Treatment of hemorrhagic head and neck lesions by direct puncture and nBCA embolization

Life-threatening bleeding in the head and neck region requires urgent management. These hemorrhagic lesions, for example, a ruptured pseudoaneurysm, are often treated by transarterial embolization (TAE), but prior intervention or surgery, inflammation, anatomic variants, and vessel tortuosity may render an endovascular approach challenging, time-consuming, and sometimes impossible. We report two cases of severe head and neck hemorrhages successfully embolized with n-butyl cyanoacrylate via direct puncture, and propose this approach as a fast, safe, and effective alternative to TAE.

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Correlation of Circulating CD64 + /CD163 + Monocyte Ratio and stroma/peri-tumoral CD163 + Monocyte Density with Human Papillomavirus Infected Cervical Lesion Severity

Abstract

HPV infected cervical cells secrete mediators that are gradually changed and have influence on infiltrating M2 phenotypic monocytes in cervical lesions. However, profiles of circulating immune cells in women with cervical lesions and M2 phenotypic monocyte activity in HPV infected cervical lesions are limited. This study aimed to investigate circulating monocyte populations correlated with M2 phenotype density and its activity in HPV infected cervical lesions. HPV DNA was investigated in cervical tissues using PCR. High risk HPV E6/E7 mRNA was detected using in situ hybridization. CD163 immunohistochemical staining was performed for M2 macrophage. CD163 and Arg1 mRNA expression were detected using real-time PCR. Circulating monocyte subpopulations were analyzed using flow cytometry. CD163 and Arg1 mRNA expression were increased according to cervical lesion severity and corresponding with density of M2 macrophage in HSIL and SCC in stroma and peri-tumoral areas. Additionally, the relationship between M2 macrophage infiltration and high risk HPV E6/E7 mRNA expression was found and corresponded with cervical lesion severity. Circulating CD14⁺CD16⁺ and CD14⁺CD163⁺ monocytes were elevated in No-SIL and cervical lesions. Interestingly, CD14⁺CD64⁺ monocyte was greatly elevated in HSIL and SCC, whereas intracellular IL-10⁺ monocytes were not significantly different between cervical lesions. The correlation between increasing ratio of circulating CD64⁺/CD163⁺ monocyte and density of infiltrating CD163⁺ monocytes was associated with severity of HPV infected cervical lesions. The elevated circulating CD64⁺/CD163⁺ monocyte ratio correlates to severity of HPV infected cervical lesions and might be a prognostic marker in cervical cancer progression.

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Correlation of Circulating CD64 + /CD163 + Monocyte Ratio and stroma/peri-tumoral CD163 + Monocyte Density with Human Papillomavirus Infected Cervical Lesion Severity

Abstract

HPV infected cervical cells secrete mediators that are gradually changed and have influence on infiltrating M2 phenotypic monocytes in cervical lesions. However, profiles of circulating immune cells in women with cervical lesions and M2 phenotypic monocyte activity in HPV infected cervical lesions are limited. This study aimed to investigate circulating monocyte populations correlated with M2 phenotype density and its activity in HPV infected cervical lesions. HPV DNA was investigated in cervical tissues using PCR. High risk HPV E6/E7 mRNA was detected using in situ hybridization. CD163 immunohistochemical staining was performed for M2 macrophage. CD163 and Arg1 mRNA expression were detected using real-time PCR. Circulating monocyte subpopulations were analyzed using flow cytometry. CD163 and Arg1 mRNA expression were increased according to cervical lesion severity and corresponding with density of M2 macrophage in HSIL and SCC in stroma and peri-tumoral areas. Additionally, the relationship between M2 macrophage infiltration and high risk HPV E6/E7 mRNA expression was found and corresponded with cervical lesion severity. Circulating CD14⁺CD16⁺ and CD14⁺CD163⁺ monocytes were elevated in No-SIL and cervical lesions. Interestingly, CD14⁺CD64⁺ monocyte was greatly elevated in HSIL and SCC, whereas intracellular IL-10⁺ monocytes were not significantly different between cervical lesions. The correlation between increasing ratio of circulating CD64⁺/CD163⁺ monocyte and density of infiltrating CD163⁺ monocytes was associated with severity of HPV infected cervical lesions. The elevated circulating CD64⁺/CD163⁺ monocyte ratio correlates to severity of HPV infected cervical lesions and might be a prognostic marker in cervical cancer progression.

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Treatment challenges in and outside a specialist network setting: pancreatic neuroendocrine tumours

Publication date: Available online 16 October 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Panagis Lykoudis, Stefano Partelli, Francesca Muffatti, Martyn Caplin, Massimo Falconi, Giuseppe Fusai
Pancreatic Neuroendocrine Neoplasms comprise a group of rare tumours with special biology, an often indolent behaviour and particular diagnostic and therapeutic requirements. The specialized biochemical tests and radiological investigations, the complexity of surgical options and the variety of medical treatments that require individual tailoring, mandate a multidisciplinary approach that can be optimally achieved through an organized network. The present study describes currents concepts in the management of these tumours as well as an insight into the challenges of delivering the pathway in and outside a Network.



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Patient satisfaction with Radioguided Occult Lesion Localisation using Iodine-125 Seeds (‘ROLLIS’) versus conventional hookwire localisation

Publication date: Available online 16 October 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Jeremy S.L. Ong, Joelin Teh, Christobel Saunders, Anita G. Bourke, Catalina Lizama, Jade Newton, Michael Phillips, Donna B. Taylor
BackgroundWomen with impalpable or poorly palpable breast cancer require radiologically guided localisation prior to breast conserving surgery. Radioguided Occult Lesion Localisation using Iodine-125 Seed (ROLLIS) is an emerging alternative to conventional Hookwire Localisation (HWL). We compared ROLLIS with conventional HWL with respect to patient reported stress and discomfort related to the localisation procedure.Patients and methodsFrom September 2013 to January 2016, women who were eligible for breast conserving surgery with impalpable or poorly palpable histologically confirmed invasive or in-situ carcinoma were recruited to the multi-centre ROLLIS randomised controlled trial and underwent either ROLLIS or HWL. Following surgery a questionnaire was administered to each participant regarding the stress and discomfort related to the localisation procedure. Multivariate analysis was performed to compare the primary outcome of patient-reported stress and discomfort between localisation groups.Results218 participants with 220 lesions were randomised and underwent breast conserving surgery following localisation. 201 (92.2%) and 202 (92.7%) of participants provided responses to the stress and discomfort components of the questionnaire respectively. HWL was associated with a statistically significant increased odds of greater stress and discomfort when compared to ROLLIS (OR=2.07, p=0.01 and OR=1.94, p=0.01 respectively). Insertion of multiple localisation devices was also associated with increased stress (OR=5.68, p<0.01) and discomfort (OR=2.96, p<0.01).ConclusionWhen compared with conventional HWL, ROLLIS is associated with significantly less stress and discomfort for patients prior to breast conserving surgery.



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Parenchymal sparing surgery for colorectal liver metastases: the need for a common definition

Publication date: Available online 16 October 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Marie Desjardin, Gregoire Desolneux, Véronique Brouste, Olivier Degrandi, Benjamin Bonhomme, Marianne Fonck, Yves Becouarn, Dominique Béchade, Serge Evrard
BackgroundThe definition of parenchymal sparing surgery (PSS) for colorectal liver metastases (CRLM) diverges requiring a clarification of the concept.MethodA consecutive series of patients were treated by PSS for their CRLMs, either by resection or intra-operative ablation (IOA), whenever possible a one-stage surgery and minimal usage of portal vein embolization. Post-operative complications were the primary endpoint with a special focus on post-operative liver failure.ResultsThree hundred and eighty-seven patients underwent a PSS out of which 328 patients received a median of 9 pre-operative cycles of chemotherapy. One hundred and twenty-eight patients had a major resection, combined with IOA in 137 patients and IOA alone in 50 cases. The 5yr-overall survival was 50.3%. There was no difference in post-operative complications between minor and major resections, validating our PSS definition based on the Tumor burden/Healthy liver ratio and not just the retrieved volume.ConclusionsPSS is defined as a high ratio of tumoral burden per specimen retrieved while favoring one-stage surgery approach. Our series, using combined resections and IOAs, matches this definition well. Furthermore, complications were correlated neither to chemotherapy nor to liver-induced toxicities, contrary to extended hepatectomies.



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Autologous fat tissue grafting improves pulmonary healing after laser metastasectomy

Publication date: Available online 16 October 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Simone Furia, Pierfrancesco Cadenelli, Francesca Andriani, Paolo Scanagatta, Leonardo Duranti, Andrea Spano, Carlotta Galeone, Luca Porcu, Ugo Pastorino
BackgroundExtensive clinical experience has demonstrated the potential usefulness of autologous fat tissue (AFT) graft in tissue reconstruction, repair or regeneration. In the present study, we evaluated the feasibility and safety of AFT in the repair of surgically injured lung surface.MethodsEighty consecutive procedures of pulmonary metastasectomy by laser precision resection, were performed in 66 patients between March 2010 and December 2012. In the first 20 procedures, AFT graft was applied on the wounded pulmonary surface without closure of parenchymal surface. The following 40 procedures were carried on without AFT (20 leaving the resection margins open and 20 closing the resection margins with a running suture). In the remaining 20 procedures, AFT was applied and the resection margins closed. The efficacy of this technique was evaluated by comparing the AFT group with the non-AFT group, with respect to prolonged alveolar air leakage (PAAL), time to drain removal, length of hospital stay, and patient survival at four years.ResultsThe occurrence of PAAL was lower in the AFT group as compared to non-AFT group (17.5% versus 42.5%, p=0.027), and median time to drain removal shorter (4 versus 6 days respectively, p=0.016). Overall 4-year survival was 70% for AFT group, and 59% for non-AFT group (p= 0.34).ConclusionsThis prospective cohort observational study demonstrated the feasibility and safety of AFT pulmonary grafting after laser metastasectomy. AFT graft improved pulmonary healing, by reducing the incidence and severity of PAAL. Moreover, there was no evidence of tumor promotion in the metastatic setting, with a similar overall survival at 4 years.



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An analysis of factors affecting the accuracy of endoscopic biopsy after neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma

Publication date: Available online 16 October 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Yin-Kai Chao, Yu-Wen Wen, Hsien-Kun Chang, Chen-Kan Tseng, Yun-Hen Liu
PurposeThe accuracy of endoscopic esophageal biopsy after neoadjuvant chemoradiotherapy (nCRT) remains suboptimal. We retrospectively examined the factors that may affect the diagnostic accuracy of post-nCRT endoscopic biopsy in patients with esophageal squamous cell carcinoma (ESCC).Materials and methodsA total of 213 ESCC patients were enrolled. Biopsy findings were cross-checked against the final pathology outcomes (ypT0 versus non-ypT0) to assess their accuracy. The independent predictors of diagnostic accuracy were identified by multivariate logistic regression analysis.ResultsPost-nCRT endoscopic biopsy results were diagnostically consistent with the final pathology outcomes in 116 (54.5%) patients. Multivariate logistic regression analysis identified a long time interval between the completion of nCRT and the endoscopic examination as the only factor independently associated with a higher diagnostic accuracy. Receiver operating characteristic curve analysis showed that the optimal cutoff value for the time interval between nCRT completion and endoscopic biopsy was 45 days. The estimated diagnostic accuracies of biopsies performed before and after the optimal cutoff time were 49.1% and 72.9%, respectively.ConclusionsEndoscopic biopsies performed ≥45 days after nCRT are associated with a higher diagnostic accuracy. This time cutoff may serve as a reference to inform the choice of the optimal treatment strategy following nCRT, especially among complete responders in whom surgery withholding is being considered.



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Perioperative morbidity, bowel function and oncologic outcome after radical cystectomy and ileal orthotopic neobladder reconstruction: Studer-pouch versus I-pouch

Publication date: Available online 20 October 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Johannes Mischinger, Mohamed F. Abdelhafez, Steffen Rausch, Tilman Todenhöfer, Eva Neumann, Stefan Aufderklamm, Arnulf Stenzl, Georgios Gakis
ObjectiveTo investigate whether the length of ileum used for ileal orthotopic neobladder (ONB) reconstruction (60cm vs. 40cm) after radical cystectomy (RC) for bladder cancer (BC) impacts on bowel function, postoperative complications or survival outcome.Material and MethodsIn this retrospective study, we included 56 patients who received an ONB (Studer (S)-Pouch: 23 patients; I-Pouch: 33 patients) after RC for BC between 2003 and 2011. Preoperative comorbidities were assessed by the Charlson Comorbidity Index (CCI) and surgical complications as graded by the Clavien-Dindo classification. Changes of perioperative bowel habits were retrospectively evaluated by the validated Gastrotintestinal Quality of Life Index (GIQLI). Kaplan–Meier analyses calculated survival outcomes between both ONB types.ResultsPreoperative CCI was comparable between S- and I-pouch patients. No significant differences were observed for 30-day major- (p=0.33) and minor (p=0.96) complication rates between both neobladder types. S-Pouch patients reported higher preoperative stool frequencies (S-pouch: mean 2.7; I-pouch: mean 3.4; p=0.049) and tended to suffer from urgency (S: mean 2.9; I: mean 3.4; p=0.059). No significant differences in postoperative bowel disorders were found between both neobladder types (S-Pouch: 15.9, IQR; I-Pouch: 16.6 IQR; p=0.84). Furthermore, we observed no overall-, cancer specific- or recurrence free survival advantage for either of both ONB variants (p=0.81; 0.65 and 0.78), respectively.ConclusionComorbidities, perioperative complication rates and bowel habits were similar between both ONB substitutes and did not influence survival outcomes. These stratified data suggest that the length of ileum used for ONB reconstruction (60- vs. 40cm) does not impact per se on postoperative bowel function.



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Simple, mild, one-step labelling of proteins with gallium-68 using a tris(hydroxypyridinone) bifunctional chelator: a 68 Ga-THP-scFv targeting the prostate-specific membrane antigen

Abstract

Background

Labelling proteins with gallium-68 using bifunctional chelators is often problematic because of unsuitably harsh labelling conditions such as low pH or high temperature and may entail post-labelling purification. To determine whether tris(hydroxypyridinone) (THP) bifunctional chelators offer a potential solution to this problem, we have evaluated the labelling and biodistribution of a THP conjugate with a new single-chain antibody against the prostate-specific membrane antigen (PSMA), an attractive target for staging prostate cancer (PCa). A single-chain variable fragment (scFv) of J591, a monoclonal antibody that recognises an external epitope of PSMA, was prepared in order to achieve biokinetics matched to the half-life of gallium-68. The scFv, J591c-scFv, was engineered with a C-terminal cysteine.

Results

J591c-scFv was produced in HEK293T cells and purified by size-exclusion chromatography. A maleimide THP derivative (THP-mal) was coupled site-specifically to the C-terminal cysteine residue. The THP-mal-J591c-scFv conjugate was labelled with ammonium acetate-buffered gallium-68 from a ⁶⁸Ge/⁶⁸Ga generator at room temperature and neutral pH. The labelled conjugate was evaluated in the PCa cell line DU145 and its PSMA-overexpressing variant in vitro and xenografted in SCID mice.

J591c-scFv was produced in yields of 4–6 mg/l culture supernatant and efficiently coupled with the THP-mal bifunctional chelator. Labelling yields > 95% were achieved at room temperature following incubation of 5 μg conjugate with gallium-68 for 5 min without post-labelling purification. ⁶⁸Ga-THP-mal-J591c-scFv was stable in serum and showed selective binding to the DU145-PSMA cell line, allowing an IC50 value of 31.5 nM to be determined for unmodified J591c-scFv. Serial PET/CT imaging showed rapid, specific tumour uptake and clearance via renal elimination. Accumulation in DU145-PSMA xenografts at 90 min post-injection was 5.4 ± 0.5%ID/g compared with 0.5 ± 0.2%ID/g in DU145 tumours (n = 4).

Conclusions

The bifunctional chelator THP-mal enabled simple, rapid, quantitative, one-step room temperature radiolabelling of a protein with gallium-68 at neutral pH without a need for post-labelling purification. The resultant gallium-68 complex shows high affinity for PSMA and favourable in vivo targeting properties in a xenograft model of PCa.

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Receipt of thoracic radiation therapy and radiotherapy dose are correlated with outcomes in a retrospective study of three hundred and six patients with extensive stage small-cell lung cancer

The importance of the thoracic radiation therapy (TRT) dose has not been clearly defined in extensive stage small-cell lung cancer (ES-SCLC) and it is unclear whether improved TRT dose translates into a survival benefit.

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Dosimetric feasibility of the hybrid Magnetic Resonance Imaging (MRI)-linac System (MRL) for brain metastases: The impact of the magnetic field

We aimed to investigate the suitability of treating patients with single brain metastases using stereotactic radiosurgery (SRS) with the MRL and to characterize the dosimetric impact at tissue-air interfaces resulting primarily from the electron return effect (ERE).

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Prognostic value of tissue necrosis, hypoxia-related markers and correlation with HPV status in head and neck cancer patients treated with bio- or chemo-radiotherapy

The aim of the present study was to investigate the role of three hypoxia-related biomarkers in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with concurrent chemoradiotherapy (3-weekly cisplatin) or bioradiotherapy (weekly cetuximab).

http://ift.tt/2leLTL8

Posterior reversible encephalopathy syndrome (PRES) induced by pazopanib, a multi-targeting tyrosine kinase inhibitor, in a patient with soft-tissue sarcoma: case report and review of the literature

Summary

Posterior reversible encephalopathy syndrome (PRES) is a clinical entity characterized by acute neurological symptoms such as severe headache, seizures, and visual disturbance, and by typical reversible lesion on brain magnetic resonance (MR) images. Since PRES is thought to be caused by vascular endothelial injury due to cytotoxic agents or acute systemic hypertension, the number of reports on PRES associated with angiogenesis inhibitors has been increasing. Although five cases that developed PRES due to pazopanib for renal cell carcinoma have already been reported, none of PRES due to pazopanib for soft-tissue sarcoma has been reported thus far. We describe a case of a 49-year-old woman with retroperitoneal soft-tissue sarcoma who developed PRES during pazopanib administration. Pazopanib at 800 mg/day was administered as her third-line treatment at relapse. After 38 days of pazopanib, she was admitted to our hospital with severe headache, vomiting, and systemic hypertension. The next day, she developed consciousness deterioration and visual disturbance together with exacerbated systemic hypertension. Brain MR images revealed hyper-intense signals on FLAIR sequences in the bilateral occipital lobes and the left thalamus. Intravenous nicardipine injection was immediately started to control her blood pressure and pazopanib was discontinued. Her symptoms gradually improved and disappeared on the fifth hospital day. After 2 weeks, hyper-intense signals on a FLAIR sequence disappeared completely. She restarted a low dose of pazopanib under good blood pressure control and experienced no subsequent recurrence of PRES.

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Posterior reversible encephalopathy syndrome (PRES) induced by pazopanib, a multi-targeting tyrosine kinase inhibitor, in a patient with soft-tissue sarcoma: case report and review of the literature

Summary

Posterior reversible encephalopathy syndrome (PRES) is a clinical entity characterized by acute neurological symptoms such as severe headache, seizures, and visual disturbance, and by typical reversible lesion on brain magnetic resonance (MR) images. Since PRES is thought to be caused by vascular endothelial injury due to cytotoxic agents or acute systemic hypertension, the number of reports on PRES associated with angiogenesis inhibitors has been increasing. Although five cases that developed PRES due to pazopanib for renal cell carcinoma have already been reported, none of PRES due to pazopanib for soft-tissue sarcoma has been reported thus far. We describe a case of a 49-year-old woman with retroperitoneal soft-tissue sarcoma who developed PRES during pazopanib administration. Pazopanib at 800 mg/day was administered as her third-line treatment at relapse. After 38 days of pazopanib, she was admitted to our hospital with severe headache, vomiting, and systemic hypertension. The next day, she developed consciousness deterioration and visual disturbance together with exacerbated systemic hypertension. Brain MR images revealed hyper-intense signals on FLAIR sequences in the bilateral occipital lobes and the left thalamus. Intravenous nicardipine injection was immediately started to control her blood pressure and pazopanib was discontinued. Her symptoms gradually improved and disappeared on the fifth hospital day. After 2 weeks, hyper-intense signals on a FLAIR sequence disappeared completely. She restarted a low dose of pazopanib under good blood pressure control and experienced no subsequent recurrence of PRES.

http://ift.tt/2iAdNAx

Dexamethasone: The wonder drug in perioperative medicine

Anesthesiologist have a greater understanding of the role of the stress response and the development of inflammation following surgery on clinical outcomes [1,2]. Exacerbation of inflammation after surgery has been shown to be associated with multiple negative postsurgical outcomes (e.g., pain, cardiovascular events) [3]. The reduction of inflammation is, therefore, a common target used by anesthesiologists to minimize postoperative complications [4–7].

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Chemical profiling of primary mesothelioma cultures defines subtypes with different expression profiles and clinical responses

Finding new treatment options for patients with malignant pleural mesothelioma is challenging due to the rarity and heterogeneity of this cancer type. The absence of druggable targets further complicates the development of new therapies. Current treatment options are therefore limited and prognosis remains poor. Experimental Design: We performed drug screening on primary mesothelioma cultures to guide treatment decisions of corresponding patients that were progressive after first or second line treatment. Results: We observed a high concordance between in vitro results and clinical outcomes. We defined three subgroups responding differently to the anti-cancer drugs tested. In addition, gene expression profiling yielded distinct signatures that segregated the differently responding subgroups. These genes signatures involved various pathways, most prominently the fibroblast growth factor pathway. Conclusions: Our primary mesothelioma culture system has proved to be suitable to test novel drugs. Chemical profiling of primary mesothelioma cultures allows personalizing treatment for a group of patients with a rare tumor type, where clinical trials are notoriously difficult. This personalized treatment strategy is expected to improve the poor prospects of mesothelioma patients.

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Tumor microvessel density as a prognostic marker in high-risk renal cell carcinoma patients treated on ECOG-ACRIN E2805

Purpose: Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis, however its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC. Methods: We obtained pre-treatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence we measured tumor MVD as the area of CD34-expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm and clinicopathologic variables. Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (p=0.021) and for patients treated with placebo (p=0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p=0.060). MVD was not associated with DFS (p=1.00). On multivariable analysis, MVD remained independently associated with improved OS (p=0.013). High MVD correlated with Fuhrman grade 1-2 (p<0.001), clear cell histology (p<0.001), and absence of necrosis (p<0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size. Conclusions:High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high risk patients for adjuvant therapy trials.

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PQR309 is a novel dual PI3K/mTOR inhibitor with pre-clinical antitumor activity in lymphomas as a single agent and in combination therapy

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types and pharmacological inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models. Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene expression profiling and comparison with other signaling inhibitors. Results: PQR309 had in vitro anti-lymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib and rituximab. Sensitivity to PQR309 was associated with specific baseline gene expression features, such as high expression of transcripts coding for BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene expression signatures induced by PQR309 and of other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib. Conclusions: Based on these results, PQR309 appeared as a novel and promising compound being worthwhile developing in the lymphoma setting.

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A Phase 1 open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers

Purpose: This Phase 1, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity. Experimental design: Patients were aged ≥18 years with WHO performance status 0-1. Dose escalation was conducted within separate continuous and intermittent (4 days/week [4/7] or 2 days/week [2/7]) schedules with safety, pharmacokinetic and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers. Results: Maximum tolerated doses were 320 mg, 480 mg and 640 mg for continuous (n=47), 4/7 (n=21) and 2/7 (n=22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for CTCAE grade ≥3 events, hyperglycemia (20%). The recommended Phase 2 dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the pre-specified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA cohort were met. Conclusions: At the recommended Phase 2 dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363.

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Molecular subtypes of pulmonary large cell neuroendocrine carcinoma predict chemotherapy treatment outcome

Purpose: Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the RB1 mutated (mostly co-mutated with TP53) and the RB1 wild-type groups. We assessed if these subtypes have a predictive value on chemotherapy outcome. Experimental Design: Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for TP53, RB1, STK11, and KEAP1 genes, as well as immunohistochemistry (IHC) for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression free survival (PFS), stratifying for non-small cell lung cancertype chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE). Results: RB1 mutation and protein loss were detected in 47% (n=37) and 72% (n=78) of the cases, respectively. RB1 wild-type LCNEC patients treated with NSCLC-GEM/TAX had a significantly longer OS (9.6 [95% CI 7.7-11.6] months) than those treated with SCLC-PE (5.8 [5.5-6.1]; P=0.026). Similar results were obtained for patients expressing RB1 in their tumors P=0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an RB1 mutation or lost RB1 protein. Conclusions: Patients with LCNEC tumors that carry a wild-type RB1 gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for RB1 mutated or with lost protein expression.

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Tumor microvessel density as a prognostic marker in high-risk renal cell carcinoma patients treated on ECOG-ACRIN E2805

Purpose: Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis, however its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC. Methods: We obtained pre-treatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence we measured tumor MVD as the area of CD34-expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm and clinicopathologic variables. Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (p=0.021) and for patients treated with placebo (p=0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p=0.060). MVD was not associated with DFS (p=1.00). On multivariable analysis, MVD remained independently associated with improved OS (p=0.013). High MVD correlated with Fuhrman grade 1-2 (p<0.001), clear cell histology (p<0.001), and absence of necrosis (p<0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size. Conclusions:High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high risk patients for adjuvant therapy trials.

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Chemical profiling of primary mesothelioma cultures defines subtypes with different expression profiles and clinical responses

Finding new treatment options for patients with malignant pleural mesothelioma is challenging due to the rarity and heterogeneity of this cancer type. The absence of druggable targets further complicates the development of new therapies. Current treatment options are therefore limited and prognosis remains poor. Experimental Design: We performed drug screening on primary mesothelioma cultures to guide treatment decisions of corresponding patients that were progressive after first or second line treatment. Results: We observed a high concordance between in vitro results and clinical outcomes. We defined three subgroups responding differently to the anti-cancer drugs tested. In addition, gene expression profiling yielded distinct signatures that segregated the differently responding subgroups. These genes signatures involved various pathways, most prominently the fibroblast growth factor pathway. Conclusions: Our primary mesothelioma culture system has proved to be suitable to test novel drugs. Chemical profiling of primary mesothelioma cultures allows personalizing treatment for a group of patients with a rare tumor type, where clinical trials are notoriously difficult. This personalized treatment strategy is expected to improve the poor prospects of mesothelioma patients.

http://ift.tt/2xlMlc6

PQR309 is a novel dual PI3K/mTOR inhibitor with pre-clinical antitumor activity in lymphomas as a single agent and in combination therapy

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types and pharmacological inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models. Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene expression profiling and comparison with other signaling inhibitors. Results: PQR309 had in vitro anti-lymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib and rituximab. Sensitivity to PQR309 was associated with specific baseline gene expression features, such as high expression of transcripts coding for BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene expression signatures induced by PQR309 and of other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib. Conclusions: Based on these results, PQR309 appeared as a novel and promising compound being worthwhile developing in the lymphoma setting.

http://ift.tt/2xlMhcm

A Phase 1 open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers

Purpose: This Phase 1, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity. Experimental design: Patients were aged ≥18 years with WHO performance status 0-1. Dose escalation was conducted within separate continuous and intermittent (4 days/week [4/7] or 2 days/week [2/7]) schedules with safety, pharmacokinetic and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers. Results: Maximum tolerated doses were 320 mg, 480 mg and 640 mg for continuous (n=47), 4/7 (n=21) and 2/7 (n=22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for CTCAE grade ≥3 events, hyperglycemia (20%). The recommended Phase 2 dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the pre-specified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA cohort were met. Conclusions: At the recommended Phase 2 dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363.

http://ift.tt/2zNAtkC

Molecular subtypes of pulmonary large cell neuroendocrine carcinoma predict chemotherapy treatment outcome

Purpose: Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the RB1 mutated (mostly co-mutated with TP53) and the RB1 wild-type groups. We assessed if these subtypes have a predictive value on chemotherapy outcome. Experimental Design: Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for TP53, RB1, STK11, and KEAP1 genes, as well as immunohistochemistry (IHC) for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression free survival (PFS), stratifying for non-small cell lung cancertype chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE). Results: RB1 mutation and protein loss were detected in 47% (n=37) and 72% (n=78) of the cases, respectively. RB1 wild-type LCNEC patients treated with NSCLC-GEM/TAX had a significantly longer OS (9.6 [95% CI 7.7-11.6] months) than those treated with SCLC-PE (5.8 [5.5-6.1]; P=0.026). Similar results were obtained for patients expressing RB1 in their tumors P=0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an RB1 mutation or lost RB1 protein. Conclusions: Patients with LCNEC tumors that carry a wild-type RB1 gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for RB1 mutated or with lost protein expression.

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Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Letter

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Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Response

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CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells

The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL-2 and expression of co-inhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNγ production by responder CD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within non-invaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNγ, TNF, IL-2 and high expression of co-inhibitory receptors. Although T cell receptor engagement was sufficient to induce CD39 on human CD8+ T cells, exposure to IL-6 and IL-27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8+ T cells, with implications for defining a biomarker of T cell dysfunction and a target for immunotherapeutic intervention.

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CBX8 exhibits oncogenic activity via AKT/{beta}-Catenin activation in hepatocellular carcinoma

Deregulation of Polycomb proteins influences the development and progression of hepatocellular carcinoma (HCC). Here we show that chromobox 8 (CBX8) expression is increased in HCC and correlates with poor outcome in two independent cohorts containing a total of 879 cases. Ectopic expression of CBX8 facilitated tumor growth and metastasis, whereas CBX8 silencing suppressed these effects. CBX8 efficiently activated AKT/β-catenin signaling via upregulation of the transcription factor EGR1 and miR-365-3p in a non-canonical manner: CBX8 directly bound the EGR1 promoter to enhance its activity. In the nucleus, CBX8 also interacted with EGR1 to prevent its degradation. Furthermore, CBX8 increased the transcription of miR-365a-3p, which promoted the nuclear localization of β-catenin by targeting the 3'-UTR ZNRF1. Inhibiting either EGR1 or miR-365a-3p partially rescued CBX8-mediated malignant phenotypes. In clinical samples, CBX8 expression closely correlated with EGR1, miR-365a-3p and nuclear β-catenin. Collectively, our results show that CBX8 functions as an oncogene to upregulate EGR1 and miR-365-3p to stimulate the AKT/β-catenin pathway. This newly identified signaling axis may suggest new therapeutic strategies against HCC.

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Comparative transcriptome analysis quantifies immune cell transcript levels, metastatic progression and survival in osteosarcoma

Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of inter-tumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103) and dogs (n=34) were generated using RNA-sequencing. Conserved inter-tumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) to quantify inter-tumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA). Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients.

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A subpopulation of stromal cells controls cancer cell homing to the bone marrow

Breast and prostate cancer cells home to the bone marrow where they presumably hijack the hematopoietic stem cell niche. We characterize here the elusive premetastatic niche by examining the role of mesenchymal stromal cells (MSC) in cancer cell homing. Decreasing the number of MSC pharmacologically enhanced cancer cell homing to the bone marrow in mice. In contrast, increasing the number of these MSC by various interventions including G-CSF administration diminished cancer cell homing. The MSC subpopulation that correlated best with cancer cells expressed stem, endothelial, and pericytic cell markers suggesting these cells represent an undifferentiated component of the niche with vascular commitment. In humans, a MSC subpopulation carrying markers for endothelial and pericytic cells was lower in the presence of cytokeratin+ cells in bone marrow. Taken together, our data show that a subpopulation of MSC with both endothelial and pericytic cell surface markers suppresses the homing of cancer cells to the bone marrow. Similar to the presence of cytokeratin+ cells in the bone marrow, this mesenchymal stromal cell subpopulation could prove useful in determining the risk of metastatic disease, and its manipulation might offer a new possibility for diminishing bone metastasis formation.

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Evidence for Kaposi's Sarcoma originating from Mesenchymal Stem Cell through KSHV-induced Mesenchymal-to-Endothelial Transition

The major transmission route for Kaposi's sarcoma-associated herpesvirus (KSHV) infection is the oral cavity through saliva. Kaposi's sarcoma (KS) frequently occurs in the oral cavity in HIV-positive individuals and is often the first presenting sign of AIDS. However, the oral target cells for KSHV infection and the cellular origin of KS remain unknown. Here we present clinical and experimental evidences that KS spindle cells may originate from virally modified oral mesenchymal stem cells (MSC). AIDS-KS spindle cells expressed neuroectodermal stem cell marker (Nestin) and oral MSC marker CD29, suggesting an oral/craniofacial MSC lineage of AIDS-associated KS. Furthermore, oral MSC were highly susceptible to KSHV infection, and infection promoted multi-lineage differentiation and mesenchymal-to-endothelial transition (MEndT). KSHV infection of oral MSCs resulted in expression of a large number of cytokines, a characteristic of KS, and upregulation of KS signature and MEndT-associated genes. These results suggest that KS may originate from pluripotent MSC and KSHV infection transforms MSC to KS-like cells through MEndT.

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Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Letter

http://ift.tt/2yMArLH

Cross-Cancer Analysis Reveals Novel Pleiotropic Associations—Response

http://ift.tt/2y4J5l6

CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells

The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL-2 and expression of co-inhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNγ production by responder CD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within non-invaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNγ, TNF, IL-2 and high expression of co-inhibitory receptors. Although T cell receptor engagement was sufficient to induce CD39 on human CD8+ T cells, exposure to IL-6 and IL-27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8+ T cells, with implications for defining a biomarker of T cell dysfunction and a target for immunotherapeutic intervention.

http://ift.tt/2gCIRLn

CBX8 exhibits oncogenic activity via AKT/{beta}-Catenin activation in hepatocellular carcinoma

Deregulation of Polycomb proteins influences the development and progression of hepatocellular carcinoma (HCC). Here we show that chromobox 8 (CBX8) expression is increased in HCC and correlates with poor outcome in two independent cohorts containing a total of 879 cases. Ectopic expression of CBX8 facilitated tumor growth and metastasis, whereas CBX8 silencing suppressed these effects. CBX8 efficiently activated AKT/β-catenin signaling via upregulation of the transcription factor EGR1 and miR-365-3p in a non-canonical manner: CBX8 directly bound the EGR1 promoter to enhance its activity. In the nucleus, CBX8 also interacted with EGR1 to prevent its degradation. Furthermore, CBX8 increased the transcription of miR-365a-3p, which promoted the nuclear localization of β-catenin by targeting the 3'-UTR ZNRF1. Inhibiting either EGR1 or miR-365a-3p partially rescued CBX8-mediated malignant phenotypes. In clinical samples, CBX8 expression closely correlated with EGR1, miR-365a-3p and nuclear β-catenin. Collectively, our results show that CBX8 functions as an oncogene to upregulate EGR1 and miR-365-3p to stimulate the AKT/β-catenin pathway. This newly identified signaling axis may suggest new therapeutic strategies against HCC.

http://ift.tt/2i3IIB2

Comparative transcriptome analysis quantifies immune cell transcript levels, metastatic progression and survival in osteosarcoma

Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of inter-tumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103) and dogs (n=34) were generated using RNA-sequencing. Conserved inter-tumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) to quantify inter-tumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA). Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients.

http://ift.tt/2i2FU7v

A subpopulation of stromal cells controls cancer cell homing to the bone marrow

Breast and prostate cancer cells home to the bone marrow where they presumably hijack the hematopoietic stem cell niche. We characterize here the elusive premetastatic niche by examining the role of mesenchymal stromal cells (MSC) in cancer cell homing. Decreasing the number of MSC pharmacologically enhanced cancer cell homing to the bone marrow in mice. In contrast, increasing the number of these MSC by various interventions including G-CSF administration diminished cancer cell homing. The MSC subpopulation that correlated best with cancer cells expressed stem, endothelial, and pericytic cell markers suggesting these cells represent an undifferentiated component of the niche with vascular commitment. In humans, a MSC subpopulation carrying markers for endothelial and pericytic cells was lower in the presence of cytokeratin+ cells in bone marrow. Taken together, our data show that a subpopulation of MSC with both endothelial and pericytic cell surface markers suppresses the homing of cancer cells to the bone marrow. Similar to the presence of cytokeratin+ cells in the bone marrow, this mesenchymal stromal cell subpopulation could prove useful in determining the risk of metastatic disease, and its manipulation might offer a new possibility for diminishing bone metastasis formation.

http://ift.tt/2gBIjFJ

Evidence for Kaposi's Sarcoma originating from Mesenchymal Stem Cell through KSHV-induced Mesenchymal-to-Endothelial Transition

The major transmission route for Kaposi's sarcoma-associated herpesvirus (KSHV) infection is the oral cavity through saliva. Kaposi's sarcoma (KS) frequently occurs in the oral cavity in HIV-positive individuals and is often the first presenting sign of AIDS. However, the oral target cells for KSHV infection and the cellular origin of KS remain unknown. Here we present clinical and experimental evidences that KS spindle cells may originate from virally modified oral mesenchymal stem cells (MSC). AIDS-KS spindle cells expressed neuroectodermal stem cell marker (Nestin) and oral MSC marker CD29, suggesting an oral/craniofacial MSC lineage of AIDS-associated KS. Furthermore, oral MSC were highly susceptible to KSHV infection, and infection promoted multi-lineage differentiation and mesenchymal-to-endothelial transition (MEndT). KSHV infection of oral MSCs resulted in expression of a large number of cytokines, a characteristic of KS, and upregulation of KS signature and MEndT-associated genes. These results suggest that KS may originate from pluripotent MSC and KSHV infection transforms MSC to KS-like cells through MEndT.

http://ift.tt/2i2T4RT

Obinutuzumab Effective in Follicular Lymphoma, but at a Cost [News in Brief]

Anti-CD20 antibody outperforms rituximab—although side effects more frequent, serious.

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Making Bryostatin 1 through Smart Chemistry [News in Brief]

Scientists devise scalable synthesis of a difficult-to-harvest natural compound, paving the way for further clinical studies.

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The Influence of Collaboration: Ralph Waters' Friendship With John Lundy and the Spread of Regional Anesthesia.

Ralph Waters, the founder of the anesthesiology department and residency program at the University of Wisconsin-Madison, and John Lundy, the chair at the Mayo Clinic beginning in 1924, collaborated to expand regional anesthetic techniques and knowledge not only at their institutions, but also at institutions around the country through correspondence, meetings, and hosting of other anesthesiologists. The Ralph Waters Collection at the University of Wisconsin Archives was searched for information on Waters' and Lundy's involvement in regional anesthesia. This included publications by Waters and other anesthesiology department faculty, as well as personal correspondence with other leaders in anesthesia at that time. Correspondence between Waters and Lundy from this collection was reviewed in detail. This article underscores the importance of exchange of ideas by physicians through didactics, organizations, and research through the story of Ralph Waters and John Lundy's mutual exchange of ideas and even friendship beginning in the 1920s. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

http://ift.tt/2i2htHa

Inhibitors of apoptosis: clinical implications in cancer

Abstract

Inhibitor of apoptosis (IAP) family comprises a group of endogenous proteins that function as main regulators of caspase activity and cell death. They are considered the main culprits in evasion of apoptosis, which is a fundamental hallmark of carcinogenesis. Overexpression of IAP proteins has been documented in various solid and hematological malignancies, rendering them resistant to standard chemotherapeutics and radiation therapy and conferring poor prognosis. This observation has urged their exploitation as therapeutic targets in cancer with promising pre-clinical outcomes. This review describes the structural and functional features of IAP proteins to elucidate the mechanism of their anti-apoptotic activity. We also provide an update on patterns of IAP expression in different tumors, their impact on treatment response and prognosis, as well as the emerging investigational drugs targeting them. This aims at shedding the light on the advances in IAP targeting achieved to date, and encourage further development of clinically applicable therapeutic approaches.

http://ift.tt/2lezNS7

Revisiting the Role of Bevacizumab in the Treatment of Breast Cancer

Publication date: Available online 24 October 2017
Source:Seminars in Oncology
Author(s): Leticia Varella, Jame Abraham, Megan Kruse




http://ift.tt/2xlIXy3

An unusual complication of the traditional treatment of a closed fracture – generalized tetanus: a case report

Tetanus is a severe infectious disease that can lead to death. The clinical manifestations are due to an exotoxin secreted by Clostridium tetani, a spore-producing Gram-positive bacillus. The penetration of the g...

http://ift.tt/2zAIFnq

Successful bridge to recovery in fulminant myocarditis using a biventricular assist device: a case report

Fulminant myocarditis is a life-threatening disease, and myocardial damage expands the right ventricle as well as the left ventricle in some cases. There is a mortality rate of over 40% in patients with fulmin...

http://ift.tt/2h6NVbA

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice

Abstract

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART^®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

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A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice

Abstract

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART^®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

http://ift.tt/2yLLQv1

Surgical Management of Primary Retroperitoneal Sarcomas: Rationale for Selective Organ Resection

Abstract

Background

Recently, some have argued for routine resection of adjacent but uninvolved organs in patients with retroperitoneal sarcoma (RPS) without stipulating the rationale for such organ resection (beyond the need to achieve a macroscopically complete resection) or examining histopathologic organ invasion (HOI). This study reviewed the authors' experience with primary RPS to investigate the rate and rationale for individual organ resection and the rate of HOI.

Methods

Operative and pathology reports for patients with primary RPS who underwent resection at our institution were retrospectively reviewed. Histopathologic organ invasion was confirmed by a dedicated sarcoma pathologist.

Results

From 2002 through 2011, 118 patients underwent resection of a primary RPS, and 99 of these patients (84%) had at least one organ resected. Kidney (n = 57), colon (n = 51), and adrenal (n = 41) were the most commonly resected organs. For the 302 organs removed, the perioperative clinical rationale for the resection was suspected invasion or tumor origin (n = 52, 17%), involved end-organ vasculature (n = 39, 13%), organ encasement (n = 42, 14%), tumor adherence (n = 127, 42%), resection required for R0/R1 resection (n = 25, 8%), or other (n = 17, 6%). The presence of HOI was found in 77 (25%) of the 302 organs resected. In the reviewed studies, HOI was identified in 34 (65%) of 52 organs suspected of invasion or tumor origin, in 19% of organs resected due to tumor encasement, and in 26% of organs with adherent tumor, even when not suspected intraoperatively, but was never identified in organs resected purely as part of a liberal en bloc resection of adjacent organs. When invasion was suspected intraoperatively, HOI was confirmed in 50, 78, and 100% of resected organs respectively for well-dedifferentiated liposarcoma, dedifferentiated liposarcoma (DDLPS), and leiomyosarcoma (LMS).

Conclusions

Histologic organ invasion was observed more commonly in organs resected with suspicion of invasion than in organs resected simply to achieve a negative margin, although this reflects a degree of subjectivity and selection bias. In more than one-fourth of adherent organs, HOI was present even when not suspected intraoperatively. Histologic subtype may predict HOI because DDLPS and LMS are associated with high rates of HOI when invasion is suspected intraoperatively. Development of a data-driven, histology-specific rationale for adjacent organ resection is critical.

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Surgical Management of Primary Retroperitoneal Sarcomas: Rationale for Selective Organ Resection

Abstract

Background

Recently, some have argued for routine resection of adjacent but uninvolved organs in patients with retroperitoneal sarcoma (RPS) without stipulating the rationale for such organ resection (beyond the need to achieve a macroscopically complete resection) or examining histopathologic organ invasion (HOI). This study reviewed the authors' experience with primary RPS to investigate the rate and rationale for individual organ resection and the rate of HOI.

Methods

Operative and pathology reports for patients with primary RPS who underwent resection at our institution were retrospectively reviewed. Histopathologic organ invasion was confirmed by a dedicated sarcoma pathologist.

Results

From 2002 through 2011, 118 patients underwent resection of a primary RPS, and 99 of these patients (84%) had at least one organ resected. Kidney (n = 57), colon (n = 51), and adrenal (n = 41) were the most commonly resected organs. For the 302 organs removed, the perioperative clinical rationale for the resection was suspected invasion or tumor origin (n = 52, 17%), involved end-organ vasculature (n = 39, 13%), organ encasement (n = 42, 14%), tumor adherence (n = 127, 42%), resection required for R0/R1 resection (n = 25, 8%), or other (n = 17, 6%). The presence of HOI was found in 77 (25%) of the 302 organs resected. In the reviewed studies, HOI was identified in 34 (65%) of 52 organs suspected of invasion or tumor origin, in 19% of organs resected due to tumor encasement, and in 26% of organs with adherent tumor, even when not suspected intraoperatively, but was never identified in organs resected purely as part of a liberal en bloc resection of adjacent organs. When invasion was suspected intraoperatively, HOI was confirmed in 50, 78, and 100% of resected organs respectively for well-dedifferentiated liposarcoma, dedifferentiated liposarcoma (DDLPS), and leiomyosarcoma (LMS).

Conclusions

Histologic organ invasion was observed more commonly in organs resected with suspicion of invasion than in organs resected simply to achieve a negative margin, although this reflects a degree of subjectivity and selection bias. In more than one-fourth of adherent organs, HOI was present even when not suspected intraoperatively. Histologic subtype may predict HOI because DDLPS and LMS are associated with high rates of HOI when invasion is suspected intraoperatively. Development of a data-driven, histology-specific rationale for adjacent organ resection is critical.

http://ift.tt/2h57ilC

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice

Abstract

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART^®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

from Cancer via ola Kala on Inoreader http://ift.tt/2yLLQv1
via IFTTT

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice

Abstract

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART^®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

http://ift.tt/2yLLQv1

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice

Abstract

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART^®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

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via IFTTT

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice

Abstract

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART^®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

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Lung, Bladder, and Kidney Cancer Mortality 40 Years After Arsenic Exposure Reduction

Background

Region II in northern Chile (population 442 570) experienced a sudden major increase in arsenic water concentrations in 1958 in the main city of Antofagasta, followed by a major reduction in exposure when an arsenic removal plant was installed in 1970. It provides a unique opportunity to study latency effects of exposure to arsenic, and this is the first study with mortality data up to 40 years after exposure reduction.

Methods

We previously identified high mortality rates in Region II up to the year 2000. Here we present rate ratios (RRs) for Region II compared with all the rest of Chile from 2001 to 2010, and with unexposed Region V (population 1 539 852) for all years from 1950 to 2010. All statistical tests were one-sided.

Results

From 2001 to 2010, comparing Region II with the rest of Chile, lung and bladder mortality were still greatly elevated (RR = 3.38, 95% confidence interval [CI] = 3.19 to 3.58, P < .001 for lung cancer in men; RR = 2.41, 95% CI = 2.20 to 2.64, P < .001 for lung cancer in women; RR = 4.79, 95% CI = 4.20 to 5.46, P < .001 for bladder cancer in men; RR = 6.43, 95% CI = 5.49 to 7.54, P < .001 for bladder cancer in women). Kidney cancer mortality was also elevated (RR = 1.75, 95% CI = 1.49 to 2.05, P < .001 for men; RR = 2.09, 95% CI = 1.69 to 2.57, P < .001 for women). Earlier short latency acute myocardial infarction mortality increases had subsided.

Conclusions

Lung, bladder, and kidney cancer mortality due to arsenic exposure have very long latencies, with increased risks manifesting 40 years after exposure reduction. Our findings suggest that arsenic in drinking water may involve one of the longest cancer latencies for a human carcinogen.

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Corrigendum

Corrigendum: "Augmentation of response to chemotherapy by microRNA-506 through regulation of RAD51 in serous ovarian cancers" by G Liu etal. J Natl Cancer Inst 2015; 107(7): doi:10.1093/jnci/djv108. Upon reviewing the manuscript, the authors found that one of the images in Figure 2C (HeyA8 cell line) was inadvertently duplicated. The image appears to be symmetrically the same as the one presented in Figure 3B. The mistake occurred while the authors were using one image as a template for adjusting picture size. The image in Figure 2C has been corrected. This change does not impact the conclusions of the study. The authors apologize for this mistake.

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International Patterns and Trends in Endometrial Cancer Incidence, 1978–2013

Abstract

Background

Cancers of the corpus uteri—primarily of the endometrium—rank as the sixth most common neoplasm in women worldwide. Analyses of the global patterns and trends of uterine cancer rates are needed in view of the ongoing obesity epidemic, a major risk factor for the disease.

Methods

Data on endometrial cancer (ICD-10 C54) incidence from population-based cancer registries in 43 populations, published in CI5plus or by registries, were extracted for 1978 to 2013. Age-standardized incidence rates were computed for all ages and for pre- (25–49 years) and postmenopausal ages (50 years and older). Temporal trends were assessed with Joinpoint analysis, and the effects of birth cohort and year of diagnosis on the overall trends were examined using age-period-cohort modeling.

Results

In 2006 to 2007, rates varied 10-fold across countries. The highest rates were in North America, Eastern and Northern Europe (19 cases per 100 000 among whites in the United States, 95% confidence interval [CI] = 18 to 20, and in Slovakia, 95% CI = 18 to 21), and the lowest rates were in middle-income countries (South Africa 1, 95% CI = 0 to 3, and India 3, 95% CI = 3 to 4). Rates during the most recent 10 data years increased in 26 of the 43 populations considered in this study, with South Africa and several countries in Asia showing the largest increase. The risk of endometrial cancer increased both in consecutive generations and over time in 11 of 23 populations, with the increases more pronounced in Japan, the Philippines, Belarus, Singapore, Costa Rica, and New Zealand.

Conclusions

Endometrial cancer incidence rates increased over time and in successive generations in several countries, especially in those countries with rapid socioeconomic transitions.

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Partial Verification Distorts Estimates of Sensitivity in Diagnostic Accuracy Studies for Fine-Needle Aspiration Cytology

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Reduced Port Laparoscopic Distal Gastrectomy with D2 Lymphadenectomy

Abstract

Background

Reduced port laparoscopic surgery (RPLS), as a more minimally invasive treatment alternative to conventional laparoscopic surgery (CLS), has been increasing in recent years.¹ With the accumulation of surgical experience and improvements in surgical techniques, the indication of RPLS has been gradually extended from benign diseases to malignant tumors, including gastric cancer.^2–4 However, due to the lack of counteraction and triangulation, lymphadenectomy during reduced port laparoscopic gastrectomy (RPLG) for gastric cancer was considered challenging. In this study, we report our experience performing RPLG with D2 lymphadenectomy for distal gastric cancer.

Methods

A disposable, single-incision, multiport, laparoscopic surgery trocar was used through a 3-cm incision at the umbilicus for the laparoscopist and surgeon's right hand. One 12-mm trocar was inserted at the upper-right quadrant for the surgeon's left hand. Distal gastrectomy with D2 lymphadenectomy was performed in the same manner with CLS.⁵ After extracting the resected specimen through the umbilicus incision, intracorporeal Roux-en-Y or B-II gastrojejunostomy was used for reconstruction.

Results

RPLG with D2 lymphadenectomy was performed on five patients from April 2017 to June 2017. No intraoperative event requiring conversion to CLS or open surgery occurred. No postoperative complication was observed. The median operating time and blood loss was 166 min and 50 ml. The mean number of retrieved lymph nodes was 32.7. Postoperatively, the mean time to first flatus, soft intake, and hospital stay was 2.6, 3.5, and 6.7 days respectively.

Conclusions

RPLG with D2 lymphadenectomy might be safe and feasible in selected patients.

http://ift.tt/2yGEklW

Do Lumpectomy Cavity Shaved Margins Really Not Impact Re-excision Rates in Breast Cancer?

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Prediction of Non-sentinel Node Status in Patients with Melanoma and Positive Sentinel Node Biopsy: An Italian Melanoma Intergroup (IMI) Study

Abstract

Background and Purpose

Approximately 20% of melanoma patients harbor metastases in non-sentinel nodes (NSNs) after a positive sentinel node biopsy (SNB), and recent evidence questions the therapeutic benefit of completion lymph node dissection (CLND). We built a nomogram for prediction of NSN status in melanoma patients with positive SNB.

Methods

Data on anthropometric and clinicopathological features of patients with cutaneous melanoma who underwent CLND after a positive SNB were collected from nine Italian centers. Multivariate logistic regression was utilized to identify predictors of NSN status in a training set, while model efficiency was validated in a validation set.

Results

Data were available for 1220 patients treated from 2000 through 2016. In the training set (n = 810), the risk of NSN involvement was higher when (1) the primary melanoma is thicker or (2) sited in the trunk/head and neck; (3) fewer nodes are excised and (4) more nodes are involved; and (5) the lymph node metastasis is larger or (6) is deeply located. The model showed high discrimination (area under the receiver operating characteristic curve 0.74, 95% confidence interval [CI] 0.70–0.79) and calibration (Brier score 0.16, 95% CI 0.15–0.17) performance in the validation set (n = 410). The nomogram including these six clinicopathological variables performed significantly better than five other previously published models in terms of both discrimination and calibration.

Conclusions

Our nomogram could be useful for follow-up personalization in clinical practice, and for patient risk stratification while conducting clinical trials or analyzing their results.

http://ift.tt/2yFUUlP

Prophylactic Cholecystectomy at Time of Surgery for Small Bowel Neuroendocrine Tumor Does Not Increase Postoperative Morbidity

Abstract

Background

Prophylactic cholecystectomy at time of surgery for small bowel neuroendocrine tumor (SBNET) has been advocated, as these patients often go on to require somatostatin analogue therapy, which is known to increase risk of cholestasis and associated complications. Little is known regarding patterns of adoption of this practice or its associated morbidity.

Methods

The American College of Surgeons National Surgical Quality Improvement Program database (2008–2014) was queried to identify patients who underwent SBNET resection. The risk differences of morbidity and mortality associated with performance of concurrent cholecystectomy were determined with multivariable adjustment for confounders.

Results

Among 1300 patients who underwent SBNET resection, 144 (11.1%) underwent concurrent cholecystectomy. Median age of patients undergoing cholecystectomy was 62 years [interquartile range (IQR) 52–69 years], and 75 were male. They more commonly had disseminated cancer (36.1 vs. 11.6%, p < 0.001) or SBNET located in duodenum (10.4 vs. 4.9%, p = 0.045) without difference in other baseline characteristics. Operative time was significantly longer in the cholecystectomy group (median 172 vs. 123 min, p < 0.001). Rate of postoperative morbidity was not significantly different between cholecystectomy and no-cholecystectomy groups (11.8 vs. 11.1%, p = 0.79). After adjustment for confounding, the risk difference of morbidity attributable to cholecystectomy was + 0.4% [95% confidence interval (CI) − 4.9 to + 5.6%]. Mortality within 30 days was not significantly different between cholecystectomy and no-cholecystectomy groups (1.4 vs. 0.6%, p = 0.29).

Conclusions

Concurrent cholecystectomy at time of resection of SBNET is not associated with higher morbidity or mortality yet is performed in a minority of patients. Prospective study can identify which patients may derive benefit from this approach.

http://ift.tt/2gEcLTk

Partial Verification Distorts Estimates of Sensitivity in Diagnostic Accuracy Studies for Fine-Needle Aspiration Cytology

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Reduced Port Laparoscopic Distal Gastrectomy with D2 Lymphadenectomy

Abstract

Background

Reduced port laparoscopic surgery (RPLS), as a more minimally invasive treatment alternative to conventional laparoscopic surgery (CLS), has been increasing in recent years.¹ With the accumulation of surgical experience and improvements in surgical techniques, the indication of RPLS has been gradually extended from benign diseases to malignant tumors, including gastric cancer.^2–4 However, due to the lack of counteraction and triangulation, lymphadenectomy during reduced port laparoscopic gastrectomy (RPLG) for gastric cancer was considered challenging. In this study, we report our experience performing RPLG with D2 lymphadenectomy for distal gastric cancer.

Methods

A disposable, single-incision, multiport, laparoscopic surgery trocar was used through a 3-cm incision at the umbilicus for the laparoscopist and surgeon's right hand. One 12-mm trocar was inserted at the upper-right quadrant for the surgeon's left hand. Distal gastrectomy with D2 lymphadenectomy was performed in the same manner with CLS.⁵ After extracting the resected specimen through the umbilicus incision, intracorporeal Roux-en-Y or B-II gastrojejunostomy was used for reconstruction.

Results

RPLG with D2 lymphadenectomy was performed on five patients from April 2017 to June 2017. No intraoperative event requiring conversion to CLS or open surgery occurred. No postoperative complication was observed. The median operating time and blood loss was 166 min and 50 ml. The mean number of retrieved lymph nodes was 32.7. Postoperatively, the mean time to first flatus, soft intake, and hospital stay was 2.6, 3.5, and 6.7 days respectively.

Conclusions

RPLG with D2 lymphadenectomy might be safe and feasible in selected patients.

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Do Lumpectomy Cavity Shaved Margins Really Not Impact Re-excision Rates in Breast Cancer?

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Prediction of Non-sentinel Node Status in Patients with Melanoma and Positive Sentinel Node Biopsy: An Italian Melanoma Intergroup (IMI) Study

Abstract

Background and Purpose

Approximately 20% of melanoma patients harbor metastases in non-sentinel nodes (NSNs) after a positive sentinel node biopsy (SNB), and recent evidence questions the therapeutic benefit of completion lymph node dissection (CLND). We built a nomogram for prediction of NSN status in melanoma patients with positive SNB.

Methods

Data on anthropometric and clinicopathological features of patients with cutaneous melanoma who underwent CLND after a positive SNB were collected from nine Italian centers. Multivariate logistic regression was utilized to identify predictors of NSN status in a training set, while model efficiency was validated in a validation set.

Results

Data were available for 1220 patients treated from 2000 through 2016. In the training set (n = 810), the risk of NSN involvement was higher when (1) the primary melanoma is thicker or (2) sited in the trunk/head and neck; (3) fewer nodes are excised and (4) more nodes are involved; and (5) the lymph node metastasis is larger or (6) is deeply located. The model showed high discrimination (area under the receiver operating characteristic curve 0.74, 95% confidence interval [CI] 0.70–0.79) and calibration (Brier score 0.16, 95% CI 0.15–0.17) performance in the validation set (n = 410). The nomogram including these six clinicopathological variables performed significantly better than five other previously published models in terms of both discrimination and calibration.

Conclusions

Our nomogram could be useful for follow-up personalization in clinical practice, and for patient risk stratification while conducting clinical trials or analyzing their results.

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via IFTTT

Prophylactic Cholecystectomy at Time of Surgery for Small Bowel Neuroendocrine Tumor Does Not Increase Postoperative Morbidity

Abstract

Background

Prophylactic cholecystectomy at time of surgery for small bowel neuroendocrine tumor (SBNET) has been advocated, as these patients often go on to require somatostatin analogue therapy, which is known to increase risk of cholestasis and associated complications. Little is known regarding patterns of adoption of this practice or its associated morbidity.

Methods

The American College of Surgeons National Surgical Quality Improvement Program database (2008–2014) was queried to identify patients who underwent SBNET resection. The risk differences of morbidity and mortality associated with performance of concurrent cholecystectomy were determined with multivariable adjustment for confounders.

Results

Among 1300 patients who underwent SBNET resection, 144 (11.1%) underwent concurrent cholecystectomy. Median age of patients undergoing cholecystectomy was 62 years [interquartile range (IQR) 52–69 years], and 75 were male. They more commonly had disseminated cancer (36.1 vs. 11.6%, p < 0.001) or SBNET located in duodenum (10.4 vs. 4.9%, p = 0.045) without difference in other baseline characteristics. Operative time was significantly longer in the cholecystectomy group (median 172 vs. 123 min, p < 0.001). Rate of postoperative morbidity was not significantly different between cholecystectomy and no-cholecystectomy groups (11.8 vs. 11.1%, p = 0.79). After adjustment for confounding, the risk difference of morbidity attributable to cholecystectomy was + 0.4% [95% confidence interval (CI) − 4.9 to + 5.6%]. Mortality within 30 days was not significantly different between cholecystectomy and no-cholecystectomy groups (1.4 vs. 0.6%, p = 0.29).

Conclusions

Concurrent cholecystectomy at time of resection of SBNET is not associated with higher morbidity or mortality yet is performed in a minority of patients. Prospective study can identify which patients may derive benefit from this approach.

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Prevalence of Co-existing Autoimmune Disease in Rheumatoid Arthritis: A Cross-Sectional Study

Abstract

Introduction

Many autoimmune diseases, including rheumatoid arthritis (RA), share common mechanisms; however, population-based studies of the magnitude of multiple autoimmune diseases in patients with RA have not been performed.

Methods

We conducted a cross-sectional study using a US administrative healthcare thcare claims database to screen for prevalence of multiple autoimmune diseases in patients with RA and osteoarthritis (OA). Each patient diagnosed with RA between January 1, 2006 and September 30, 2014 was age- and sex-matched with five patients with OA. The prevalence of 37 pre-specified autoimmune diseases during the 24-month period before and after RA or OA diagnosis was compared.

Results

Overall, 286,601 patients with RA and 992,838 matched patients (from 1,421,624 records) with OA were evaluated. During the baseline period, at least one and more than one autoimmune diseases were identified in 24.3% and 6.0% of patients with RA compared with 10.5% and 1.4% of patients with OA, respectively. Highest prevalence rates for patients with RA were for systemic lupus erythematosus (3.8% versus 0.7% for OA) and psoriatic arthritis (3.2% versus 0.4%). Highest odds ratios (ORs) comparing RA with OA were for the prevalence of ankylosing spondylitis (OR 8.0; 95% CI 7.6, 8.5) and psoriatic arthritis (OR 7.8; 95% CI 7.6, 8.1).

Conclusion

Patients with RA have more concurrent autoimmune diseases than patients with OA. These data suggest that the interrelationship between RA and other autoimmune diseases, and outcomes associated with the occurrence of multiple autoimmune diseases, may play an important role in disease understanding, management, and treatment decisions.

Funding

Bristol-Myers Squibb.

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Prevalence of Co-existing Autoimmune Disease in Rheumatoid Arthritis: A Cross-Sectional Study

Abstract

Introduction

Many autoimmune diseases, including rheumatoid arthritis (RA), share common mechanisms; however, population-based studies of the magnitude of multiple autoimmune diseases in patients with RA have not been performed.

Methods

We conducted a cross-sectional study using a US administrative healthcare thcare claims database to screen for prevalence of multiple autoimmune diseases in patients with RA and osteoarthritis (OA). Each patient diagnosed with RA between January 1, 2006 and September 30, 2014 was age- and sex-matched with five patients with OA. The prevalence of 37 pre-specified autoimmune diseases during the 24-month period before and after RA or OA diagnosis was compared.

Results

Overall, 286,601 patients with RA and 992,838 matched patients (from 1,421,624 records) with OA were evaluated. During the baseline period, at least one and more than one autoimmune diseases were identified in 24.3% and 6.0% of patients with RA compared with 10.5% and 1.4% of patients with OA, respectively. Highest prevalence rates for patients with RA were for systemic lupus erythematosus (3.8% versus 0.7% for OA) and psoriatic arthritis (3.2% versus 0.4%). Highest odds ratios (ORs) comparing RA with OA were for the prevalence of ankylosing spondylitis (OR 8.0; 95% CI 7.6, 8.5) and psoriatic arthritis (OR 7.8; 95% CI 7.6, 8.1).

Conclusion

Patients with RA have more concurrent autoimmune diseases than patients with OA. These data suggest that the interrelationship between RA and other autoimmune diseases, and outcomes associated with the occurrence of multiple autoimmune diseases, may play an important role in disease understanding, management, and treatment decisions.

Funding

Bristol-Myers Squibb.

http://ift.tt/2xkwPNs

Impact of surgical resection extension on outcome for primary well-differentiated thyroid cancer—a retrospective analysis

Abstract

Background

The surgical resection extension in well-differentiated thyroid cancer is controversially discussed with the possibility of an overtreatment on the one hand against the risk of local disease recurrence. The aim of this study is to evaluate how the surgical resection extension with the adjunction of radioiodine therapy affects postoperative morbidity and the oncologic outcome of patients primarily treated for well-differentiated thyroid cancer.

Methods

All patients undergoing primary surgery for a well-differentiated, non-recurrent thyroid cancer from January 2005 to April 2013 at Tuebingen University Hospital were retrospectively analyzed.

Results

Papillary thyroid cancer (PTC) was present in 73 patients (including 27 papillary microcarinoma) and follicular thyroid cancer in 14 patients. Fifty-six of 87 patients (64%) underwent one-stage surgery, of which 26 patients (30%) received simultaneous lymph node dissection (LND). The remaining 31 patients (36%) underwent a two-stage completion surgery (29 patients with LND). Only in three patients a single lymph node metastasis was newly detected during two-stage completion surgery. Patients with LND at either one-stage and two-stage completion surgery had a significant higher rate of transient postoperative hypocalcemia.

Postoperative adjuvant radioiodine therapy was performed in 68 of 87 patients (78%). After a median follow-up of 69 months [range 9–104], one local recurrence was documented in a patient suffering from PTC 23 months after surgery.

Conclusion

No prophylactic two-stage lymphadenectomy should be performed in case of well-differentiated thyroid cancer to avoid unnecessary complication without any proven oncologic benefit.

http://ift.tt/2xkxvCB

Postoperative C-reactive protein/albumin ratio as a novel predictor for short-term complications following gastrectomy of gastric cancer

Abstract

Background

Postoperative complications following gastric cancer resection remain a clinical problem. Early detection of postoperative complications is needed before critical illness develops. The purpose of this study was to evaluate the prognostic value of C-reactive protein/albumin ratio in patients with gastric cancer.

Methods

A total of 322 patients undergoing curative (R0) gastrectomy between 2015 and 2017 were retrospectively analyzed. Univariate and multivariate analyses were performed to identify clinical factors predicting postoperative complications. The cutoff values and diagnostic accuracy of C-reactive protein/albumin ratio and C-reactive protein were determined by receiver-operating characteristic curves.

Results

Among all of the patients, 85 (26.4%) developed postoperative complications. The optimal cutoff of C-reactive protein/albumin ratio was set at 3.04 based on the ROC analysis. Multivariate analysis identified C-reactive protein/albumin ratio was an independent risk factors for complications after gastrectomy (OR 3.037; 95% CI 1.248–7.392; P = 0.014). Additionally, C-reactive protein/albumin ratio showed a higher diagnostic accuracy than C-reactive protein on postoperative day 3 (AUC: 0.685 vs 0.660; sensitivity: 0.624 vs 0.471; specificity: 0.722 vs 0.835).

Conclusions

Elevated C-reactive protein/albumin ratio was an independent predictor for postoperative complications following gastrectomy of gastric cancer, and the diagnostic accuracy was higher than C-reactive protein alone. Overall, postoperative C-reactive protein/albumin ratio may help to identify patients with high probability of postoperative complications.

http://ift.tt/2zN2WXN

Impact of surgical resection extension on outcome for primary well-differentiated thyroid cancer—a retrospective analysis

Abstract

Background

The surgical resection extension in well-differentiated thyroid cancer is controversially discussed with the possibility of an overtreatment on the one hand against the risk of local disease recurrence. The aim of this study is to evaluate how the surgical resection extension with the adjunction of radioiodine therapy affects postoperative morbidity and the oncologic outcome of patients primarily treated for well-differentiated thyroid cancer.

Methods

All patients undergoing primary surgery for a well-differentiated, non-recurrent thyroid cancer from January 2005 to April 2013 at Tuebingen University Hospital were retrospectively analyzed.

Results

Papillary thyroid cancer (PTC) was present in 73 patients (including 27 papillary microcarinoma) and follicular thyroid cancer in 14 patients. Fifty-six of 87 patients (64%) underwent one-stage surgery, of which 26 patients (30%) received simultaneous lymph node dissection (LND). The remaining 31 patients (36%) underwent a two-stage completion surgery (29 patients with LND). Only in three patients a single lymph node metastasis was newly detected during two-stage completion surgery. Patients with LND at either one-stage and two-stage completion surgery had a significant higher rate of transient postoperative hypocalcemia.

Postoperative adjuvant radioiodine therapy was performed in 68 of 87 patients (78%). After a median follow-up of 69 months [range 9–104], one local recurrence was documented in a patient suffering from PTC 23 months after surgery.

Conclusion

No prophylactic two-stage lymphadenectomy should be performed in case of well-differentiated thyroid cancer to avoid unnecessary complication without any proven oncologic benefit.

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Postoperative C-reactive protein/albumin ratio as a novel predictor for short-term complications following gastrectomy of gastric cancer

Abstract

Background

Postoperative complications following gastric cancer resection remain a clinical problem. Early detection of postoperative complications is needed before critical illness develops. The purpose of this study was to evaluate the prognostic value of C-reactive protein/albumin ratio in patients with gastric cancer.

Methods

A total of 322 patients undergoing curative (R0) gastrectomy between 2015 and 2017 were retrospectively analyzed. Univariate and multivariate analyses were performed to identify clinical factors predicting postoperative complications. The cutoff values and diagnostic accuracy of C-reactive protein/albumin ratio and C-reactive protein were determined by receiver-operating characteristic curves.

Results

Among all of the patients, 85 (26.4%) developed postoperative complications. The optimal cutoff of C-reactive protein/albumin ratio was set at 3.04 based on the ROC analysis. Multivariate analysis identified C-reactive protein/albumin ratio was an independent risk factors for complications after gastrectomy (OR 3.037; 95% CI 1.248–7.392; P = 0.014). Additionally, C-reactive protein/albumin ratio showed a higher diagnostic accuracy than C-reactive protein on postoperative day 3 (AUC: 0.685 vs 0.660; sensitivity: 0.624 vs 0.471; specificity: 0.722 vs 0.835).

Conclusions

Elevated C-reactive protein/albumin ratio was an independent predictor for postoperative complications following gastrectomy of gastric cancer, and the diagnostic accuracy was higher than C-reactive protein alone. Overall, postoperative C-reactive protein/albumin ratio may help to identify patients with high probability of postoperative complications.

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