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Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence.Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated.Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome.Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416–28. ©2018 AACR.

PDF file - 77K, Long term changes in the persistence of TCR Vβ clonotypes in the blood following TIL adoptive transfer in representative responding patients

PDF file - 58K, Demographics and clinical characteristics of enrolled patients

PDF file - 1856K, Fig. S1. Schema of TIL adoptive cell therapy clinical trial; Fig. S2. Recovery of total white blood cell counts (WBC), absolute lymphocyte counts (ALC), and absolute neutrophil counts (ANC) during adoptive transfer TIL therapy in 31 treated patients; Fig. S3. Durable partial response of an intrathoracic melanoma mass near the aorta and heart in one patient at 6 weeks and 18 months after TIL infusion; Figure S4. Kaplan-Meier curves of overall survival and progression-free survival for all 31 treated patients; Figure S5. Kaplan-Meier curves of landmark-based overall survival and progression-free survival for irRC responding and non-responding TIL-treated patients; Fig. S6. Change in tumor burden over the first 20-22 months following TIL transfer therapy in responders and non-responders; Fig. S7. Box and whisker plot showing that telomere length of infused TIL was not significantly different between responders and non-responders

Supplementary figures and tables

PDF file - 69K, Derivation of the irRC best overall score

PDF file - 115K

PDF file - 76k, Table S3. Associations between categorical patient variables and clinical response; Table S4. Associations between continuous variables and clinical response

Water resources on the Canadian Prairies are at risk due to human settlement, agricultural intensification, and climatic change. The Red River Valley (RRV), Manitoba, Canada, represents a nexus of these cumulative stressors. Here land use change, combined with a recent increase in precipitation and runoff, imperils the protective function of tributaries draining to Lake Winnipeg. A concerted research effort over the past decade has greatly improved availability of data and knowledge about the RRV. However, a full synthesis of these data and information remain lacking. We undertook a review to identify and compare contemporary and historical land use, climatic, hydrologic, and water quality condition within the RRV. Then, using current knowledge of the ecological condition of streams in the RRV and elsewhere, we completed an ecological causal assessment of RRV tributaries to identify linkages and knowledge gaps between anthropogenic drivers and ecological endpoints. We found wastewater to be the candidate cause of ecological effects in RRV streams best supported by empirical evidence. A lack of complete lines of evidence linking agriculture, the greatest diffuse source of nutrient inputs, and ecological effects in RRV tributaries underscored a need for stressor-specific indicators and improved biomonitoring strategies to better detect likely impacts of land use. We also identified a need for research to connect well-known causal elements in the RRV, such as climatic variables and hydrological alteration, to ecological effects. Our findings provide direction for future research and can aid in development of an adaptive management strategy for tributaries of the RRV.

Lake Winnipeg has undergone rapid eutrophication over the last several decades with a large portion of the associated nutrient loads delivered via the Red River. Consequently, subcatchments of the Red River Valley (RRV) are priorities for nutrient management, an aim that requires identification of key nutrient sources to stream food webs. We identified the primary sources of nitrogen to food webs of rural streams of the RRV, as well as variation in nitrogen input between spring and summer. We measured δ15N of particulate organic matter (POM) and collector-gatherer invertebrates collected in spring and summer from 20 subcatchments, which exhibited a range of agricultural intensity and size of municipal wastewater lagoons. δ15N values of POM and collector-gatherer invertebrates were best predicted by the presence of wastewater treatment lagoons, with δ15N values increasing with the number of people served by lagoons in spring and summer. When present, wastewater contributed a greater proportion of nitrogen to stream food webs than agricultural sources. Waste sources also had a greater relative contribution to food webs in summer than spring. Despite wastewater lagoons releasing nitrogen in short-term, pulsed discharges, the influence of wastewater on food web nitrogen persisted from the summer release into the following spring. Based on the observed importance of wastewater as a source of nitrogen to stream food webs, we recommend management agencies consider additional actions to reduce nutrient losses from wastewater treatment facilities as well as agricultural lands to more effectively protect aquatic ecosystems.

Introduction Short-term outcomes after distal pancreatectomy (DP) for retroperitoneal (RP) tumors are unknown. We sought to identify rates of postoperative pancreatic fistula (POPF) and morbidity after en bloc DP with RP tumor resection. Methods A retrospective review of 43 patients who underwent DP with RP tumor resection (1/2011–12/2017) was performed. Results Seventeen patients had RP sarcoma, 12 renal cell carcinoma, 11 gastrointestinal stromal tumor, and 3 adrenocortical carcinoma. Grade III-IV complications occurred in 7 patients. Grade B POPF occurred in 14 patients, grade C POPF in none, and biochemical leak in 6. Of 22 patients who developed radiographically evident peri-pancreatic fluid collections, 7 required percutaneous drainage. The 90-day readmission rate was 33%. Conclusions DP with RP tumor resection is associated with high rates of clinically relevant POPF compared to historical results for DP for primary pancreatic tumors. Multi-center studies to identify targetable predictors and risk mitigation strategies for POPF in this rare high-risk population are needed.

PURPOSE Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma. PATIENTS AND METHODS Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis. RESULTS At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined. CONCLUSION Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.

OBJECTIVES: Retroperitoneal sarcomas (RPS) are often large at diagnosis calling into question the 7(th) edition AJCC size classification of 15cm). We evaluated the prognostic ability of the 8(th) edition using the National Cancer Database (NCDB). METHODS: Patients with RPS treated between 1998–2011 were identified from the NCDB; overall survival (OS) was compared. RESULTS: Of the 6,427 patients identified, 9% had tumors ≤5 cm (n=580), 19.4% 515cm (n=3,045). With the 8(th) edition, stage II patients (G2/3 ≤5cm) have a similar OS to stage IIIA patients (G2/3 5cm10cm) show a decrease in OS. Tumor size as a continuous variable had a modest effect on survival (HR 1.004, p=0.04). On multivariate analysis, higher T-stage was associated with decreased OS (T4 HR 1.3, p

Patients with well-differentiated liposarcomas (WDLPS) of the extremity and trunk are treated primarily with surgical resection, with radiation used for a number of anecdotal reasons, including large size and positive margins. In this study, we evaluate the appropriate role for radiation in these tumors. A retrospective chart review of patients with extremity and trunk soft tissue liposarcomas referred to a free-standing cancer center from January 1995 to December 2011 was performed. One hundred eighty-three patients with extremity and trunk soft tissue WDLPS were identified: 61 per cent were female, median age was 60 years (range, 19–84 years) and 2 per cent had a focal area of dedifferentiation, margin status was positive in 57 per cent. Fourteen per cent of patients received radiation. Fifty patients developed recurrent disease; 28 per cent of these received radiation. Median time to recurrence was 18 years (range, 0.7–22 years). Of the 50 patients who recurred, 14 (28%) received radiation. Radiation was associated with decreased second recurrence when administered for recurrent disease (P = 0.03). On multivariable analysis, tumor size ≤ 10 cm (P = 0.014) and anatomically difficult area of resection (P = 0.008) were predictive of increased risk of recurrence. Older age (P = 0.02), dedifferentiated liposarcomas (P < 0.001), and difficult area of resection (P = 0.02) were associated with the administration of radiotherapy. Administration of radiation therapy was not associated with decreased time to recurrence in WDLPS overall; however, it should be considered in patients with recurrent disease.

BACKGROUND Retroperitoneal sarcomas (RPS) are rare tumors for which complete surgical resection remains the mainstay of treatment. The objective of the current study was to determine the impact of hospital case volume on outcomes in patients with RPS. METHODS A total of 6950 patients with primary RPS who underwent surgical resection were identified from the National Cancer Data Base (1998-2011). Treating hospitals were classified by annual case volume; low-volume hospitals (LVHs) and high-volume hospitals (HVHs) were defined as those with ≤10 cases per year and >10 cases per year, respectively. Overall survival (OS) was compared using Kaplan-Meier curves. Cox proportional hazard models were created to compare risks. RESULTS Of the 1131 reporting hospitals, the majority (1127 hospitals; 99.6%) were LVHs treating the majority of patients (6270 patients; 90.2%). Patients treated at LVHs were more likely to have lower grade and smaller tumors, receive radiotherapy, and undergo incomplete macroscopic (R2) resection. Patients treated at HVHs had lower 30-day readmission rates (1.8% vs 3.4%; P

Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses over adjuvant treatment1; however, optimal regimens have not been defined. Herein, we report results from a randomized phase II study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma (NCT02519322). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs), and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results are the first to describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.

BACKGROUND: The benefit of preoperative chemoradiation (CXRT) over preoperative chemotherapy alone (“chemotherapy” hereafter) is unknown. By analyzing the National Cancer Database (NCDB), we investigated whether preoperative CXRT improves the incidence of primary tumor pathologic complete response (ypT0) and overall survival (OS) compared with preoperative chemotherapy in patients with gastric cancer. METHODS: Patients with non-metastatic gastric adenocarcinoma who underwent CXRT or chemotherapy followed by gastrectomy were included. Propensity score matching with a ratio of 1:1 was implemented to reduce selection bias. A conditional logistic regression model was used to compare incidences of ypT0 between groups, and Cox proportional hazards model was used to compare OS. RESULTS: We identified 8,464 patients. Median patient age was 63 years; 76% were male and 79% were white. ypT0 was observed in 16.1% of patients in the CXRT group and 6.6% in the chemotherapy group (p < 0.001). After propensity score matching, a total of 2,408 patients were matched. CXRT was associated with a higher incidence of ypT0 (OR 2.28, 95% CI 1.76–2.95; p < 0.0001) and higher frequency of R0 resection (92% vs. 86%; p < 0.001). However, CXRT was not associated with longer OS (HR 1.03, 95% CI 0.92–1.15; p = 0.63). Safety profiles (30-day mortality, 30-day readmission, and length of hospital stay) were equivalent between groups. CONCLUSIONS: In this study of gastric cancer patients from the NCDB, CXRT was associated with a higher incidence of ypT0 and R0 resection compared with chemotherapy, although it was not associated with a longer OS.

Because of the low incidence of nongastrointestinal stromal tumor (non-GIST) spindle cell sarcomas of the colon or rectum, the clinical behavior and ideal surgical treatment of these tumors and patient outcomes are poorly defined. The purpose of this study was to characterize these tumors and to determine the best surgical approach. We identified 1056 patients with non-GIST spindle cell sarcomas of the colon or rectum (1998–2010) in the National Cancer Database and collected data for each patient that included patient and tumor characteristics, tumor site (colon vs rectum), surgery type, and outcomes. The median overall survival was significantly longer in patients with rectal tumors than in those with colon tumors ( P < 0.01). Patients with colon tumors who underwent anatomic surgical resection showed a trend toward longer median survival than those with no surgical treatment [hazard ratio (HR), 1.94; P = 0.09] or who underwent local excision (HR, 1.74; P = 0.09). Patients with rectal tumors did not benefit from anatomic surgical resection, but there was a trend favoring local excision (HR, 0.55; P = 0.06). Local sphincter-sparing procedures should be considered for rectal non-GIST tumors whenever technically feasible.

Current evidence regarding salvage resection for recurrent retroperitoneal (RP) sarcomas generally lacks detailed histology-specific analyses, but the aggressiveness of these tumors varies widely by histology. We investigated associations between timing and extent of salvage surgery and survival outcomes in patients with recurrent RP well-differentiated liposarcoma (WDLPS). The University of Texas MD Anderson Cancer Center Surgical Oncology sarcoma database was reviewed to identify patients with RP WDLPS who underwent surgical resection for first recurrent disease (salvage surgery) in 1995–2015. Medical records were retrospectively reviewed to identify factors associated with overall survival and disease-free survival. We identified 52 patients who underwent salvage surgery for RP WDLPS for first local recurrence; 28 (54%) underwent salvage surgery within 6 months after recurrence. Concomitant organ resections were performed in 32 (62%) patients, 4 (13%) of whom had pathologic invasion of resected organs. After R0/R1 resections (n = 45), 38 (84%) experienced a second local recurrence. Multivariable analyses revealed that organ invasion at the primary surgery [hazard ratio (HR) 13.08; p = 0.005] and disease-free interval

The 8th edition American Joint Committee on Cancer (AJCC) staging for soft tissue sarcomas of the trunk/extremities divides T stage into four categories and upstages nodal disease to stage IV. We used the National Cancer Database (NCDB) to evaluate the prognostic power of the new system. A total of 26,144 patients were identified from the NCDB from 2004 to 2013. Overall survival (OS) was compared using Kaplan–Meier and Cox proportional hazard models. Including T3 (10 cm > × >15 cm) and T4 (> 15 cm) categories resulted in an increased number of patients classified as stage III (5120 as IIIA [19.6%] and 4280 as IIIB [16.4%], vs. 7882 [30.1%] previously), and there was a small increase in the number of patients classified as stage IV (2776 [10.6%], vs. 2565 [9.8%] previously). In the 7th edition, the hazard ratio (HR) for death increases with stage, with large incremental increases between stages II–III and III–IV. In the 8th edition, the HR for death demonstrates smaller incremental increases between each stage. Five-year OS for 7th edition T1 and T2 patients was 78.8 and 58.8% (p

BACKGROUND The role of surgical resection in the treatment of patients with metastatic/recurrent gastrointestinal stromal tumors (GIST) is unclear. The aim of this study was to identify preoperative factors associated with oncologic outcomes for recurrent/metastatic GIST after tyrosine kinase inhibitor (TKI) therapy. METHODS We identified 107 patients with metastatic or recurrent GIST treated with TKIs and surgical resection (2002-2012). Patients that underwent palliative or incomplete resection were excluded. Complete resection was achieved in 87 patients which comprise the analytic cohort. Univariate and multivariate analyses were conducted to identify risk factors for GIST-specific survival (DSS) and time-to-recurrence (TTR). RESULTS At a median follow-up of 51 months (91 months for survivors), median DSS was 74 months and TTR was 21 months. By univariate analysis, unifocal disease, duration of TKI

Background No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed. Methods Patients with clinical T2-4bN0-1M0 gastric adenocarcinoma, as defined by the eighth edition of the American Joint Committee on Cancer staging manual, who underwent gastrectomy from 2006 to 2014 were identified from the NCDB. Multiple logistic regression was conducted to examine factors associated with preoperative chemotherapy use. Results This study identified 16,945 patients who met the criteria, and 8286 of these patients (49%) underwent preoperative chemotherapy. The use of preoperative chemotherapy remarkably increased over the study period, from 34% in 2006 to 65% in 2014. Preoperative chemotherapy was more commonly used for cardia tumors than noncardia tumors (83% vs 44% in 2014). In a multivariable analysis, races and ethnicities other than non-Hispanic (NH) white race were associated with less frequent use of preoperative chemotherapy in comparison with NH whites after adjustments for social, tumor, and hospital factors. The insurance status and the education level mediated an enhanced effect of racial/ethnic disparities in preoperative chemotherapy use. The use of preoperative chemotherapy and radiation therapy was associated with reduced racial/ethnic disparities in overall survival. Conclusions Racial/ethnic disparities in the use of preoperative chemotherapy and in outcomes exist among patients with gastric cancer in the United States. Efforts to improve the access to high-quality cancer care in minority groups may reduce racial disparities in gastric cancer in the United States. Cancer 2018;124:998-1007. © 2018 American Cancer Society.

Summary Background Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation. Methods We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients (aged ≥18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAFV600E or BRAFV600K (ie, Val600Glu or Val600Lys)-mutated melanoma. Eligible patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of more than 3 years, and no previous exposure to BRAF or MEK inhibitors. Exclusion criteria included metastases to bone, brain, or other sites where complete surgical excision was in doubt. We randomly assigned patients (1:2) to either upfront surgery and consideration for adjuvant therapy (standard of care group) or neoadjuvant plus adjuvant dabrafenib and trametinib (8 weeks of neoadjuvant oral dabrafenib 150 mg twice per day and oral trametinib 2 mg per day followed by surgery, then up to 44 weeks of adjuvant dabrafenib plus trametinib starting 1 week after surgery for a total of 52 weeks of treatment). Randomisation was not masked and was implemented by the clinical trial conduct website maintained by the trial centre. Patients were stratified by disease stage. The primary endpoint was investigator-assessed event-free survival (ie, patients who were alive without disease progression) at 12 months in the intent-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT02231775. Findings Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18·6 months (IQR 14·6–23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19·7 months [16·2–not estimable] vs 2·9 months [95% CI 1·7–not estimable]; hazard ratio 0·016, 95% CI 0·00012–0·14, p Interpretation Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III–IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib. Funding Novartis Pharmaceuticals Corporation.

Introduction et but de l’etude Les poches vides de nutrition parenterale (NP) sont destinees a la reception, au stockage et a l’administration de melanges nutritifs. La fabrication des melanges de NP binaires est semi-automatisee a l’aide d’un automate Baxa EM2400 (Baxter). En 2019, de nouvelles recommandations relatives a la photoprotection des melanges nutritifs pour les prematures et enfants de moins de 2 ans ont ete publiees. Les 2 objectifs de cette etude sont : – obtenir une vue d’ensemble des differents types de poches vides mono-compartimentees de NP disponibles sur le marche ; – connaitre les alternatives compatibles avec notre processus de fabrication ainsi qu’avec les exigences des services de soins (reanimations neonatales et pediatriques). Materiel et methodes Une analyse des fiches techniques des differents fournisseurs de poches vides de NP a ete realisee. Cela a ete complete par un recueil des modalites de production et d’administration ainsi qu’une recherche bibliographique concernant la reglementation et les recommandations pour definir les criteres techniques de choix. Resultats et analyse statistique Quatre fournisseurs proposent des poches vides de NP : Baxter, SLB, Hemedis et Bexen. Tous les fournisseurs ont des poches monocouches en ethylene vinyle acetate (EVA) ; seuls Hemedis et Bexen commercialisent des poches en EVA teintees photoprotectrices. Baxter, Hemedis et Bexen ont des poches multicouches en EVA/ethylene alcool de vinyle (EVOH) jouant un role de barriere a l’oxygene. Toutes les poches ont 3 sites d’acces : un site de remplissage (R), un site d’administration (A) et un site d’addition (I). La connectique Luer-Lock (LL) pour le site R existe pour toutes les poches sauf les multicouches de Baxter disponibles avec la connectique Large Bore (LB). Concernant le site A, 2 systemes existent : twist-off ou membrane. Toutes les poches sont munies d’un systeme de septum avec bouchon pour le site d’addition. Les criteres de compatibilite avec l’automate Baxa sont : la presence d’une connectique compatible (site R) pour raccorder la poche avec la tubulure de l’automate et la possibilite d’inserer un connecteur avec un site de prelevement pour le controle analytique des poches. Toutes les poches sont techniquement compatibles sauf les multicouches de chez Baxter (connectique LB ne permettant pas l’insertion du site de prelevement). La presence d’œillets permettant un bon positionnement de la poche sur la balance lors de la production. Toutes les poches sont compatibles sauf les multicouches de chez Baxter. Anoter que, en plus de Baxter, seul SLB fournit une etude validant le remplissage aseptique des poches avec notre l’automate. Conclusion Les poches monocouches sont compatibles avec le processus mais l’etude de SLB confirme leur compatibilite avec l’automate. Baxter ne propose pas de poches multicouches compatibles. Le dispositif de clamp permet le verrouillage definitif du site R contrairement au pince clamp re-ouvrables. Pour le site A, il n’y a pas de difference en terme de securite microbiologique entre le systeme twist-off et la membrane. Concernant les recommandations de photoprotection, 2 fournisseurs proposent des poches photoprotectrices. Notons que Baxter n’en propose pas, d’ou l’importance de la question de la compatibilite des poches des autres fournisseurs avec l’automate Baxter.

The purpose of this study was to determine the frequency of tumor-related gastrointestinal obstruction and identify variables associated with functional outcomes and survival in patients with advanced malignancy and gastrointestinal obstruction.We reviewed the medical records of 490 patients with advanced cancer, who underwent surgical consultation for gastrointestinal obstruction between January 2000 and May 2014. We used chi-square and logistic regression analyses to identify variables associated with survival and eating at discharge.Obstructions were tumor-related in 334 (68%) patients, adhesion-related in 96 (20%), and of unclear etiology in 60 (12%). The obstruction site was the gastric outlet in 78 (16%), small bowel in 312 (64%), and large bowel in 100 (20%). Treatment was classified as medical (49% of patients), surgical (32%), and procedural (interventional radiology or endoscopy) (17%). Sixty-eight percent of patients were eating at the time of discharge, and 42% died within 90 days of surgical consultation. Median overall survival rates for patients managed with procedural, medical, and surgical treatment were 69, 135, and 314 days, respectively (p0.001). Intact primary/local recurrence, carcinomatosis, and albumin level3.5 g/dL were negatively associated with eating at discharge. Compared with medical management, surgery was not associated with the ability to eat. Variables associated with death within 90 days of consultation included an intact primary/local recurrence, carcinomatosis, abdominal visceral metastasis, and procedural treatment.Patients managed with surgery demonstrated improved survival on unadjusted analysis. However, on multivariate analysis that included the imaging extent of disease, surgery was not associated with outcome, which highlights the importance of patient selection and the need for additional research to identify variables critical for treatment selection.

Lymphedema is a condition of localized protein-rich swelling from damaged or malfunctioning lymphatics. Because the immune system is compromised, there is a high risk of infection. Infection in patients with lymphedema may present in a variety of ways.The goals of this review were to standardize the terminology of skin breakdown in the context of lymphedema, synthesize the available information to create best practice recommendations in support of the American Lymphedema Framework Project update to its Best Practices document, and create recommendations for further research.Publications on skin care and wounds were retrieved, summarized, and evaluated by a team of investigators and clinical experts.Terms for lymphedema-associated skin breakdown were compiled and paired with photographs of commonly noted skin changes among patients with lymphedema. A list of standard dermatological terms was created. A more extensive literature search was then conducted by all authors.Skin disorders associated with lymphedema have been classified into 5 categories. Descriptions, photographs, and recommendations for treatment are presented.Skin care is an important defense against infection. Because of the lack of research, a consensus of thought and content leaders' opinion should guide the best practices for wound care in lymphedema.

New indications have been found for regional nodal irradiation (RNI) in breast cancer treatment, yet the relationship of RNI and lymphedema risk is uncertain. We sought to determine the association of RNI and lymphedema. We searched MEDLINE, EMBASE, and Scopus for articles in English on humans published from 1995 to 2015, using search terms breast neoplasm, treatment, and morbidity. Two investigators independently selected articles and extracted information, including manuscripts reporting incidence of lymphedema by radiation targets. Meta-analyses, review papers, case–control studies, matched-pair studies, repetitive datasets, and retrospective studies were excluded. A total of 2399 abstracts were identified and 323 corresponding articles reviewed. Twenty-one studies met inclusion criteria. Data were pooled using a random effects mixed model. Network meta-analyses were performed to determine the association of radiation targets alone and radiation targets plus extent of axillary surgery on incidence of lymphedema. The addition of RNI to breast/CW irradiation was associated with an increased incidence of lymphedema (OR 2.85; 95% CI 1.24–6.55). In patients treated with sentinel lymph node biopsy or axillary sampling, there was no association of lymphedema with the addition of RNI to breast/CW irradiation (OR 1.58; 95% CI 0.54–4.66; pooled incidence 5.7 and 4.1%, respectively). Among patients treated with axillary lymph node dissection (ALND), treatment with RNI in addition to breast/CW radiation was associated with a significantly higher risk of lymphedema (OR 2.74; 95% CI 1.38–5.44; pooled incidence 18.2 and 9.4%, respectively). RNI is associated with a significantly higher risk of lymphedema than irradiation of the breast/CW, particularly after ALND.

Genome-wide association study (GWAS)-identified single-nucleotide polymorphisms (SNPs) are tag SNPs located in both transcribed and non-coding regulatory DNA regions, rather than representing causal or functional variants for disease. To identify functional variants or genes for melanoma susceptibility, we used functional mapping and annotation (FUMA) to perform functional annotation of the summary statistics of 2541 significant melanoma risk SNPs (P < 5 × 10−8) identified by GWAS. The original GWAS melanoma study included 15 990 cases and 26 409 controls, representing the largest international meta-analysis of melanoma susceptibility. We prioritized 330 unique genes, including those in immune cytokine signaling pathways, from 19 loci through positional, expression quantitative trait locus, and chromatin interaction mapping. In comparison, only 38 melanoma-related genes were identified in the original meta-analysis. In addition to the well-known melanoma susceptibility genes confirmed in the meta-analysis (MC1R, CDKN2A, TERT, OCA2 and ARNT/SETDB1), we also identified additional novel genes using FUMA to map SNPs to genes. Through chromatin interaction mapping, we prioritized IFNA7, IFNA10, IFNA16, IFNA17, IFNA14, IFNA6, IFNA21, IFNA4, IFNE and IFNA5; these 10 most significant genes are all involved in immune system and cytokine signaling pathways. In the gene analysis, we identified 72 genes with a P < 2.5 × 10−6. The genes associated with melanoma risk were DEF8 (P = 1.09 × 10−57), DBNDD1 (P = 2.19 × 10−42), SPATA33 (P = 3.54 × 10−38) and MC1R (P = 1.04 × 10−36). In summary, this study identifies novel putative melanoma susceptibility genes and provides a guide for further experimental validation of functional variants and disease-related genes.

Patients with well-differentiated liposarcomas (WDLPS) of the extremity and trunk are treated primarily with surgical resection, with radiation used for a number of anecdotal reasons, including large size and positive margins. In this study, we evaluate the appropriate role for radiation in these tumors. A retrospective chart review of patients with extremity and trunk soft tissue liposarcomas referred to a free-standing cancer center from January 1995 to December 2011 was performed. One hundred eighty-three patients with extremity and trunk soft tissue WDLPS were identified: 61 per cent were female, median age was 60 years (range, 19-84 years) and 2 per cent had a focal area of dedifferentiation, margin status was positive in 57 per cent. Fourteen per cent of patients received radiation. Fifty patients developed recurrent disease; 28 per cent of these received radiation. Median time to recurrence was 18 years (range, 0.7-22 years). Of the 50 patients who recurred, 14 (28%) received radiation. Radiation was associated with decreased second recurrence when administered for recurrent disease (

Objective To identify health disparities in pediatric patients with melanoma that affect disease presentation and outcome. Study design This was a retrospective cohort study of all persons aged ≤18 years diagnosed with melanoma and enrolled in the Texas Cancer Registry between 1995 and 2009. Socioeconomic status (SES) and driving distance to the nearest pediatric cancer treatment center were calculated for each patient. Logistic regression was used to determine factors associated with advanced-stage disease. Life table methods and Cox regression were used to estimate survival probability and hazard ratios. Results A total of 185 adolescents (age >10 years) and 50 young children (age ≤10 years) were identified. Hispanics (n = 27; 12%) were 3 times more likely than non-Hispanic whites (n = 177; 75%) to present with advanced disease (OR, 3.8; 95% CI, 1.7-8.8). Young children were twice as likely as adolescents to present with advanced disease (OR, 2.2; 95% CI, 1.1-4.3). Distance to treatment center and SES did not affect stage of disease at presentation. Hispanics and those in the lowest SES quartile had a significantly higher mortality risk (hazard ratios, 3.0 [95% CI, 1.2-7.8] and 4.3 [95% CI, 1.4-13.9], respectively). In the adjusted survival model, only advanced disease was predictive of mortality ( P Conclusion Hispanics and young children with melanoma are more likely to present with advanced disease, and advanced disease is the single most important predictor of survival. Heightened awareness among physicians is needed to facilitate early detection of melanoma within these groups.

Motivated by a study for soft tissue sarcoma, this article considers the analysis of diseases recurrence and survival. A multivariate frailty hazard model is established for joint modeling of three correlated time-to-event outcomes: local disease recurrence, distant disease recurrence (metastasis), and death. The goals are to find out (i) the effects of treatments on local and distant disease recurrences, and death, (ii) the effects of local and distant disease recurrences on death, and (iii) the correlation between local and distant recurrences. By our approach, all these three important questions, which are commonly asked in similar medical research studies, can be answered by a single model. We put the proposed joint frailty model in a Bayesian framework and use a hybrid Monte Carlo algorithm for the computation of posterior distributions. This hybrid algorithm relies on the evaluation of the gradient of target log density and a guided walk progress, and it combines these two strategies to suppress random walk behavior. A further distinction is that the hybrid algorithm can update all the components of a multivariate state vector simultaneously. Simulation studies are conducted to assess the proposed joint frailty model and the computation algorithm. The motivating soft tissue sarcoma data set is analyzed for illustration purpose. Copyright © 2016 John Wiley & Sons, Ltd.

PurposeTo evaluate for an association between 25-hydroxyvitamin D levels (vitamin D) and outcome measures in patients with melanoma after evaluation is controlled for systemic inflammatory response (SIR) on the basis of simultaneous C-reactive protein (CRP) measurement.Materials and MethodsPlasma samples from 1,042 prospectively observed patients with melanoma were assayed for vitamin D and CRP. The associations of demographics and CRP with vitamin D were determined, followed by a determination of the association between vitamin D and stage and outcome measures from the date of blood draw. The vitamin D level was considered sufficient if it was 30 to 100 ng/mL. Kaplan-Meier and Cox regression analyses were performed.ResultsThe median vitamin D level was 25.0 ng/mL. The median follow-up time was 7.1 years. A lower vitamin D was associated with the blood draw during fall/winter months (P < .001), older age (P = .001), increased CRP (P < .001), increased tumor thickness (P < .001), ulcerated tumor (P = .0105), and advanced melanoma stage (P = .0024). On univariate analysis, lower vitamin D was associated with poorer overall (OS; P < .001), melanoma-specific survival (MSS; P = .0025), and disease-free survival (DFS; P = .0466). The effect of vitamin D on these outcome measures persisted after adjustment for CRP and other covariates. Multivariable hazards ratios per unit decrease of vitamin D were 1.02 for OS (95% CI, 1.01 to 1.04; P = .0051), 1.02 for MSS (95% CI, 1.00 to 1.04; P = .048), and 1.02 for DFS (95% CI, 1.00 to 1.04; P = .0427).ConclusionLower vitamin D levels in patients with melanoma were associated with poorer outcomes. Although lower vitamin D was strongly associated with higher CRP, the associations of lower vitamin D with poorer OS, MSS, and DFS were independent of this association. Investigation of mechanisms responsible for these associations may be of value to patients with melanoma.

Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The purpose of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes. A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA, and outcome. At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63 %. Clinical variables associated with improved DSS included age

Background Previous economic evaluations compared specific chemotherapy agents using input parameters from clinical trials and resource utilization costs. Cost-effectiveness of treatment groups (drug classes) using community-level effectiveness and cost data, however, has not been assessed for elderly patients with breast cancer. Objective To assess the cost-effectiveness of chemotherapy regimens by age and disease stage under "real-world" conditions for patients with breast cancer. Methods The Surveillance Epidemiology and End Results-Medicare data were used to identify patients with breast cancer with American Joint Committee on Cancer stage I/II/IIIa, hormone receptor–negative (estrogen receptor–negative and progesterone receptor–negative) patients from 1992 to 2009. Patients were categorized into three adjuvant treatment groups: 1) no chemotherapy, 2) anthracycline, and 3) non–anthracycline-based chemotherapy. Median life-years and quality-adjusted life-years (QALYs) were measured using Kaplan-Meier analysis and were evaluated against average total health care costs (2013 US dollars). Results A total of 4575 patients (propensity score–matched) were included for the primary analysis. The anthracycline group experienced 12.05 QALYs and mean total health care costs of $119,055, resulting in an incremental cost-effectiveness ratio of $7,688 per QALY gained as compared with the no chemotherapy group (QALYs 7.81; average health care cost $86,383). The non–anthracycline-based group was dominated by the anthracycline group with lower QALYs (9.56) and higher health care costs ($122,791). Base-case results were found to be consistent with the best-case and worst-case scenarios for utility assignments. Incremental cost-effectiveness ratios varied by age group (range $3,790–$90,405 per QALY gained). Conclusions Anthracycline-based chemotherapy was found cost-effective for elderly patients with early stage (stage I, II, IIIa) breast cancer considering the US threshold of $100,000 per QALY. Further research may be needed to characterize differential effects across age groups.

Soft tissue sarcomas are a heterogeneous and rare group of solid tumors of mesenchymal origin that can arise anywhere in the body. Although surgical resection is the mainstay of treatment for patients with localized disease, disease recurrence is common and 5-year overall survival is poor (~ 65%). Both radiation therapy and conventional chemotherapy are used to reduce local and distant recurrence. However, the utility of radiation therapy is often limited by disease location (in the case of retroperitoneal sarcomas, for instance) while systemic therapy with conventional lines of chemotherapy offer limited efficacy and are often poorly tolerated and associated with significant toxicity. Within the past decade, major advances have been made in the treatment of other malignancies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma with the advent of immune-checkpoint inhibitors such as ipilimumab (anti-CTLA4), pembrolizumab (anti-PD1), and nivolumab (anti-PD1). The recently published SARC028 (NCT02301039), an open label, phase II, multicenter trial of pembrolizumab in patients with advanced bone and soft tissue sarcomas reported promising activity in select histologic subtypes of advanced STS, including undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. There is a clear need for novel and effective adjuncts in the treatment of STS. We hypothesize that immune checkpoint blockade will be effective in patients with surgically resectable primary or locally recurrent dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma when administered in the neoadjuvant setting. The primary aim of this phase II, single-center, open label, randomized non-comparative trial is to determine the pathologic response to neoadjuvant nivolumab monotherapy and combination nivolumab/ipilimumab in patients with resectable dedifferentiated liposarcoma of the retroperitoneum or undifferentiated pleomorphic sarcoma of the trunk or extremity treated with concurrent standard of care neoadjuvant radiation therapy. This study will help define the role of single agent anti-PD1 and combination anti-CTLA4 and anti-PD1 therapy in patients with surgically resectable dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma. ClinicalTrials.gov NCT03307616 , registered October 12, 2017.

To investigate the role of tumor cytokines/chemokines in melanoma immune response, we estimated proportions of immune cell subsets in melanoma tumors from TCGA, followed by evaluation of association between cytokine/chemokine expression and these subsets. We then investigated association of immune cell subsets, chemokines, and cytokines with patient survival. Finally, we evaluated immune cell TIL score for correlation with melanoma patient outcome in a separate cohort. There was good agreement between RNA-seq estimation of T-cell subset with pathologist-determined TIL score. Expression levels of cytokines IL-12A, IFNG, IL-10, and chemokines CXCL9 and CXCL10 were positively correlated with PDCD1, CTLA-4, and CD8+ T cell subset, but negatively correlated with tumor purity (Bonferroni-corrected P

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome. Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416–28. ©2018 AACR.

Because of the low incidence of nongastrointestinal stromal tumor (non-GIST) spindle cell sarcomas of the colon or rectum, the clinical behavior and ideal surgical treatment of these tumors and patient outcomes are poorly defined. The purpose of this study was to characterize these tumors and to determine the best surgical approach. We identified 1056 patients with non-GIST spindle cell sarcomas of the colon or rectum (1998-2010) in the National Cancer Database and collected data for each patient that included patient and tumor characteristics, tumor site (colon vs rectum), surgery type, and outcomes. The median overall survival was significantly longer in patients with rectal tumors than in those with colon tumors (P0.01). Patients with colon tumors who underwent anatomic surgical resection showed a trend toward longer median survival than those with no surgical treatment [hazard ratio (HR), 1.94; P = 0.09] or who underwent local excision (HR, 1.74; P = 0.09). Patients with rectal tumors did not benefit from anatomic surgical resection, but there was a trend favoring local excision (HR, 0.55; P = 0.06). Local sphincter-sparing procedures should be considered for rectal non-GIST tumors whenever technically feasible.

Background The good preparation practices recommend a control of chemotherapy compound to minimise the risk of mistakes before patient’s administration. We tried to put in place an automated analytic method taking into account financial and technical criteria to control IV chemotherapy preparations. Purpose The purpose was to evaluate the identification and qualification performances of a new quality control system: the spectrophotometer (Druglog, pharmacolog, Uppsala). Material and methods The system is based on absorption spectroscopy in the ultraviolet and visual spectral range calculated according to the Beer-lambert law. Eight cytotoxic drugs were initially chosen based on level of clinical use. The statistical approach used for validation referred to the International Conference Harmonisation.1 Each drug calibration was made in triplicate the same day. These operations were repeated for three different sets and three different days. A mathematical model of linear regression representing the relationship between absorbance and concentration of the molecule has been applied. We were able to determine statistically the best calibration curve for each drug through the correlation coefficient’s (R²). Each validation standard was then analysed by the spectrophotometer to determine the relative error of the concentrations measured. Finally, a number of tests were performed on cytotoxic infusion kits. Results All calibration curves present a linear profile: R² average and maximal are higher than 0.98 except irinotecan with R²=0.96. The system has specifically identified each validation standard. The results show that the system can measure all compounds with a relative error less than 12%. The tests in production are presented in the following table. All drugs were correctly identified. Conclusion We can doubt the linearity of the irinotecan calibration and enquire about any matrix effect, or even a stability problem with NaCl diluent. During production tests, no kits were found with erroneous drugs. The dosing error rates were higher than those of the validation standards. We have considered a problem with the homogenisation kits. These first results are promising but we will therefore continue the collaboration with Pharmacolog and Uppsala to perform our analytical method of control. Reference and/or Acknowledgements ICH harmonised tripartite guideline validation of analytical procedures No conflict of interest

Soft tissue sarcomas are a heterogeneous group of neoplasms that arise throughout the body, but most commonly in the extremity and trunk. A multidisciplinary treatment approach has resulted in local control rates exceeding 90% and 5-year survival rates exceeding 70%. For patients with localized soft tissue sarcoma, limb-sparing surgical resection is the mainstay of therapy, with radiation therapy and chemotherapy used as adjuncts to reduce local and distant recurrences. Amputation is reserved for patients with primary or recurrent tumors that cannot be grossly resected with a limb-sparing procedure and preservation of function, which should occur in less than 5% of patients. Most patients who die of soft tissue sarcoma die of metastatic disease, which becomes evident within 2 to 3 years of initial diagnosis in 80% of cases, highlighting the need for improved systemic therapy options and optimal treatment at the time of diagnosis. This review contains 13 figures, 4 tables and 53 references Key words: amputation, multimodality, radiation therapy, soft tissue sarcoma, staging, surgery, treatment, wide resection

Introduction The incidence and clinical significance of lymph node metastasis (LNM, N1) in soft tissue sarcoma (STS) is unclear. Recent studies have focused on extremity/trunk STS (ETSTS). We sought to define the subgroup of patients with LNM at sarcoma diagnosis across all disease sites and histologies. Methods We identified and categorized 89,870 STS patients from the National Cancer Data Base (1998–2012) by nodal stage. Pathologically confirmed LNM (pN1) were identified in 1404 patients; 1750 had clinically suspicious but not pathologically confirmed LNM (cN1). Survival analyses were performed by Kaplan-Meier method. Results Of 3154 patients (3.5%) with pN1 or cN1 LNM at presentation, 1310 had synchronous distant metastasis (M1). LNM affected a small proportion of patients (5.8% head/neck, 5.3% intrathoracic, 5.1% intra-abdominal, 2.0% ETSTS). Angiosarcoma (6%), epithelioid (13%), clear cell (16%), and small cell sarcoma (19%) had the highest incidence of LNM, although liposarcoma, fibrous histiocytoma, and leiomyosarcoma accounted for the greatest number of LNM patients. For pN1M0 disease, median overall survival (OS) was 28.2 months, varying by histology. Among patients with pN1M0 STS, angiosarcoma, clear cell sarcoma, leiomyosarcoma, and fibrous histiocytoma were associated with worse median OS (19.4, 23.8, 27.1, and 29.3 months) compared to epithelioid sarcoma and liposarcoma (49.6 and 56.0 months, p Conclusion Despite clinical suspicion, pathologic LN evaluation in STS is inconsistently performed. LNM occurs across anatomic disease sites and is unevenly distributed across histologies. Although M1 disease portends poor prognosis regardless of LN status, LNM predicts worse OS in a histology-dependent manner in M0 disease.