hypothesized that the effects of RT would be influenced by age, contributing to differences in treatment outcome.MethodsUsing Surveillance, Epidemiology, and End Results (1990-2011), we identified 30,898 adult patients (>18 y) with nonmetastatic STS undergoing initial surgery. We compared patient demographics, tumor characteristics, and treatments by age. Multivariable analyses were used to analyze overall survival (OS) and disease-specific survival (DSS). Hazard ratios (HRs) were calculated based on multivariable Cox proportional hazards models.ResultsMean age at diagnosis was 56.6 ± 16.8 y, and 33.6% of patients were ≥65 y. Of the total, 52.1% of patients were male and 67% were white; 59.9% of patients underwent surgery alone, 33.3% received adjuvant RT, and 6.8% neoadjuvant RT. On multivariable analysis, age, sex, year of diagnosis, histology, grade, size, marital status, and RT predicted OS, whereas age, year of diagnosis, ethnicity, histology, site, grade, RT, size, and marital status predicted DSS. In all patients, RT was associated with improved OS and DSS compared to surgery alone (median OS 136 ± 13 mo with RT versus 118 ± 9 mo without RT and 5-y OS 63.2 ± 1.4% with RT versus 60.5 ± 1.2% without, P < 0.01). Patients ≥65 y derived greater improvements in OS and DSS compared with patients

BackgroundSurgical morbidity and mortality (M&M) for patients with disseminated malignancy (DMa) is high, and some have questioned the role of surgery. Therefore, we sought to characterize temporal trends in M&M among DMa patients, hypothesizing that surgical intervention would remain prevalent.MethodsWe queried the American College of Surgeons National Surgical Quality Improvement Program from 2006-2010. Excluding patients undergoing a primary hepatic operation, we identified 21,755 patients with DMa. Parametric and/or nonparametric statistics and logistic regression were used to evaluate temporal trends and predictors of M&M.ResultsThe prevalence of surgical intervention for DMa declined slightly over the time period, from 1.9%-1.6% of all procedures (P < 0.01). Among DMa patients, the most frequent operations performed were bowel resection, other gastrointestinal procedures, and multivisceral resections, these all showed small statistically significant decreases over time (P < 0.01). The rate of emergency operations also decreased (P < 0.01). In contrast, the rate of preoperative independent functional status rose, whereas the rate of preoperative weight loss and sepsis decreased (P < 0.01). Rates of 30-d morbidity (33.7 versus 26.6%), serious morbidity (19.8 versus 14.2%), and mortality (10.4 versus 9.3%) all decreased over the study period (P < 0.05). Multivariate analysis identified standard predictors (e.g., impaired functional status, preoperative weight loss, preoperative sepsis, and hypoalbuminemia) of worse 30-d M&M.ConclusionsThirty-day morbidity, serious morbidity, and mortality have decreased incrementally for patients with DMa undergoing surgical intervention, but surgical intervention remains prevalent. These data further highlight the importance of careful patient selection and goal-directed therapy in patients with incurable malignancy.

IntroductionDespite some recent advances in treatment options, pancreatic cancer remains a devastating disease with poor outcomes. In a trend contrary to most malignancies, both incidence and mortality continue to rise due to pancreatic cancer. The majority of patients present with advanced disease and there are no treatment options for this stage that have demonstrated a median survival > 1 year. As the penultimate step prior to Phase III studies involving hundreds of patients, Phase II clinical trials provide an early opportunity to evaluate the efficacy of new treatments that are desperately needed for this disease.Areas coveredThis review covers the results of published Phase II clinical trials in advanced pancreatic adenocarcinoma published within the past 5 years. The treatment results are framed in the context of the current standards of care and the historic challenge of predicting Phase III success from Phase II trial results.Expert opinionPromising therapies remain elusive in pancreatic cancer based on recent Phase II clinical trial results. Optimization and standardization of clinical trial design in the Phase II setting, with consistent incorporation of biomarkers, is needed to more accurately identify promising therapies that warrant Phase III evaluation.

BackgroundPancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena.MethodsWe examined the ability of cellular arginine depletion through treatment with PEG-ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined.ResultsCombination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2.ConclusionThe ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer.

ObjectivesTo evaluate readmission rates and associated factors to identify potentially preventable readmissions.BackgroundThe decision to penalize hospitals for readmissions is compelling health care systems to develop processes to minimize readmissions. Research to identify preventable readmissions is critical to achieve these goals.MethodsWe performed a retrospective review of University HealthSystem Consortium database for cancer patients hospitalized from January 2010 to September 2013. Outcome measures were 7-, 14-, and 30-day readmission rates and readmission diagnoses. Hospital and disease characteristics were evaluated to evaluate relationships with readmission.ResultsA total of 2,517,886 patients were hospitalized for cancer treatment. Readmission rates at 7, 14, and 30 days were 2.2%, 3.7%, and 5.6%, respectively. Despite concern that premature hospital discharge may be associated with increased readmissions, a shorter initial length of stay predicted lower readmission rates. Furthermore, high-volume centers and designated cancer centers had higher readmission rates. Evaluating institutional data (N = 2517 patients) demonstrated that factors associated with higher readmission rates include discharge from a medical service, site of malignancy, and emergency primary admission. When examining readmission within 7 days for surgical services, the most common readmission diagnoses were infectious causes (46.3%), nausea/vomiting/dehydration (26.8%), and pain (6.1%).ConclusionsA minority of patients after hospitalization for cancer-related therapy are readmitted with potentially preventable conditions such as nausea, vomiting, dehydration, and pain. However, most factors associated with readmission cannot be modified. In addition, high-volume centers and designated cancer centers have higher readmission rates, which may indicate that readmission rates may not be an appropriate marker for quality improvement.

Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. However, excessive autophagy could be cytotoxic, contributing to cell death, but its mechanism remains elusive. Arginine starvation has emerged as a potential therapy for several types of cancers, owing to their tumor-selective deficiency of the arginine metabolism. We demonstrated here that arginine depletion by arginine deiminase induces a cytotoxic autophagy in argininosuccinate synthetase (ASS1)-deficient prostate cancer cells. Advanced microscopic analyses of arginine-deprived dying cells revealed a novel phenotype with giant autophagosome formation, nucleus membrane rupture, and histone-associated DNA leakage encaptured by autophagosomes, which we shall refer to as chromatin autophagy, or chromatophagy. In addition, nuclear inner membrane (lamin A/C) underwent localized rearrangement and outer membrane (NUP98) partially fused with autophagosome membrane. Further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, presumably leading to DNA damage accumulation. Addition of ROS scavenger N-acetyl cysteine or knockdown of ATG5 or BECLIN1 attenuated the chromatophagy phenotype. Our data uncover an atypical autophagy-related death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments.

BackgroundThe relationship between procedural relative value units (RVUs) for surgical procedures and other measures of surgeon effort are poorly characterized. We hypothesized that RVUs would poorly correlate with quantifiable metrics of surgeon effort.MethodsUsing the 2010 American College of Surgeons - National Surgical Quality Improvement Program (NSQIP) database, we selected 11 primary current procedural terminology codes associated with high volume surgical procedures. We then identified all patients with a single reported procedural RVU who underwent nonemergent, inpatient general surgical operations. We used linear regression to correlate length of stay (LOS), operative time, overall morbidity, frequency of serious adverse events (SAEs), and mortality with RVUs. We used multivariable logistic regression using all preoperative NSQIP variables to determine other significant predictors of our outcome measures.ResultsAmong 14,481 patients, RVUs poorly correlated with individual LOS (R(2) = 0.05), operative time (R(2) = 0.10), and mortality (R(2) = 0.35). There was a moderate correlation between RVUs and SAEs (R(2) = 0.79) and RVUs and overall morbidity (R(2) = 0.75). However, among low- to mid-level RVU procedures (11-35) there was a poor correlation between SAEs (R(2) = 0.15), overall morbidity (R(2) = 0.05), and RVUs. On multivariable analysis, RVUs were significant predictors of operative time, LOS, and SAEs (odds ratio 1.06, 95% confidence interval: 1.05-1.07), but RVUs were not a significant predictor of mortality (odds ratio 1.02, 95% confidence interval: 0.99-1.05).ConclusionsFor common, index general surgery procedures, the current RVU assignments poorly correlate with certain metrics of surgeon work, while moderately correlating with others. Given the increasing emphasis on measuring and tracking surgeon productivity, more objective measures of surgeon work and productivity should be developed.

Background/aimThe Akt signaling pathway mediates a potent anti-apoptotic signal in pancreatic cancer and inhibition of this pathway has become an attractive mechanism to increase the efficacy of traditional chemotherapies. Autophagy is a lysosomal catabolic pathway by which eukaryotic cells recycle macromolecules and organelles. Although autophagy may function as a survival mechanism under metabolic stress conditions, it also serves as an alternate route to programmed cell death distinct from apoptosis. In the present study, we examined the role of autophagy in Akt-mediated regulation of cell death in pancreatic cancer.Materials and methodsMia-PaCa-2 and PANC-1 human pancreatic cancer cell lines were used in our experiments. The small-molecule inhibitor A-443654 was used to inhibit Akt, and rapamycin was used to inhibit mTOR. Autophagy was inhibited with Chloroquine and 3-methyladenine. Autophagy was assessed by immunoblotting for light chain-3 (LC-3) processing as well as fluorescence microscopy for autophagosome formation following transfection with a LC-3/GFP construct. Cell death was determined by fluorescence-activated cell sorting (FACS) with quantitation of the sub-G0 content.ResultsInhibition of either Akt or mTOR induced autophagy; inhibition of Akt but not of mTOR led to traditional caspase-mediated apoptosis. When autophagy was inhibited, cell death was abrogated following Akt, but not mTOR, inhibition.ConclusionThe Akt signaling pathway regulates both autophagy and apoptosis through divergent pathways; mTOR mediates autophagy signaling but appears to be un-involved in cell death. Autophagy appears to play a role in the regulation of cell survival by Akt, but only when proximal signaling pathways not involving mTOR are simultaneously activated.

Sentinel lymph node biopsy for breast cancer is a method to localize and excise the first draining lymph node from an invasive cancer of the breast. The histopathologic evaluation of the sentinel lymph node is used for predicting recurrence and survival and thus, guiding oncologists for treatment-decision making to administer adjuvant therapies. The ability to identify the sentinel node depends on methods to map lymphatic drainage from the breast to the sentinel node and accurately discriminate that node from other non-sentinel lymph nodes of the axilla. This review covers the clinical demand for technologies to assist the surgeon in intraoperative lymphatic mapping to specifically identify the sentinel lymph node in patients with breast cancer. Performance characteristics are reviewed for superparamagnetic iron oxide tracers used in lymphatic mapping compared to other current available technologies for lymphatic mapping. The Magtrace (superparamagnetic iron oxide tracer) Sentimag (handheld magnetic probe) system is an FDA-approved technology for intraoperative lymphatic mapping to facilitate sentinel lymph node biopsy in breast cancer with technologic performance characteristics that are equivalent to 99Technetium-sulfur colloid. Barriers to broader utilization primarily center around the need for nonmetallic devices to be used for the conduct of surgery, which would interfere with the paramagnetic method for tracer localization. [ABSTRACT FROM AUTHOR]