BTSA1 Activates BAX to Promote Apoptosis in Acute Myeloid Leukemia [Leukemia]

The small-molecule BAX activator BTSA1 promotes apoptosis of AML cells in vitro and in vivo.

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A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors [Research Articles]

Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway–dependent cancers, the scope of mechanisms enabling resistance to SMO inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to SMO inhibitors and maintains a "persister" state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance.

Significance: Using a transposon screen and clinical datasets, we identified mutations in ciliogenesis genes as a new class of resistance to SMO inhibitors. Mechanistically, cilia-mutant tumors can either grow slowly in a "persister" state or evolve and progress rapidly in an "aggressive" state. Cancer Discov; 7(12); 1436–49. ©2017 AACR.

See related commentary by Goranci-Buzhala et al., p. 1374.

This article is highlighted in the In This Issue feature, p. 1355

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NIH Funds Pediatric Data Resource Center [News in Brief]

Children's Hospital of Philadelphia will lead a collaborative effort—funded with $14.8 million from the NIH—to pool genomic and phenotypic data from tens of thousands of patients to study the causes of pediatric cancer and structural birth defects.

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Identified Selective USP7 Inhibitors Compete with Ubiquitin Binding [Ubiquitination]

Specific USP7 inhibitors stabilized p53 and exhibited toxicity in tumor cells in vitro and in vivo.

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Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax [Review]

Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax.

Significance: Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2-selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors. Cancer Discov; 7(12); 1376–93. ©2017 AACR.

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FDA Disperses $22 Million for Rare Diseases [News in Brief]

The FDA has awarded 15 grants totaling $22 million over 4 years through its Orphan Products Clinical Trials Grant Program. One third of the awards will support ongoing clinical trials of therapies for rare cancers for which there are few approved or effective treatment options.

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Nivolumab Induces Tumor Evolution in Patients with Melanoma [Immunotherapy]

Nivolumab treatment results in immunoediting and loss of tumor cells expressing neoantigens.

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Breast Cancer Cells Recycle Ammonia to Generate Amino Acids [Metabolism]

Ammonia generated from glutamate metabolism enhances the proliferation of breast cancer cells.

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Keap1 Loss Drives Kras-Mutant Lung Cancer and Glutaminolysis Dependency [Lung Cancer]

Loss of Keap1 hyperactivates NRF2 to induce glutaminolysis-dependent Kras-driven lung cancer.

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Glucose Indirectly Fuels the TCA Cycle in Tumors via Lactate [Metabolism]

Circulating lactate derived from glucose is preferentially used as fuel for the TCA cycle over glucose.

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CNS Endothelial Cell Activation Emerges as a Driver of CAR T Cell-Associated Neurotoxicity [In the Spotlight]

Summary: Central nervous system (CNS) toxicity associated with chimeric antigen receptor–based therapeutics has emerged as a significant cause of morbidity and mortality, and insights into the pathophysiology of this syndrome have been lacking. A new study provides evidence that cytokine-induced CNS endothelial cell activation leading to disruption of the blood–brain barrier plays an early and critical role in this phenomenon. These insights provide new opportunities for targeted therapeutic interventions to modulate endothelial cell activation. Cancer Discov; 7(12); 1371–3. ©2017 AACR.

See related article by Gust et al., p. 1404.

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Lactate Fuels the TCA Cycle in Non-Small Cell Lung Cancer [Metabolism]

In many patients with NSCLC, lactate is a major fuel source for the tumor TCA cycle.

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Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells [Research Articles]

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor–modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19⁺ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.

Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404–19. ©2017 AACR.

See related commentary by Mackall and Miklos, p. 1371.

This article is highlighted in the In This Issue feature, p. 1355

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SEMA3C Depletion Promotes Neuroblastoma Metastatic Dissemination [Neuroblastoma]

A neuroblastoma chick embryo xenograft model recapitulates tumor initiation and dissemination.

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H3.3K27M Expression Combined with Trp53 Loss Induces High-Grade Glioma [Glioma]

In utero expression of H3.3^K27M with Trp53 loss in mice recapitulates human pediatric high-grade glioma.

http://ift.tt/2AvNRed

BTSA1 Activates BAX to Promote Apoptosis in Acute Myeloid Leukemia [Leukemia]

The small-molecule BAX activator BTSA1 promotes apoptosis of AML cells in vitro and in vivo.

http://ift.tt/2AvKWlE

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

In a phase III trial involving more than 1,200 patients with follicular lymphoma, obinutuzumab plus chemotherapy reduced the risk of disease progression, relapse, or death by 34% compared with rituximab plus chemotherapy. However, patients receiving obinutuzumab experienced more serious side effects than those receiving rituximab.

http://ift.tt/2ArtmRC

Identified Selective USP7 Inhibitors Compete with Ubiquitin Binding [Ubiquitination]

Specific USP7 inhibitors stabilized p53 and exhibited toxicity in tumor cells in vitro and in vivo.

http://ift.tt/2AvDqHt

Trastuzumab Deruxtecan Is Safe and Active in HER2-Expressing Tumors [Clinical Trials]

Trastuzumab deruxtecan achieved responses in patients with breast, gastric, and gastroesophageal tumors.

http://ift.tt/2Ar059H

BRCA1-BARD1 Activates RAD51 for DNA Repair by Homologous Recombination [DNA Repair]

BRCA1–BARD1 binds to RAD51 to enhance its activity in the promotion of homologous DNA pairing.

http://ift.tt/2AsnRCy

FDA Disperses $22 Million for Rare Diseases [News in Brief]

The FDA has awarded 15 grants totaling $22 million over 4 years through its Orphan Products Clinical Trials Grant Program. One third of the awards will support ongoing clinical trials of therapies for rare cancers for which there are few approved or effective treatment options.

http://ift.tt/2Avqj96

Nivolumab Induces Tumor Evolution in Patients with Melanoma [Immunotherapy]

Nivolumab treatment results in immunoediting and loss of tumor cells expressing neoantigens.

http://ift.tt/2Art90M

Breast Cancer Cells Recycle Ammonia to Generate Amino Acids [Metabolism]

Ammonia generated from glutamate metabolism enhances the proliferation of breast cancer cells.

http://ift.tt/2AvKYdg

Keap1 Loss Drives Kras-Mutant Lung Cancer and Glutaminolysis Dependency [Lung Cancer]

Loss of Keap1 hyperactivates NRF2 to induce glutaminolysis-dependent Kras-driven lung cancer.

http://ift.tt/2AqlD6A

Adrenergic Nerves May Promote Angiogenesis in Prostate Cancer [Prostate Cancer]

Deleting Adrb2, encoding the β2-adrenergic receptor, in tumor endothelial cells suppresses angiogenesis.

http://ift.tt/2AveJuC

Glucose Indirectly Fuels the TCA Cycle in Tumors via Lactate [Metabolism]

Circulating lactate derived from glucose is preferentially used as fuel for the TCA cycle over glucose.

http://ift.tt/2Arshta

CNS Endothelial Cell Activation Emerges as a Driver of CAR T Cell-Associated Neurotoxicity [In the Spotlight]

Summary: Central nervous system (CNS) toxicity associated with chimeric antigen receptor–based therapeutics has emerged as a significant cause of morbidity and mortality, and insights into the pathophysiology of this syndrome have been lacking. A new study provides evidence that cytokine-induced CNS endothelial cell activation leading to disruption of the blood–brain barrier plays an early and critical role in this phenomenon. These insights provide new opportunities for targeted therapeutic interventions to modulate endothelial cell activation. Cancer Discov; 7(12); 1371–3. ©2017 AACR.

See related article by Gust et al., p. 1404.

http://ift.tt/2AwJX4M

Lactate Fuels the TCA Cycle in Non-Small Cell Lung Cancer [Metabolism]

In many patients with NSCLC, lactate is a major fuel source for the tumor TCA cycle.

http://ift.tt/2A5n0bZ

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells [Research Articles]

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor–modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19⁺ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.

Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404–19. ©2017 AACR.

See related commentary by Mackall and Miklos, p. 1371.

This article is highlighted in the In This Issue feature, p. 1355

http://ift.tt/2AXNyeX

SEMA3C Depletion Promotes Neuroblastoma Metastatic Dissemination [Neuroblastoma]

A neuroblastoma chick embryo xenograft model recapitulates tumor initiation and dissemination.

http://ift.tt/2A6oxi0

Pharmacokinetics of recombinant asparaginase in children with acute lymphoblastic leukemia

Abstract

Purpose

The objective of this study was to assess the pharmacokinetics of recombinant asparaginase (rASNase, Spectrila^®) in children with acute lymphoblastic leukemia using a population pharmacokinetic approach in order to explore potential dosing recommendations.

Methods

Data on serum asparaginase activities of 124 children from three clinical studies were included in the analysis, covering an age range from 3 days to 17 years. Most patients received 5000 U/m² rASNase intravenously every 3 days. The non-linear mixed effects modelling software (NONMEM^®) was utilized to identify drivers of rASNase pharmacokinetics in children. Different dose adjustments were simulated for their ability to increase rASNase trough activities in children who do not reach the threshold of 100 U/L.

Results

A two-compartment model with allometric weight scaling (0.75 on clearance [CL] and inter-compartmental clearance [Q] and 1 on central [V ₁] and peripheral [V ₂] volume of distribution) was the best model to describe the pharmacokinetics of rASNase. PK parameters for the median child (19.5 kg) were: CL = 0.0592 L/h, V ₁ = 1.18 L, Q = 0.307 L/h, V ₂ = 0.316 L. Organ functions, such as liver or kidney function and laboratory values, such as fibrinogen or antithrombin III levels, showed no influence on rASNase pharmacokinetics. In simulations, changing the administration interval from 72 to 48 h was appropriate to maintain rASNase activities above the therapeutic threshold, in patients with activities below 100 U/L 72 h after the first dose.

Conclusions

Drug monitoring is recommended to identify patients with insufficient ASNase trough activities in serum and to modify the treatment schedule, if necessary. Shortening of the treatment interval might be preferable over increasing the rASNase dose.

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A giant popliteal lipoblastoma in a 23-month-old girl: a case report

Lipoblastomas are rare benign tumors that arise from embryonic white fat and almost always occur in babies and children. Here, we report a case of a giant popliteal lipoblastoma in a 23-month-old Japanese girl...

http://ift.tt/2ilquvE

Pharmacokinetics of recombinant asparaginase in children with acute lymphoblastic leukemia

Abstract

Purpose

The objective of this study was to assess the pharmacokinetics of recombinant asparaginase (rASNase, Spectrila^®) in children with acute lymphoblastic leukemia using a population pharmacokinetic approach in order to explore potential dosing recommendations.

Methods

Data on serum asparaginase activities of 124 children from three clinical studies were included in the analysis, covering an age range from 3 days to 17 years. Most patients received 5000 U/m² rASNase intravenously every 3 days. The non-linear mixed effects modelling software (NONMEM^®) was utilized to identify drivers of rASNase pharmacokinetics in children. Different dose adjustments were simulated for their ability to increase rASNase trough activities in children who do not reach the threshold of 100 U/L.

Results

A two-compartment model with allometric weight scaling (0.75 on clearance [CL] and inter-compartmental clearance [Q] and 1 on central [V ₁] and peripheral [V ₂] volume of distribution) was the best model to describe the pharmacokinetics of rASNase. PK parameters for the median child (19.5 kg) were: CL = 0.0592 L/h, V ₁ = 1.18 L, Q = 0.307 L/h, V ₂ = 0.316 L. Organ functions, such as liver or kidney function and laboratory values, such as fibrinogen or antithrombin III levels, showed no influence on rASNase pharmacokinetics. In simulations, changing the administration interval from 72 to 48 h was appropriate to maintain rASNase activities above the therapeutic threshold, in patients with activities below 100 U/L 72 h after the first dose.

Conclusions

Drug monitoring is recommended to identify patients with insufficient ASNase trough activities in serum and to modify the treatment schedule, if necessary. Shortening of the treatment interval might be preferable over increasing the rASNase dose.

http://ift.tt/2jhelJ5

Salvage stereotactic radiosurgery for recurrent gliomas with prior radiation therapy

Future Oncology, Ahead of Print.


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The effect of tumor-derived exosomes on immune regulation and cancer immunotherapy

Future Oncology, Ahead of Print.


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Salvage stereotactic radiosurgery for recurrent gliomas with prior radiation therapy

Future Oncology, Ahead of Print.


http://ift.tt/2zP8rFh

The effect of tumor-derived exosomes on immune regulation and cancer immunotherapy

Future Oncology, Ahead of Print.


http://ift.tt/2ntFPzB

The effect of prone and supine treatment positions for the pre-operative treatment of rectal cancer on organ-at-risk sparing and setup reproducibility using volumetric modulated arc therapy

To compare organ-at-risk doses and setup reproducibility using the prone and supine orientations in volumetric modulated arc therapy (VMAT) for rectal cancer.

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A 10-year clinical outcome of radiotherapy as an adjuvant or definitive treatment for primary tracheal adenoid cystic carcinoma

To evaluate the role of radiotherapy (RT) as an adjuvant or definitive treatment in primary tracheal adenoid cystic carcinoma (ACC) for local tumor control and survival.

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The effect of prone and supine treatment positions for the pre-operative treatment of rectal cancer on organ-at-risk sparing and setup reproducibility using volumetric modulated arc therapy

To compare organ-at-risk doses and setup reproducibility using the prone and supine orientations in volumetric modulated arc therapy (VMAT) for rectal cancer.

http://ift.tt/2jPGkyI

A 10-year clinical outcome of radiotherapy as an adjuvant or definitive treatment for primary tracheal adenoid cystic carcinoma

To evaluate the role of radiotherapy (RT) as an adjuvant or definitive treatment in primary tracheal adenoid cystic carcinoma (ACC) for local tumor control and survival.

http://ift.tt/2imuRGI

Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer

Purpose: Determine the localized expression pattern and clinical significance of VISTA/PD-1H in human NSCLC. Experimental Design: Using multiplex quantitative immunofluorescence (QIF), we performed localized measurements of VISTA, PD-1 and PD-L1 protein in 758 stage I-IV NSCLCs from 3 independent cohorts represented in tissue microarray format. The targets were selectively measured in cytokeratin+ tumor epithelial cells, CD3+ T-cells, CD4+ T-helper cells, CD8+ cytotoxic T-cells, CD20+ B-lymphocytes and CD68+ tumor-associated macrophages. We determined the association between the targets, clinico-pathological/molecular variables and survival. Genomic analyses of lung cancer cases from TCGA was also performed. Results: VISTA protein was detected in 99% of NSCLCs with a predominant membranous/cytoplasmic staining pattern. Expression in tumor and stromal cells was seen in 21% and 98% of cases, respectively. The levels of VISTA were positively associated with PD-L1, PD-1, CD8+ T-cells and CD68+ macrophages. VISTA expression was higher in T-lymphocytes than in macrophages; and in cytotoxic T-cells than in T-helper cells. Elevated VISTA was associated with absence of EGFR mutations and lower mutational burden in lung adenocarcinomas. Presence of VISTA in tumor compartment predicted longer 5-year survival. Conclusions: VISTA is frequently expressed in human NSCLC and shows association with increased TILs, PD-1 axis markers, specific genomic alterations and outcome. These results support the immuno-modulatory role of VISTA in human NSCLC and suggests its potential as therapeutic target.

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NAMPT is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and resistance to therapy through Sirt1 and PARP

Purpose: Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men worldwide. However, despite current progress, many patients with advanced and metastatic tumors still die from the malignancy. Refractory disease often relies on nicotinamide adenine dinucleotide(NAD)-dependent mechanisms. NAD metabolism and a stable NAD regeneration circuit are required to maintain tissue homeostasis and metabolism. However, high levels of NAD confer therapy resistance to tumors. Experimental Design: ectopic overexpression of nicotinamide phosphoribosil transferase (NAMPT) and shRNAs in CRC cell lines, Tumorigenic and stemness properties and transcription measurement in culture and in vivo. Transcriptional analisis in public databases. Therapeutic approaches.Results: NAMPT, the rate-limiting enzyme responsible for the highest source of physiological NAD biosynthesis, increases tumorigenic properties and induces cancer stem cell-like properties through pathways that control stem cell signaling, thus enriching the cancer-initiating cell (CIC) population. Furthermore, NAMPT expression correlated with high levels of CIC-like cells in colon tumors directly extracted from patients, and transcription meta-analysis revealed that NAMPT is also a key factor that induces cancer stem pathways in CRC tumors. This effect is mediated by PARP and SIRT1. Additionally, we report a novel NAMPT-driven signature that stratifies prognosis from high to low expression groups. The NAMPT signature contained SIRT1 and PARP1 levels as well as other CSC-related genes. Finally, NAMPT inhibition increased the sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres. Conclusions: NAMPT represents a novel therapeutic target in colon cancer progression and relapse, particularly the CIC subset of human colon cancers.

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Lymph Node Metastases in Colon Cancer are Polyclonal

Purpose:  Recent studies have highlighted the existence of sub-clones in tumors. Lymph nodes are generally the first location of metastasis for most solid epithelial tumors including colorectal cancer (CRC). We sought to understand the genetic origin of lymph node metastasis in CRC by evaluating the relationship between CRC tumor sub-clones present in primary tumors and lymph nodes. Experimental Design:  A total of 33 samples from seven CRC's, including two or three spatially disparate regions from each primary tumor and one to four matched lymph nodes for each tumor, underwent next-generation whole-exome DNA sequencing, Affymetrix OncoScan SNP arrays, and targeted deep confirmatory sequencing. We performed mapping between SNPs and copy number events from the primary tumor and matched lymph node samples, allowing us to profile heterogeneity and the mutational origin of LN metastases. The computational method PyClone was used to define sub-clones within each tumor. The method Citup was subsequently used to infer phylogenetic relationships among sub-clones. Results:  We found there was substantial heterogeneity in mutations and copy number changes among all samples from any given patient. For each patient, the primary tumor regions and matched lymph node metastases were each polyclonal and the clonal populations differed from one lymph node to another. In some patients, the cancer cell populations in a given lymph node originated from multiple distinct regions of a tumor. Conclusions: Our data support a model of lymph node metastatic spread in colorectal cancer whereby metastases originate from multiple waves of seeding from the primary tumor over time.

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via IFTTT

Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer

Purpose: Determine the localized expression pattern and clinical significance of VISTA/PD-1H in human NSCLC. Experimental Design: Using multiplex quantitative immunofluorescence (QIF), we performed localized measurements of VISTA, PD-1 and PD-L1 protein in 758 stage I-IV NSCLCs from 3 independent cohorts represented in tissue microarray format. The targets were selectively measured in cytokeratin+ tumor epithelial cells, CD3+ T-cells, CD4+ T-helper cells, CD8+ cytotoxic T-cells, CD20+ B-lymphocytes and CD68+ tumor-associated macrophages. We determined the association between the targets, clinico-pathological/molecular variables and survival. Genomic analyses of lung cancer cases from TCGA was also performed. Results: VISTA protein was detected in 99% of NSCLCs with a predominant membranous/cytoplasmic staining pattern. Expression in tumor and stromal cells was seen in 21% and 98% of cases, respectively. The levels of VISTA were positively associated with PD-L1, PD-1, CD8+ T-cells and CD68+ macrophages. VISTA expression was higher in T-lymphocytes than in macrophages; and in cytotoxic T-cells than in T-helper cells. Elevated VISTA was associated with absence of EGFR mutations and lower mutational burden in lung adenocarcinomas. Presence of VISTA in tumor compartment predicted longer 5-year survival. Conclusions: VISTA is frequently expressed in human NSCLC and shows association with increased TILs, PD-1 axis markers, specific genomic alterations and outcome. These results support the immuno-modulatory role of VISTA in human NSCLC and suggests its potential as therapeutic target.

http://ift.tt/2jg1ab2

A First-in-Human Phase 1 Study of Subcutaneous Outpatient Recombinant Human IL-15 (rhIL-15) in Adults with Advanced Solid Tumors

Purpose: Preclinical data established Interleukin-15 as a homeostatic factor and powerful stimulator of NK and CD8+ T cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL-15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday - Friday) SC injections of rhIL-15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL-15 and immune biomarkers were evaluated. Results: Nineteen patients were treated with rhIL-15 at dose levels of 0.25, 0.5, 1, 2 and 3 mcg/kg/day. Fourteen patients completed ≥ 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8+ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients.  Conclusions: SC rhIL-15 treatment was well tolerated, producing substantial increases in circulating NK and CD8+ T cells. This protocol establishes a safe outpatient SC rhIL-15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent.

http://ift.tt/2BzAGbq

NAMPT is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and resistance to therapy through Sirt1 and PARP

Purpose: Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men worldwide. However, despite current progress, many patients with advanced and metastatic tumors still die from the malignancy. Refractory disease often relies on nicotinamide adenine dinucleotide(NAD)-dependent mechanisms. NAD metabolism and a stable NAD regeneration circuit are required to maintain tissue homeostasis and metabolism. However, high levels of NAD confer therapy resistance to tumors. Experimental Design: ectopic overexpression of nicotinamide phosphoribosil transferase (NAMPT) and shRNAs in CRC cell lines, Tumorigenic and stemness properties and transcription measurement in culture and in vivo. Transcriptional analisis in public databases. Therapeutic approaches.Results: NAMPT, the rate-limiting enzyme responsible for the highest source of physiological NAD biosynthesis, increases tumorigenic properties and induces cancer stem cell-like properties through pathways that control stem cell signaling, thus enriching the cancer-initiating cell (CIC) population. Furthermore, NAMPT expression correlated with high levels of CIC-like cells in colon tumors directly extracted from patients, and transcription meta-analysis revealed that NAMPT is also a key factor that induces cancer stem pathways in CRC tumors. This effect is mediated by PARP and SIRT1. Additionally, we report a novel NAMPT-driven signature that stratifies prognosis from high to low expression groups. The NAMPT signature contained SIRT1 and PARP1 levels as well as other CSC-related genes. Finally, NAMPT inhibition increased the sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres. Conclusions: NAMPT represents a novel therapeutic target in colon cancer progression and relapse, particularly the CIC subset of human colon cancers.

http://ift.tt/2jhceVF

Lymph Node Metastases in Colon Cancer are Polyclonal

Purpose:  Recent studies have highlighted the existence of sub-clones in tumors. Lymph nodes are generally the first location of metastasis for most solid epithelial tumors including colorectal cancer (CRC). We sought to understand the genetic origin of lymph node metastasis in CRC by evaluating the relationship between CRC tumor sub-clones present in primary tumors and lymph nodes. Experimental Design:  A total of 33 samples from seven CRC's, including two or three spatially disparate regions from each primary tumor and one to four matched lymph nodes for each tumor, underwent next-generation whole-exome DNA sequencing, Affymetrix OncoScan SNP arrays, and targeted deep confirmatory sequencing. We performed mapping between SNPs and copy number events from the primary tumor and matched lymph node samples, allowing us to profile heterogeneity and the mutational origin of LN metastases. The computational method PyClone was used to define sub-clones within each tumor. The method Citup was subsequently used to infer phylogenetic relationships among sub-clones. Results:  We found there was substantial heterogeneity in mutations and copy number changes among all samples from any given patient. For each patient, the primary tumor regions and matched lymph node metastases were each polyclonal and the clonal populations differed from one lymph node to another. In some patients, the cancer cell populations in a given lymph node originated from multiple distinct regions of a tumor. Conclusions: Our data support a model of lymph node metastatic spread in colorectal cancer whereby metastases originate from multiple waves of seeding from the primary tumor over time.

http://ift.tt/2BzgJRT

Vascular anatomy of the jejunal mesentery and complications associated with division of the first jejunal venous trunk during pancreaticoduodenectomy

Background

Little is known about the anatomy of the jejunal veins (JVs) flowing into the superior mesenteric vein (SMV), and whether they can be safely divided during pancreaticoduodenectomy.

Methods

Computed tomography was used to review the jejunal branches off the superior mesenteric artery (SMA) and into the SMV in 123 consecutive patients. The common trunk of the JVs (jejunal venous trunk, JVT) was classified as ventral or dorsal to the SMA.

Results

The first JVT involved multiple JVs in 108 (87.8%) cases. The first JVT diameter (≥7 or <7 mm) was significantly associated with the number of JVs (≥4 or <4; P < 0.05). Surgical outcomes were not significantly different between cases in which the first JVT was sacrificed (n = 32) or preserved (n = 91), except for operation time and portal venous resection frequency. One of the 32 cases (3.1%) with first JVT sacrifice showed severe congestion of the jejunal limb requiring emergency jejunal resection.

Conclusions

The size and topology of the first JVT are associated with the number of JVs involved. This is important for understanding the resectional area of the mesojejunum and the pathogenesis of jejunal congestion.

http://ift.tt/2ii6x8L

Perioperative cytokine levels portend early death after pancreatectomy for ductal adenocarcinoma

Background

Soluble signaling molecules may play an important role in malignant pathogenesis. We hypothesize that perioperative cytokine levels are associated with outcomes in patients with pancreatic adenocarcinoma (PDAC) undergoing surgical resection.

Methods

One hundered and eighteen patients with benign or malignant pancreatic disease were enrolled in a prospective study through a protocol for banking biologic samples. Peripheral blood was drawn at time of operation, and a multiplex cytokine assay was performed. Statistical analysis was via χ² and Kaplan Meier methods.

Results

Of 118 patients enrolled, 85 (72%) had a diagnosis of PDAC, and 60 (70%) ultimately underwent partial pancreatectomy. Cytokine levels were not associated with postoperative complications in this initial cohort. A plasma level of monocyte chemoattractant protein-1 (MCP-1) pg/mL ≤118 was associated with better overall survival (OS) (median survival 21 months vs 12.8 months, P = 0.023), as was non-detectable interleukin-8 (IL-8) (19 months) versus detectable IL-8 (12.8 months, P = 0.05). Patients with both MCP-1 >118 pg/mL and detectable IL-8 had a median survival of 10.6 months (P = 0.028).

Conclusions

MCP-1 and IL-8 cytokine levels are associated with decreased survival following pancreatectomy for PDAC, and may be useful biomarkers. Measurement of these cytokine levels at different time points in future investigations will be important to validate these findings.

http://ift.tt/2ii6sSv

Prognostic impact of postoperative pulmonary complications following salvage esophagectomy after definitive chemoradiotherapy

Background

Postoperative complications after esophagectomy for esophageal cancer have a negative effect on patients' survival. Although postoperative complications are more frequently observed after salvage esophagectomy than after planned esophagectomy, the effects of postoperative complications on long-term oncologic outcomes after salvage esophagectomy remain unclear.

Methods

This retrospective study of 70 esophageal cancer patients after definitive chemoradiotherapy (dCRT) compared long-term outcomes between those with and without complications. The association between morbidity and overall survival (OS) was evaluated by a Cox regression analysis. To identify the risk factors for pulmonary complications, logistic regression analysis was carried out.

Results

Postoperative complications occurred in 42 (60.0%) patients. Pulmonary complications and anastomotic leakage occurred in 23 (32.9%) and 9 (12.9%) patients, respectively. Overall complications and anastomotic leakage did not affect long-term outcomes. Survival was significantly worse for patients with pulmonary complications. Radiation dose (<60 Gy), response to dCRT (complete), ypStage (0-II), residual disease (R0), and pulmonary complications (negative) were independent factors related to a favorable OS. BMI (<20 kg/m²), ASA-PS (2-3), and radiation dose (>60 Gy) were significant factors affecting the occurrence of pulmonary complications.

Conclusions

Development of postoperative pulmonary complications was independently associated with poor prognosis in patients who underwent salvage esophagectomy after dCRT.

http://ift.tt/2jPnwjp

Oncologic effects of preoperative biliary drainage in resectable hilar cholangiocarcinoma: Percutaneous biliary drainage has no adverse effects on survival

Background and Objectives

The objective of the current study was to define long-term survival of patients with resectable hilar cholangiocarcinoma (HCCA) after preoperative percutaneous transhepatic biliary drainage (PTBD) versus endoscopic biliary drainage (EBD).

Methods

Between 2000 and 2014, 240 patients who underwent curative-intent resection for HCCA were identified at 10 major hepatobiliary centers. Postoperative morbidity and mortality, as well as disease-specific survival (DSS) and recurrence-free survival (RFS) were analyzed among patients.

Results

The median decrease in total bilirubin levels after biliary drainage was similar comparing PTBD (n = 104) versus EBD (n = 92) (mg/dL, 4.9 vs 4.9, P = 0.589) before surgery. There was no difference in baseline demographic characteristics, type of surgical procedure performed, final AJCC tumor stage or postoperative morbidity among patients who underwent EBD only versus PTBD (all P > 0.05). Patients who underwent PTBD versus EBD had a comparable long-term DSS (median, 43.7 vs 36.9 months, P = 0.802) and RFS (median, 26.7 vs 24.0 months, P = 0.571). The overall pattern of recurrence relative to regional or distant disease was also the same among patients undergoing PTBD and EBD (P = 0.669)

Conclusions

Oncologic outcomes including DSS and RFS were similar among patients who underwent PTBD versus EBD with no difference in tumor recurrence location.

http://ift.tt/2ij8Ubu

Diagnostic staging laparoscopy in gastric cancer treatment: A cost-effectiveness analysis

Background and Objectives

Accurate preoperative staging helps avert morbidity, mortality, and cost associated with non-therapeutic laparotomy in gastric cancer (GC) patients. Diagnostic staging laparoscopy (DSL) can detect metastases with high sensitivity, but its cost-effectiveness has not been previously studied. We developed a decision analysis model to assess the cost-effectiveness of preoperative DSL in GC workup.

Methods

Analysis was based on a hypothetical cohort of GC patients in the U.S. for whom initial imaging shows no metastases. The cost-effectiveness of DSL was measured as cost per quality-adjusted life-year (QALY) gained. Drivers of cost-effectiveness were assessed in sensitivity analysis.

Results

Preoperative DSL required an investment of $107 012 per QALY. In sensitivity analysis, DSL became cost-effective at a threshold of $100 000/QALY when the probability of occult metastases exceeded 31.5% or when test sensitivity for metastases exceeded 86.3%. The likelihood of cost-effectiveness increased from 46% to 93% when both parameters were set at maximum reported values.

Conclusions

The cost-effectiveness of DSL for GC patients is highly dependent on patient and test characteristics, and is more likely when DSL is used selectively where procedure yield is high, such as for locally advanced disease or in detecting peritoneal and superficial versus deep liver lesions.

http://ift.tt/2jOuXad

Characteristics and long-term survival of patients diagnosed with pure tubular carcinoma of the breast

Background and Objectives

Pure tubular carcinomas (TC) of the breast are generally considered to have an excellent prognosis. This study aimed to analyze the characteristics and survival of patients with TC.

Methods

This was a retrospective study conducted at the CHU de Québec—Université Laval. Databases were searched for all cases treated between April 1997 and December 2010. Survival was retrieved from the Province of Quebec Ministry of Health. Follow-up was censored on December 31, 2011. Overall survival (OS) was compared to patients with invasive ductal carcinoma (ICD) matched for age, tumor size, lymph node involvement, year of diagnosis, ER, PgR, and HER2, histological grade, lymphovascular invasion, and chemotherapy.

Results

The frequency of TC was 2.9% (n = 223/7563). Tumors size was 7.4 ± 8.8 mm, without lymphovascular invasion (95.1%), ER-positive (98.2%), PgR-positive (69.5%), and HER2-negative (100%). Patients were followed up for 7.1 ± 2.7 years. The actuarial 13-year OS was 89.0% for TC, compared to 85.8% for IDC (P = 0.13). For TC, the 13-year OS was 95.8% in NO patients compared to 90.0% for N1-3 (P = 0.01).

Conclusion

Despite the general popular belief that patients with TC fare better than patients with IDC, the 13-year OS of TC was similar to that of grade I IDC.

http://ift.tt/2ii6j1p

Effects of local multivisceral resection for clinically locally advanced rectal cancer on long-term outcomes

Introduction

Multivisceral resection is occasionally needed to obtain clear margins in patients with transmural rectal cancer. Most series demonstrate equivalent outcomes between those patients who undergo multivisceral resections and those who do not, provided an R0-resection is achieved. This study focuses solely on patients who received neoadjuvant treatment for clinically transmural rectal cancers and underwent a local multivisceral R0-resection.

Methods

A retrospective, single center analysis of consecutive series of patients who received a surgical R0-resection after neoadjuvant treatment for a clinically transmural, non-metastatic, primary rectal cancer. All patients were operated on between 2004 and 2015.

Results

A total of 279 patients was included, of whom 29 patients underwent a local multivisceral R0-resection (LMVR). These patients were more often female and less often diagnosed through screening. Pathologic AJCC-staging was significantly lower for non-LMVR patients, with more favorable tumor characteristics. LMVR patients demonstrated higher rates of distant disease recurrence, and impaired survival, even after adjusting for disease stage.

Conclusion

An R0-resection after neoadjuvant therapy led to comparative local control of disease; however, patients with multivisceral resection had more distant recurrence and impaired survival, compared to those did not undergo a multivisceral resection. Further research should determine optimal postoperative care.

http://ift.tt/2jPdA9l

Clinical outcomes in breast angiosarcoma patients: A rare tumor with unique challenges

Background

Breast angiosarcoma (AS) accounts for less than 1% of all breast cancers. The goal of this study was to determine patient outcomes in radiation-associated angiosarcoma of the breast (RAAS) and sporadic AS. We evaluated patterns of recurrence and predictors of breast AS survival.

Methods

Patients with pathologically confirmed AS from 1994 to 2014 referred to Mount Sinai Hospital/Princess Margaret Cancer Centre were included. Primary outcome was overall survival (OS). Secondary outcomes were disease-free survival (DFS), clinicopathologic characteristics, patterns of recurrence and factors predictive of survival. Kaplan-Meier and log-rank tests were used for OS and DFS.

Results

Twenty-six patients were included: 6 with sporadic AS and 20 with RAAS. Median follow-up was 24 months. Five-year OS for RAAS and sporadic subgroups were 44% and 40%, respectively (P = ns). Five-year DFS for RAAS and sporadic subgroups were 23% and 20%, respectively (P = ns). Overall recurrence rate was 67% with median time to recurrence of 11 months. Age, tumor depth, margin status, and tumor size were not statistically significant predictive factors for OS and DFS.

Discussion

Breast AS is associated with poor survival and high recurrence rates. Prognosis may be mainly determined by its aggressive biology. Referral to tertiary care centers for multimodality treatment is recommended.

http://ift.tt/2ihvPE1

Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple Negative Breast Cancer [Research Articles]

Triple negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole exome sequencing (WES) and RNAseq to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1. Amplifications or translocations that resulted in elevated oncoprotein expressions or oncoprotein-containing fusions, respectively, as well as frame-shift mutations of tumor suppressors were identified in approximately 50% of the tumors evaluated. While the spectrum of sporadic genetic alterations was diverse, the majority had in common the ability to activate the MAPK/PI3K pathways. Importantly, we demonstrated that approved or experimental drugs efficiently induce tumor regression specifically in tumors harboring somatic aberrations of the drug target. Our study suggests that the combination of WES and RNAseq on human TNBC will lead to the identification of actionable therapeutic targets for precision medicine guided TNBC treatment.

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Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines

Osimertinib is a third-generation EGFR-TKI with a high selective potency against T790M-mutant NSCLC patients. Considering that osimertinib can lead to enhanced HER-2 expression on cell surface and HER-2 overex...

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via IFTTT

Downregulation of miR-141-3p promotes bone metastasis via activating NF-κB signaling in prostate cancer

Clinically, prostate cancer (PCa) exhibits a high avidity to metastasize to bone. miR-141-3p is an extensively studied miRNA in cancers and downregulation of miR-141-3p has been widely reported to be involved ...

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Vascular anatomy of the jejunal mesentery and complications associated with division of the first jejunal venous trunk during pancreaticoduodenectomy

Background

Little is known about the anatomy of the jejunal veins (JVs) flowing into the superior mesenteric vein (SMV), and whether they can be safely divided during pancreaticoduodenectomy.

Methods

Computed tomography was used to review the jejunal branches off the superior mesenteric artery (SMA) and into the SMV in 123 consecutive patients. The common trunk of the JVs (jejunal venous trunk, JVT) was classified as ventral or dorsal to the SMA.

Results

The first JVT involved multiple JVs in 108 (87.8%) cases. The first JVT diameter (≥7 or <7 mm) was significantly associated with the number of JVs (≥4 or <4; P < 0.05). Surgical outcomes were not significantly different between cases in which the first JVT was sacrificed (n = 32) or preserved (n = 91), except for operation time and portal venous resection frequency. One of the 32 cases (3.1%) with first JVT sacrifice showed severe congestion of the jejunal limb requiring emergency jejunal resection.

Conclusions

The size and topology of the first JVT are associated with the number of JVs involved. This is important for understanding the resectional area of the mesojejunum and the pathogenesis of jejunal congestion.

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via IFTTT

Risk of peritoneal metastases in patients who had negative peritoneal staging and received therapy for localized gastric adenocarcinoma

Background

Positive peritoneal cytology (+PCyt) or gross carcinomatosis (GPC) carries a poor prognosis. Laparoscopic staging to detect +PCyt/GPC is recommended for all ≥T1b gastric adenocarcinoma (GAC). The natural history of patients with GAC who have baseline −PCyt and then undergo multimodality therapy is not well documented, particularly for the risk of subsequent GPC.

Methods

We identified 238 GAC patients with baseline −PCyt who were followed for the development of peritoneal carcinomatosis (PC). Standard statistical methods were employed.

Results

Of 238 patients, 192 had attempted surgery after preoperative therapy. Of these, 13 patients (6.8%) had GPC and one had liver metastases, thus surgery was aborted. We followed 164 patients who had an R0 resection. The median follow-up duration was 3.4 (range, 0.6-18) years. The rate of PC was 13.4%, (22/164 patients) and the median time to PC was 15.6 months. Female gender was associated with PC on multivariate analysis. The 5-year OS rate for patients without subsequent PC was 75%.

Conclusion Even with baseline −Cyt, ∼25% of patients develop PC following multimodality therapy. Patients who do not develop PC have an excellent OS rate. Further research is warranted to detect PC at baseline by the use of biomarkers.

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via IFTTT

Perioperative cytokine levels portend early death after pancreatectomy for ductal adenocarcinoma

Background

Soluble signaling molecules may play an important role in malignant pathogenesis. We hypothesize that perioperative cytokine levels are associated with outcomes in patients with pancreatic adenocarcinoma (PDAC) undergoing surgical resection.

Methods

One hundered and eighteen patients with benign or malignant pancreatic disease were enrolled in a prospective study through a protocol for banking biologic samples. Peripheral blood was drawn at time of operation, and a multiplex cytokine assay was performed. Statistical analysis was via χ² and Kaplan Meier methods.

Results

Of 118 patients enrolled, 85 (72%) had a diagnosis of PDAC, and 60 (70%) ultimately underwent partial pancreatectomy. Cytokine levels were not associated with postoperative complications in this initial cohort. A plasma level of monocyte chemoattractant protein-1 (MCP-1) pg/mL ≤118 was associated with better overall survival (OS) (median survival 21 months vs 12.8 months, P = 0.023), as was non-detectable interleukin-8 (IL-8) (19 months) versus detectable IL-8 (12.8 months, P = 0.05). Patients with both MCP-1 >118 pg/mL and detectable IL-8 had a median survival of 10.6 months (P = 0.028).

Conclusions

MCP-1 and IL-8 cytokine levels are associated with decreased survival following pancreatectomy for PDAC, and may be useful biomarkers. Measurement of these cytokine levels at different time points in future investigations will be important to validate these findings.

from Cancer via ola Kala on Inoreader http://ift.tt/2ii6sSv
via IFTTT

Prognostic impact of postoperative pulmonary complications following salvage esophagectomy after definitive chemoradiotherapy

Background

Postoperative complications after esophagectomy for esophageal cancer have a negative effect on patients' survival. Although postoperative complications are more frequently observed after salvage esophagectomy than after planned esophagectomy, the effects of postoperative complications on long-term oncologic outcomes after salvage esophagectomy remain unclear.

Methods

This retrospective study of 70 esophageal cancer patients after definitive chemoradiotherapy (dCRT) compared long-term outcomes between those with and without complications. The association between morbidity and overall survival (OS) was evaluated by a Cox regression analysis. To identify the risk factors for pulmonary complications, logistic regression analysis was carried out.

Results

Postoperative complications occurred in 42 (60.0%) patients. Pulmonary complications and anastomotic leakage occurred in 23 (32.9%) and 9 (12.9%) patients, respectively. Overall complications and anastomotic leakage did not affect long-term outcomes. Survival was significantly worse for patients with pulmonary complications. Radiation dose (<60 Gy), response to dCRT (complete), ypStage (0-II), residual disease (R0), and pulmonary complications (negative) were independent factors related to a favorable OS. BMI (<20 kg/m²), ASA-PS (2-3), and radiation dose (>60 Gy) were significant factors affecting the occurrence of pulmonary complications.

Conclusions

Development of postoperative pulmonary complications was independently associated with poor prognosis in patients who underwent salvage esophagectomy after dCRT.

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

Oncologic effects of preoperative biliary drainage in resectable hilar cholangiocarcinoma: Percutaneous biliary drainage has no adverse effects on survival

Background and Objectives

The objective of the current study was to define long-term survival of patients with resectable hilar cholangiocarcinoma (HCCA) after preoperative percutaneous transhepatic biliary drainage (PTBD) versus endoscopic biliary drainage (EBD).

Methods

Between 2000 and 2014, 240 patients who underwent curative-intent resection for HCCA were identified at 10 major hepatobiliary centers. Postoperative morbidity and mortality, as well as disease-specific survival (DSS) and recurrence-free survival (RFS) were analyzed among patients.

Results

The median decrease in total bilirubin levels after biliary drainage was similar comparing PTBD (n = 104) versus EBD (n = 92) (mg/dL, 4.9 vs 4.9, P = 0.589) before surgery. There was no difference in baseline demographic characteristics, type of surgical procedure performed, final AJCC tumor stage or postoperative morbidity among patients who underwent EBD only versus PTBD (all P > 0.05). Patients who underwent PTBD versus EBD had a comparable long-term DSS (median, 43.7 vs 36.9 months, P = 0.802) and RFS (median, 26.7 vs 24.0 months, P = 0.571). The overall pattern of recurrence relative to regional or distant disease was also the same among patients undergoing PTBD and EBD (P = 0.669)

Conclusions

Oncologic outcomes including DSS and RFS were similar among patients who underwent PTBD versus EBD with no difference in tumor recurrence location.

from Cancer via ola Kala on Inoreader http://ift.tt/2ij8Ubu
via IFTTT

Diagnostic staging laparoscopy in gastric cancer treatment: A cost-effectiveness analysis

Background and Objectives

Accurate preoperative staging helps avert morbidity, mortality, and cost associated with non-therapeutic laparotomy in gastric cancer (GC) patients. Diagnostic staging laparoscopy (DSL) can detect metastases with high sensitivity, but its cost-effectiveness has not been previously studied. We developed a decision analysis model to assess the cost-effectiveness of preoperative DSL in GC workup.

Methods

Analysis was based on a hypothetical cohort of GC patients in the U.S. for whom initial imaging shows no metastases. The cost-effectiveness of DSL was measured as cost per quality-adjusted life-year (QALY) gained. Drivers of cost-effectiveness were assessed in sensitivity analysis.

Results

Preoperative DSL required an investment of $107 012 per QALY. In sensitivity analysis, DSL became cost-effective at a threshold of $100 000/QALY when the probability of occult metastases exceeded 31.5% or when test sensitivity for metastases exceeded 86.3%. The likelihood of cost-effectiveness increased from 46% to 93% when both parameters were set at maximum reported values.

Conclusions

The cost-effectiveness of DSL for GC patients is highly dependent on patient and test characteristics, and is more likely when DSL is used selectively where procedure yield is high, such as for locally advanced disease or in detecting peritoneal and superficial versus deep liver lesions.

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

Characteristics and long-term survival of patients diagnosed with pure tubular carcinoma of the breast

Background and Objectives

Pure tubular carcinomas (TC) of the breast are generally considered to have an excellent prognosis. This study aimed to analyze the characteristics and survival of patients with TC.

Methods

This was a retrospective study conducted at the CHU de Québec—Université Laval. Databases were searched for all cases treated between April 1997 and December 2010. Survival was retrieved from the Province of Quebec Ministry of Health. Follow-up was censored on December 31, 2011. Overall survival (OS) was compared to patients with invasive ductal carcinoma (ICD) matched for age, tumor size, lymph node involvement, year of diagnosis, ER, PgR, and HER2, histological grade, lymphovascular invasion, and chemotherapy.

Results

The frequency of TC was 2.9% (n = 223/7563). Tumors size was 7.4 ± 8.8 mm, without lymphovascular invasion (95.1%), ER-positive (98.2%), PgR-positive (69.5%), and HER2-negative (100%). Patients were followed up for 7.1 ± 2.7 years. The actuarial 13-year OS was 89.0% for TC, compared to 85.8% for IDC (P = 0.13). For TC, the 13-year OS was 95.8% in NO patients compared to 90.0% for N1-3 (P = 0.01).

Conclusion

Despite the general popular belief that patients with TC fare better than patients with IDC, the 13-year OS of TC was similar to that of grade I IDC.

from Cancer via ola Kala on Inoreader http://ift.tt/2ii6j1p
via IFTTT

Effects of local multivisceral resection for clinically locally advanced rectal cancer on long-term outcomes

Introduction

Multivisceral resection is occasionally needed to obtain clear margins in patients with transmural rectal cancer. Most series demonstrate equivalent outcomes between those patients who undergo multivisceral resections and those who do not, provided an R0-resection is achieved. This study focuses solely on patients who received neoadjuvant treatment for clinically transmural rectal cancers and underwent a local multivisceral R0-resection.

Methods

A retrospective, single center analysis of consecutive series of patients who received a surgical R0-resection after neoadjuvant treatment for a clinically transmural, non-metastatic, primary rectal cancer. All patients were operated on between 2004 and 2015.

Results

A total of 279 patients was included, of whom 29 patients underwent a local multivisceral R0-resection (LMVR). These patients were more often female and less often diagnosed through screening. Pathologic AJCC-staging was significantly lower for non-LMVR patients, with more favorable tumor characteristics. LMVR patients demonstrated higher rates of distant disease recurrence, and impaired survival, even after adjusting for disease stage.

Conclusion

An R0-resection after neoadjuvant therapy led to comparative local control of disease; however, patients with multivisceral resection had more distant recurrence and impaired survival, compared to those did not undergo a multivisceral resection. Further research should determine optimal postoperative care.

from Cancer via ola Kala on Inoreader http://ift.tt/2jPdA9l
via IFTTT

Clinical outcomes in breast angiosarcoma patients: A rare tumor with unique challenges

Background

Breast angiosarcoma (AS) accounts for less than 1% of all breast cancers. The goal of this study was to determine patient outcomes in radiation-associated angiosarcoma of the breast (RAAS) and sporadic AS. We evaluated patterns of recurrence and predictors of breast AS survival.

Methods

Patients with pathologically confirmed AS from 1994 to 2014 referred to Mount Sinai Hospital/Princess Margaret Cancer Centre were included. Primary outcome was overall survival (OS). Secondary outcomes were disease-free survival (DFS), clinicopathologic characteristics, patterns of recurrence and factors predictive of survival. Kaplan-Meier and log-rank tests were used for OS and DFS.

Results

Twenty-six patients were included: 6 with sporadic AS and 20 with RAAS. Median follow-up was 24 months. Five-year OS for RAAS and sporadic subgroups were 44% and 40%, respectively (P = ns). Five-year DFS for RAAS and sporadic subgroups were 23% and 20%, respectively (P = ns). Overall recurrence rate was 67% with median time to recurrence of 11 months. Age, tumor depth, margin status, and tumor size were not statistically significant predictive factors for OS and DFS.

Discussion

Breast AS is associated with poor survival and high recurrence rates. Prognosis may be mainly determined by its aggressive biology. Referral to tertiary care centers for multimodality treatment is recommended.

from Cancer via ola Kala on Inoreader http://ift.tt/2ihvPE1
via IFTTT

Vascular anatomy of the jejunal mesentery and complications associated with division of the first jejunal venous trunk during pancreaticoduodenectomy

Background

Little is known about the anatomy of the jejunal veins (JVs) flowing into the superior mesenteric vein (SMV), and whether they can be safely divided during pancreaticoduodenectomy.

Methods

Computed tomography was used to review the jejunal branches off the superior mesenteric artery (SMA) and into the SMV in 123 consecutive patients. The common trunk of the JVs (jejunal venous trunk, JVT) was classified as ventral or dorsal to the SMA.

Results

The first JVT involved multiple JVs in 108 (87.8%) cases. The first JVT diameter (≥7 or <7 mm) was significantly associated with the number of JVs (≥4 or <4; P < 0.05). Surgical outcomes were not significantly different between cases in which the first JVT was sacrificed (n = 32) or preserved (n = 91), except for operation time and portal venous resection frequency. One of the 32 cases (3.1%) with first JVT sacrifice showed severe congestion of the jejunal limb requiring emergency jejunal resection.

Conclusions

The size and topology of the first JVT are associated with the number of JVs involved. This is important for understanding the resectional area of the mesojejunum and the pathogenesis of jejunal congestion.

http://ift.tt/2ii6x8L

Risk of peritoneal metastases in patients who had negative peritoneal staging and received therapy for localized gastric adenocarcinoma

Background

Positive peritoneal cytology (+PCyt) or gross carcinomatosis (GPC) carries a poor prognosis. Laparoscopic staging to detect +PCyt/GPC is recommended for all ≥T1b gastric adenocarcinoma (GAC). The natural history of patients with GAC who have baseline −PCyt and then undergo multimodality therapy is not well documented, particularly for the risk of subsequent GPC.

Methods

We identified 238 GAC patients with baseline −PCyt who were followed for the development of peritoneal carcinomatosis (PC). Standard statistical methods were employed.

Results

Of 238 patients, 192 had attempted surgery after preoperative therapy. Of these, 13 patients (6.8%) had GPC and one had liver metastases, thus surgery was aborted. We followed 164 patients who had an R0 resection. The median follow-up duration was 3.4 (range, 0.6-18) years. The rate of PC was 13.4%, (22/164 patients) and the median time to PC was 15.6 months. Female gender was associated with PC on multivariate analysis. The 5-year OS rate for patients without subsequent PC was 75%.

Conclusion Even with baseline −Cyt, ∼25% of patients develop PC following multimodality therapy. Patients who do not develop PC have an excellent OS rate. Further research is warranted to detect PC at baseline by the use of biomarkers.

http://ift.tt/2jNxcLd

Perioperative cytokine levels portend early death after pancreatectomy for ductal adenocarcinoma

Background

Soluble signaling molecules may play an important role in malignant pathogenesis. We hypothesize that perioperative cytokine levels are associated with outcomes in patients with pancreatic adenocarcinoma (PDAC) undergoing surgical resection.

Methods

One hundered and eighteen patients with benign or malignant pancreatic disease were enrolled in a prospective study through a protocol for banking biologic samples. Peripheral blood was drawn at time of operation, and a multiplex cytokine assay was performed. Statistical analysis was via χ² and Kaplan Meier methods.

Results

Of 118 patients enrolled, 85 (72%) had a diagnosis of PDAC, and 60 (70%) ultimately underwent partial pancreatectomy. Cytokine levels were not associated with postoperative complications in this initial cohort. A plasma level of monocyte chemoattractant protein-1 (MCP-1) pg/mL ≤118 was associated with better overall survival (OS) (median survival 21 months vs 12.8 months, P = 0.023), as was non-detectable interleukin-8 (IL-8) (19 months) versus detectable IL-8 (12.8 months, P = 0.05). Patients with both MCP-1 >118 pg/mL and detectable IL-8 had a median survival of 10.6 months (P = 0.028).

Conclusions

MCP-1 and IL-8 cytokine levels are associated with decreased survival following pancreatectomy for PDAC, and may be useful biomarkers. Measurement of these cytokine levels at different time points in future investigations will be important to validate these findings.

http://ift.tt/2ii6sSv

Prognostic impact of postoperative pulmonary complications following salvage esophagectomy after definitive chemoradiotherapy

Background

Postoperative complications after esophagectomy for esophageal cancer have a negative effect on patients' survival. Although postoperative complications are more frequently observed after salvage esophagectomy than after planned esophagectomy, the effects of postoperative complications on long-term oncologic outcomes after salvage esophagectomy remain unclear.

Methods

This retrospective study of 70 esophageal cancer patients after definitive chemoradiotherapy (dCRT) compared long-term outcomes between those with and without complications. The association between morbidity and overall survival (OS) was evaluated by a Cox regression analysis. To identify the risk factors for pulmonary complications, logistic regression analysis was carried out.

Results

Postoperative complications occurred in 42 (60.0%) patients. Pulmonary complications and anastomotic leakage occurred in 23 (32.9%) and 9 (12.9%) patients, respectively. Overall complications and anastomotic leakage did not affect long-term outcomes. Survival was significantly worse for patients with pulmonary complications. Radiation dose (<60 Gy), response to dCRT (complete), ypStage (0-II), residual disease (R0), and pulmonary complications (negative) were independent factors related to a favorable OS. BMI (<20 kg/m²), ASA-PS (2-3), and radiation dose (>60 Gy) were significant factors affecting the occurrence of pulmonary complications.

Conclusions

Development of postoperative pulmonary complications was independently associated with poor prognosis in patients who underwent salvage esophagectomy after dCRT.

http://ift.tt/2jPnwjp

Oncologic effects of preoperative biliary drainage in resectable hilar cholangiocarcinoma: Percutaneous biliary drainage has no adverse effects on survival

Background and Objectives

The objective of the current study was to define long-term survival of patients with resectable hilar cholangiocarcinoma (HCCA) after preoperative percutaneous transhepatic biliary drainage (PTBD) versus endoscopic biliary drainage (EBD).

Methods

Between 2000 and 2014, 240 patients who underwent curative-intent resection for HCCA were identified at 10 major hepatobiliary centers. Postoperative morbidity and mortality, as well as disease-specific survival (DSS) and recurrence-free survival (RFS) were analyzed among patients.

Results

The median decrease in total bilirubin levels after biliary drainage was similar comparing PTBD (n = 104) versus EBD (n = 92) (mg/dL, 4.9 vs 4.9, P = 0.589) before surgery. There was no difference in baseline demographic characteristics, type of surgical procedure performed, final AJCC tumor stage or postoperative morbidity among patients who underwent EBD only versus PTBD (all P > 0.05). Patients who underwent PTBD versus EBD had a comparable long-term DSS (median, 43.7 vs 36.9 months, P = 0.802) and RFS (median, 26.7 vs 24.0 months, P = 0.571). The overall pattern of recurrence relative to regional or distant disease was also the same among patients undergoing PTBD and EBD (P = 0.669)

Conclusions

Oncologic outcomes including DSS and RFS were similar among patients who underwent PTBD versus EBD with no difference in tumor recurrence location.

http://ift.tt/2ij8Ubu

Diagnostic staging laparoscopy in gastric cancer treatment: A cost-effectiveness analysis

Background and Objectives

Accurate preoperative staging helps avert morbidity, mortality, and cost associated with non-therapeutic laparotomy in gastric cancer (GC) patients. Diagnostic staging laparoscopy (DSL) can detect metastases with high sensitivity, but its cost-effectiveness has not been previously studied. We developed a decision analysis model to assess the cost-effectiveness of preoperative DSL in GC workup.

Methods

Analysis was based on a hypothetical cohort of GC patients in the U.S. for whom initial imaging shows no metastases. The cost-effectiveness of DSL was measured as cost per quality-adjusted life-year (QALY) gained. Drivers of cost-effectiveness were assessed in sensitivity analysis.

Results

Preoperative DSL required an investment of $107 012 per QALY. In sensitivity analysis, DSL became cost-effective at a threshold of $100 000/QALY when the probability of occult metastases exceeded 31.5% or when test sensitivity for metastases exceeded 86.3%. The likelihood of cost-effectiveness increased from 46% to 93% when both parameters were set at maximum reported values.

Conclusions

The cost-effectiveness of DSL for GC patients is highly dependent on patient and test characteristics, and is more likely when DSL is used selectively where procedure yield is high, such as for locally advanced disease or in detecting peritoneal and superficial versus deep liver lesions.

http://ift.tt/2jOuXad

Characteristics and long-term survival of patients diagnosed with pure tubular carcinoma of the breast

Background and Objectives

Pure tubular carcinomas (TC) of the breast are generally considered to have an excellent prognosis. This study aimed to analyze the characteristics and survival of patients with TC.

Methods

This was a retrospective study conducted at the CHU de Québec—Université Laval. Databases were searched for all cases treated between April 1997 and December 2010. Survival was retrieved from the Province of Quebec Ministry of Health. Follow-up was censored on December 31, 2011. Overall survival (OS) was compared to patients with invasive ductal carcinoma (ICD) matched for age, tumor size, lymph node involvement, year of diagnosis, ER, PgR, and HER2, histological grade, lymphovascular invasion, and chemotherapy.

Results

The frequency of TC was 2.9% (n = 223/7563). Tumors size was 7.4 ± 8.8 mm, without lymphovascular invasion (95.1%), ER-positive (98.2%), PgR-positive (69.5%), and HER2-negative (100%). Patients were followed up for 7.1 ± 2.7 years. The actuarial 13-year OS was 89.0% for TC, compared to 85.8% for IDC (P = 0.13). For TC, the 13-year OS was 95.8% in NO patients compared to 90.0% for N1-3 (P = 0.01).

Conclusion

Despite the general popular belief that patients with TC fare better than patients with IDC, the 13-year OS of TC was similar to that of grade I IDC.

http://ift.tt/2ii6j1p

Effects of local multivisceral resection for clinically locally advanced rectal cancer on long-term outcomes

Introduction

Multivisceral resection is occasionally needed to obtain clear margins in patients with transmural rectal cancer. Most series demonstrate equivalent outcomes between those patients who undergo multivisceral resections and those who do not, provided an R0-resection is achieved. This study focuses solely on patients who received neoadjuvant treatment for clinically transmural rectal cancers and underwent a local multivisceral R0-resection.

Methods

A retrospective, single center analysis of consecutive series of patients who received a surgical R0-resection after neoadjuvant treatment for a clinically transmural, non-metastatic, primary rectal cancer. All patients were operated on between 2004 and 2015.

Results

A total of 279 patients was included, of whom 29 patients underwent a local multivisceral R0-resection (LMVR). These patients were more often female and less often diagnosed through screening. Pathologic AJCC-staging was significantly lower for non-LMVR patients, with more favorable tumor characteristics. LMVR patients demonstrated higher rates of distant disease recurrence, and impaired survival, even after adjusting for disease stage.

Conclusion

An R0-resection after neoadjuvant therapy led to comparative local control of disease; however, patients with multivisceral resection had more distant recurrence and impaired survival, compared to those did not undergo a multivisceral resection. Further research should determine optimal postoperative care.

http://ift.tt/2jPdA9l

Clinical outcomes in breast angiosarcoma patients: A rare tumor with unique challenges

Background

Breast angiosarcoma (AS) accounts for less than 1% of all breast cancers. The goal of this study was to determine patient outcomes in radiation-associated angiosarcoma of the breast (RAAS) and sporadic AS. We evaluated patterns of recurrence and predictors of breast AS survival.

Methods

Patients with pathologically confirmed AS from 1994 to 2014 referred to Mount Sinai Hospital/Princess Margaret Cancer Centre were included. Primary outcome was overall survival (OS). Secondary outcomes were disease-free survival (DFS), clinicopathologic characteristics, patterns of recurrence and factors predictive of survival. Kaplan-Meier and log-rank tests were used for OS and DFS.

Results

Twenty-six patients were included: 6 with sporadic AS and 20 with RAAS. Median follow-up was 24 months. Five-year OS for RAAS and sporadic subgroups were 44% and 40%, respectively (P = ns). Five-year DFS for RAAS and sporadic subgroups were 23% and 20%, respectively (P = ns). Overall recurrence rate was 67% with median time to recurrence of 11 months. Age, tumor depth, margin status, and tumor size were not statistically significant predictive factors for OS and DFS.

Discussion

Breast AS is associated with poor survival and high recurrence rates. Prognosis may be mainly determined by its aggressive biology. Referral to tertiary care centers for multimodality treatment is recommended.

http://ift.tt/2ihvPE1

The effect of prone and supine treatment positions for the pre-operative treatment of rectal cancer on organ-at-risk sparing and setup reproducibility using volumetric modulated arc therapy

Abstract

Background and purpose

To compare organ-at-risk doses and setup reproducibility using the prone and supine orientations in volumetric modulated arc therapy (VMAT) for rectal cancer.

Materials and methods

Seventeen consecutive rectal cancer patients undergoing preoperative radiation were selected and setup in either the prone (N = 8) or supine (N = 9) position. All patients were treated using posteriorly-applied VMAT. Bladder and small bowel dose and cone beam CT (CBCT) reproducibility metrics were retrospectively collected.

Results

Dose metrics for bladder and small bowel did not show significant differences between the prone and supine orientations. The prone data had a trend for smaller irradiated volumes than supine for the small bowel at lower doses—V20 (prone: 135 ± 99 cm³; supine: 201 ± 162 cm³) and V30 (prone: 78 ± 71 cm³; supine: 105 ± 106 cm³). At higher doses, the trend reversed as exemplified by the small bowel V50.4 (prone: 20 ± 28 cm³; supine: 10 ± 14 cm³). CBCT data showed that rotational errors in pitch and roll were significantly larger for the prone vs. supine orientation (pitch: 2.0° ± 1.3° vs. 0.8° ± 1.1° p < 0.001; roll: 1.0° ± 0.9° vs. 0.3° ± 0.5°, p < 0.001).

Conclusions

Bladder and small bowel doses were not significantly different when comparing VMAT plans developed for the prone and supine orientations. The supine orientation demonstrated improved setup reproducibility.

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The effect of prone and supine treatment positions for the pre-operative treatment of rectal cancer on organ-at-risk sparing and setup reproducibility using volumetric modulated arc therapy

Abstract

Background and purpose

To compare organ-at-risk doses and setup reproducibility using the prone and supine orientations in volumetric modulated arc therapy (VMAT) for rectal cancer.

Materials and methods

Seventeen consecutive rectal cancer patients undergoing preoperative radiation were selected and setup in either the prone (N = 8) or supine (N = 9) position. All patients were treated using posteriorly-applied VMAT. Bladder and small bowel dose and cone beam CT (CBCT) reproducibility metrics were retrospectively collected.

Results

Dose metrics for bladder and small bowel did not show significant differences between the prone and supine orientations. The prone data had a trend for smaller irradiated volumes than supine for the small bowel at lower doses—V20 (prone: 135 ± 99 cm³; supine: 201 ± 162 cm³) and V30 (prone: 78 ± 71 cm³; supine: 105 ± 106 cm³). At higher doses, the trend reversed as exemplified by the small bowel V50.4 (prone: 20 ± 28 cm³; supine: 10 ± 14 cm³). CBCT data showed that rotational errors in pitch and roll were significantly larger for the prone vs. supine orientation (pitch: 2.0° ± 1.3° vs. 0.8° ± 1.1° p < 0.001; roll: 1.0° ± 0.9° vs. 0.3° ± 0.5°, p < 0.001).

Conclusions

Bladder and small bowel doses were not significantly different when comparing VMAT plans developed for the prone and supine orientations. The supine orientation demonstrated improved setup reproducibility.

http://ift.tt/2BHJDAj

Phase I–III development of the EORTC QLQ-ANL27, a health-related quality of life questionnaire for anal cancer

There is currently no health-related quality of life (HRQoL) measure specific to anal cancer. Our objective was to develop an anal cancer HRQoL module to supplement the EORTC QLQ-C30 questionnaire using EORTC Quality of Life Group Guidelines.

http://ift.tt/2ntzeVN

Implications of Hyperthermic Intraperitoneal Chemotherapy Perfusion-Related Hyperglycemia

Abstract

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) administration can be associated with hyperglycemia during perfusion. Little is known about this effect, and no previous studies have examined patient characteristics associated with perfusion-related hyperglycemia.

Methods

We retrospectively identified consecutive patients at a single institution treated with HIPEC from 8/2003 to 10/2016 who had intraoperative blood glucose measured. Hypertonic 1.5% dextrose-containing peritoneal dialysate was used as carrier solution in all patients. Comparisons were made using parametric [Student's t test, analysis of variance (ANOVA)], and nonparametric tests (χ ², Kruskal–Wallis) where appropriate.

Results

There were 85 patients identified, with average age of 53 ± 12 years, 69 (81%) with appendiceal or colorectal peritoneal cancer. Most patients were perfused with mitomycin C (69%) or oxaliplatin (24%). Intraoperative hyperglycemia (> 180 mg/dL) affected the majority of patients (86%), with values up to 651 mg/dL. Insulin was required for treatment in 66% of patients. Peak hyperglycemia occurred within an hour of perfusion in 91%, and resolved by postoperative day one in 91% of patients. Glucose > 309 mg/dL (highest quartile) was associated with longer operating time (p = 0.03) and with use of oxaliplatin compared with mitomycin C (p = 0.01). No association was found with other comorbidities, peritoneal carcinomatosis index score, or postoperative outcomes.

Conclusions

Most patients experience hyperglycemia during HIPEC. This is not clearly associated with patient factors, and may be due to use of dextrose-containing carrier solution. Since perioperative hyperglycemia has potential negative impact, use of dextrose-containing carrier solution should be questioned and is worth investigating further.

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Use of a Purse-String Suture to Reduce Skin Graft Requirements

Abstract

Background

When a wound cannot be closed in a linear fashion and either a local flap or skin graft is needed, a purse-string suture can be a useful adjunct to wound closure. Local tissue architecture is maintained in cases where clear surgical margins have not been achieved at the time of extirpative skin cancer surgery. We hypothesized that this technique could be applied to a range of wound sizes and locations to avoid or reduce the need for skin grafting.

Methods

We applied a non-absorbable purse-string suture to wounds in 18 patients over a 15-month period and measured the defect size before and after application of the suture intraoperatively. Residual defects were covered with full- or split-thickness skin grafts. Postoperative wound area, scar hypertrophy, partial graft loss and dehiscence following suture removal were additional outcomes.

Results

Ten patients achieved primary wound closure with the purse-string suture, while additional skin grafting was required in eight patients. Wounds closed primarily did not re-expand. Skin-grafted subjects had a 53.8% intraoperative wound area reduction but the skin grafts expanded during recovery, and ultimate reduction diminished to 11% on late follow-up. Wounds accounting for this late re-expansion were located on the extremities.

Conclusions

Purse-string sutures are helpful for wound closure in wounds that cannot be closed primarily. They can decrease the size of a skin graft if the wound cannot be closed completely. Wound re-expansion, particularly in extremity defects, may occur following early removal of the tension-bearing purse string.

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Stereotactic radiosurgery for central nervous system hemangioblastoma: systematic review and meta-analysis

Abstract

Hemangioblastomas are rare, benign, vascular tumors of the central nervous system (CNS), often associated with von-hippel lindau (VHL) disease. Current therapeutic options include microsurgical resection or stereotactic radiosurgery (SRS). With no randomized controlled studies and minimal data beyond single-institution reviews, the optimal management approach for patients with CNS hemangioblastomas is unclear. We completed a Pubmed/SCOPUS literature search from January 1990 to January 2017 for eligible studies on SRS for CNS hemangioblastomas. Relevant articles were identified and reviewed in accordance to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. 26 studies met eligibility criteria for qualitative synthesis, representing 596 subjects and 1535 tumors. The Gamma Knife was the most published SRS method for CNS hemangioblastomas. After critical study appraisal for intra-study bias, 14 studies were used for quantitative meta-analysis of 5-year progression free survival (PFS). The pooled 5-year PFS across all eligible studies was 88.4%. No difference was observed between spine versus intracranial studies. Individual patient data (IPD) was extracted from 14 studies, representing 322 tumors. Univariate analysis of IPD revealed that VHL patients were younger, and had smaller tumors compared to those with sporadic disease. Adverse events were associated with increasing marginal dose, independent of tumor volume. VHL status, sex, radiosurgical method, tumor location, and tumor volume were not found to be significantly associated with tumor progression. Multiple studies show excellent tumor control at 5-year follow up, however, the long-term efficacy of SRS for CNS hemangioblastomas still needs to be investigated, and the studies exploring the role of SRS for early treatment of asymptomatic lesions is wanting.

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A comparison of tumour size measurements with palpation, ultrasound and mammography in male breast cancer: first results of the prospective register study

Abstract

Purpose

Precise presurgical diagnosis of tumour size is essential for adequate treatment of male breast cancer (MBC). This study is aimed to compare the accuracy of clinical measurement (CE), ultrasound (US) and mammography (MG) for preoperative estimation of tumour size.

Methods

This study was conducted as a prospective, multicentre register study. One hundred and twenty-nine male patients with invasive breast cancer were included. CE, US and MG were performed in 107, 110 and 75 patients, respectively, and the estimated tumour size was compared with the histopathological (HP) tumour size.

Results

All methods tended to underestimate the HP tumour size. None of the methods were significantly more accurate than the others in determining the maximal tumour diameter. The sensitivity within 5 mm tolerance for US was 65.5%, which was better than for MG (61.3%) and CE (56.6%). In the group of patients with pT2 tumours, MG showed significantly better accuracy than US. The measurements obtained with each method were significantly correlated with the HP measurements. The highest correlation coefficient was observed for MG (0.788), followed by US (0.741) and CE (0.671).

Conclusions

Our data demonstrate that MG and US have similar accuracy with regard to tumour size estimation. US assessment showed the highest sensitivity in determining tumour size, followed by MG and CE. However, MG demonstrated a significant advantage for estimating the real tumour size for pT2 tumours compared to US or CE.

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Implications of Hyperthermic Intraperitoneal Chemotherapy Perfusion-Related Hyperglycemia

Abstract

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) administration can be associated with hyperglycemia during perfusion. Little is known about this effect, and no previous studies have examined patient characteristics associated with perfusion-related hyperglycemia.

Methods

We retrospectively identified consecutive patients at a single institution treated with HIPEC from 8/2003 to 10/2016 who had intraoperative blood glucose measured. Hypertonic 1.5% dextrose-containing peritoneal dialysate was used as carrier solution in all patients. Comparisons were made using parametric [Student's t test, analysis of variance (ANOVA)], and nonparametric tests (χ ², Kruskal–Wallis) where appropriate.

Results

There were 85 patients identified, with average age of 53 ± 12 years, 69 (81%) with appendiceal or colorectal peritoneal cancer. Most patients were perfused with mitomycin C (69%) or oxaliplatin (24%). Intraoperative hyperglycemia (> 180 mg/dL) affected the majority of patients (86%), with values up to 651 mg/dL. Insulin was required for treatment in 66% of patients. Peak hyperglycemia occurred within an hour of perfusion in 91%, and resolved by postoperative day one in 91% of patients. Glucose > 309 mg/dL (highest quartile) was associated with longer operating time (p = 0.03) and with use of oxaliplatin compared with mitomycin C (p = 0.01). No association was found with other comorbidities, peritoneal carcinomatosis index score, or postoperative outcomes.

Conclusions

Most patients experience hyperglycemia during HIPEC. This is not clearly associated with patient factors, and may be due to use of dextrose-containing carrier solution. Since perioperative hyperglycemia has potential negative impact, use of dextrose-containing carrier solution should be questioned and is worth investigating further.

http://ift.tt/2ij7zBG

Use of a Purse-String Suture to Reduce Skin Graft Requirements

Abstract

Background

When a wound cannot be closed in a linear fashion and either a local flap or skin graft is needed, a purse-string suture can be a useful adjunct to wound closure. Local tissue architecture is maintained in cases where clear surgical margins have not been achieved at the time of extirpative skin cancer surgery. We hypothesized that this technique could be applied to a range of wound sizes and locations to avoid or reduce the need for skin grafting.

Methods

We applied a non-absorbable purse-string suture to wounds in 18 patients over a 15-month period and measured the defect size before and after application of the suture intraoperatively. Residual defects were covered with full- or split-thickness skin grafts. Postoperative wound area, scar hypertrophy, partial graft loss and dehiscence following suture removal were additional outcomes.

Results

Ten patients achieved primary wound closure with the purse-string suture, while additional skin grafting was required in eight patients. Wounds closed primarily did not re-expand. Skin-grafted subjects had a 53.8% intraoperative wound area reduction but the skin grafts expanded during recovery, and ultimate reduction diminished to 11% on late follow-up. Wounds accounting for this late re-expansion were located on the extremities.

Conclusions

Purse-string sutures are helpful for wound closure in wounds that cannot be closed primarily. They can decrease the size of a skin graft if the wound cannot be closed completely. Wound re-expansion, particularly in extremity defects, may occur following early removal of the tension-bearing purse string.

http://ift.tt/2iPnmfk

Stereotactic radiosurgery for central nervous system hemangioblastoma: systematic review and meta-analysis

Abstract

Hemangioblastomas are rare, benign, vascular tumors of the central nervous system (CNS), often associated with von-hippel lindau (VHL) disease. Current therapeutic options include microsurgical resection or stereotactic radiosurgery (SRS). With no randomized controlled studies and minimal data beyond single-institution reviews, the optimal management approach for patients with CNS hemangioblastomas is unclear. We completed a Pubmed/SCOPUS literature search from January 1990 to January 2017 for eligible studies on SRS for CNS hemangioblastomas. Relevant articles were identified and reviewed in accordance to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. 26 studies met eligibility criteria for qualitative synthesis, representing 596 subjects and 1535 tumors. The Gamma Knife was the most published SRS method for CNS hemangioblastomas. After critical study appraisal for intra-study bias, 14 studies were used for quantitative meta-analysis of 5-year progression free survival (PFS). The pooled 5-year PFS across all eligible studies was 88.4%. No difference was observed between spine versus intracranial studies. Individual patient data (IPD) was extracted from 14 studies, representing 322 tumors. Univariate analysis of IPD revealed that VHL patients were younger, and had smaller tumors compared to those with sporadic disease. Adverse events were associated with increasing marginal dose, independent of tumor volume. VHL status, sex, radiosurgical method, tumor location, and tumor volume were not found to be significantly associated with tumor progression. Multiple studies show excellent tumor control at 5-year follow up, however, the long-term efficacy of SRS for CNS hemangioblastomas still needs to be investigated, and the studies exploring the role of SRS for early treatment of asymptomatic lesions is wanting.

http://ift.tt/2jNj2cK

A comparison of tumour size measurements with palpation, ultrasound and mammography in male breast cancer: first results of the prospective register study

Abstract

Purpose

Precise presurgical diagnosis of tumour size is essential for adequate treatment of male breast cancer (MBC). This study is aimed to compare the accuracy of clinical measurement (CE), ultrasound (US) and mammography (MG) for preoperative estimation of tumour size.

Methods

This study was conducted as a prospective, multicentre register study. One hundred and twenty-nine male patients with invasive breast cancer were included. CE, US and MG were performed in 107, 110 and 75 patients, respectively, and the estimated tumour size was compared with the histopathological (HP) tumour size.

Results

All methods tended to underestimate the HP tumour size. None of the methods were significantly more accurate than the others in determining the maximal tumour diameter. The sensitivity within 5 mm tolerance for US was 65.5%, which was better than for MG (61.3%) and CE (56.6%). In the group of patients with pT2 tumours, MG showed significantly better accuracy than US. The measurements obtained with each method were significantly correlated with the HP measurements. The highest correlation coefficient was observed for MG (0.788), followed by US (0.741) and CE (0.671).

Conclusions

Our data demonstrate that MG and US have similar accuracy with regard to tumour size estimation. US assessment showed the highest sensitivity in determining tumour size, followed by MG and CE. However, MG demonstrated a significant advantage for estimating the real tumour size for pT2 tumours compared to US or CE.

http://ift.tt/2BwOQdc

Fat Cells May Hinder Effectiveness of Chemotherapy

For the first time, researchers have shown that fat cells can absorb two commonly used chemotherapy drugs and break them down chemically into a less toxic form, potentially reducing the drugs' effectiveness.

http://ift.tt/2BKnQI7

Fat Cells May Hinder Effectiveness of Chemotherapy

For the first time, researchers have shown that fat cells can absorb two commonly used chemotherapy drugs and break them down chemically into a less toxic form, potentially reducing the drugs' effectiveness.

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Predictive power of splenic thickness for post-hepatectomy liver failure in HBV-associated hepatocellular carcinoma patients

Abstract

Background

The purpose of this case series is to investigate the relationship between splenic thickness (ST) and postoperative outcomes after hepatic resection in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) patients.

Methods

The clinical data of 320 patients with HBV-associated HCC who had undergone liver resection were retrospectively analyzed. The value of ST in predicting postoperative outcomes was evaluated.

Results

A total of 320 patients were enrolled in the study. An increase in ST was significantly associated with an increase in portal vein diameter (PVD), indocyanine green retention rate 15 min (ICG R15), and total bilirubin (TBIL); however, it was negatively correlated with platelet count (PLT). Post-hepatectomy liver failure (PHLF) occurred in 35 (10.9%) patients. Multivariate logistic regression analysis showed that ST was an independent predictor of morbidity and mortality after hepatectomy. Meanwhile, ST was associated with an almost sixfold increased risk for developing perioperative complications (OR 5.678; 95% CI 2.873 to 11.224; P < 0.001) and almost 13-fold increased risk for mortality after hepatectomy (OR 13.007; 95% CI 1.238 to 136.627; P = 0.033).The area under the receiver operating characteristic (ROC) curve (AUC) of ST for predicting the incidence of PHLF was 0.754 (95% confidence interval (CI) 0.667 to 0.841; P < 0.001), with a sensitivity of 57.1% and a specificity of 82.5%, which were significantly greater than those of the ICG R15 level (AUC 0.670; 95% CI 0.560 to 0.779; P < 0.001). The critical value of ST was 43.5 mm.

Conclusions

ST, which is an easy, inexpensive, and routinely available perioperative marker, showed a favorable predictive value for postoperative outcomes in HBV-associated HCC patients.

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Predictive power of splenic thickness for post-hepatectomy liver failure in HBV-associated hepatocellular carcinoma patients

Abstract

Background

The purpose of this case series is to investigate the relationship between splenic thickness (ST) and postoperative outcomes after hepatic resection in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) patients.

Methods

The clinical data of 320 patients with HBV-associated HCC who had undergone liver resection were retrospectively analyzed. The value of ST in predicting postoperative outcomes was evaluated.

Results

A total of 320 patients were enrolled in the study. An increase in ST was significantly associated with an increase in portal vein diameter (PVD), indocyanine green retention rate 15 min (ICG R15), and total bilirubin (TBIL); however, it was negatively correlated with platelet count (PLT). Post-hepatectomy liver failure (PHLF) occurred in 35 (10.9%) patients. Multivariate logistic regression analysis showed that ST was an independent predictor of morbidity and mortality after hepatectomy. Meanwhile, ST was associated with an almost sixfold increased risk for developing perioperative complications (OR 5.678; 95% CI 2.873 to 11.224; P < 0.001) and almost 13-fold increased risk for mortality after hepatectomy (OR 13.007; 95% CI 1.238 to 136.627; P = 0.033).The area under the receiver operating characteristic (ROC) curve (AUC) of ST for predicting the incidence of PHLF was 0.754 (95% confidence interval (CI) 0.667 to 0.841; P < 0.001), with a sensitivity of 57.1% and a specificity of 82.5%, which were significantly greater than those of the ICG R15 level (AUC 0.670; 95% CI 0.560 to 0.779; P < 0.001). The critical value of ST was 43.5 mm.

Conclusions

ST, which is an easy, inexpensive, and routinely available perioperative marker, showed a favorable predictive value for postoperative outcomes in HBV-associated HCC patients.

http://ift.tt/2ALay0h