Neoadjuvant treatment of pancreatic adenocarcinoma: a systematic review and meta-analysis of 5520 patients

Abstract

Background

Recent years have seen standardization of the anatomic definitions of pancreatic adenocarcinoma, and increasing utilization of neoadjuvant therapy (NAT). The aim of the current review was to summarize the evidence for NAT in pancreatic adenocarcinoma since 2009, when consensus criteria for resectable (R), borderline resectable (BR), and locally advanced (LA) disease were endorsed.

Methods

PubMed search was undertaken along with extensive backward search of the references of published articles to identify studies utilizing NAT for pancreatic adenocarcinoma. Abstracts from ASCO-GI 2014 and 2015 were also searched.

Results

A total of 96 studies including 5520 patients were included in the final quantitative synthesis. Pooled estimates revealed 36% grade ≥ 3 toxicities, 5% biliary complications, 21% hospitalization rate and low mortality (0%, range 0–16%) during NAT. The majority of patients (59%) had stable disease. On an intention-to-treat basis, R0-resection rates varied from 63% among R patients to 23% among LA patients. R0 rates were > 80% among all patients who were resected after NAT. Among R and BR patients who underwent resection after NAT, median OS was 30 and 27.4 months, respectively.

Conclusions

The current study summarizes the recent literature for NAT in pancreatic adenocarcinoma and demonstrates improving outcomes after NAT compared to those historically associated with a surgery-first approach for pancreatic adenocarcinoma.

from Cancer via ola Kala on Inoreader http://ift.tt/2g7MDjl
via IFTTT

Neoadjuvant treatment of pancreatic adenocarcinoma: a systematic review and meta-analysis of 5520 patients

Abstract

Background

Recent years have seen standardization of the anatomic definitions of pancreatic adenocarcinoma, and increasing utilization of neoadjuvant therapy (NAT). The aim of the current review was to summarize the evidence for NAT in pancreatic adenocarcinoma since 2009, when consensus criteria for resectable (R), borderline resectable (BR), and locally advanced (LA) disease were endorsed.

Methods

PubMed search was undertaken along with extensive backward search of the references of published articles to identify studies utilizing NAT for pancreatic adenocarcinoma. Abstracts from ASCO-GI 2014 and 2015 were also searched.

Results

A total of 96 studies including 5520 patients were included in the final quantitative synthesis. Pooled estimates revealed 36% grade ≥ 3 toxicities, 5% biliary complications, 21% hospitalization rate and low mortality (0%, range 0–16%) during NAT. The majority of patients (59%) had stable disease. On an intention-to-treat basis, R0-resection rates varied from 63% among R patients to 23% among LA patients. R0 rates were > 80% among all patients who were resected after NAT. Among R and BR patients who underwent resection after NAT, median OS was 30 and 27.4 months, respectively.

Conclusions

The current study summarizes the recent literature for NAT in pancreatic adenocarcinoma and demonstrates improving outcomes after NAT compared to those historically associated with a surgery-first approach for pancreatic adenocarcinoma.

http://ift.tt/2g7MDjl

Acute pancreatitis with eruptive xanthoma

Eruptive xanthomas are benign skin lesions caused by localised deposition of lipids in the dermis. Xanthomas can present as early manifestations of systemic disorders, which are typically caused by elevated levels of serum triglycerides and uncontrolled diabetes. Early recognition and treatment of the underlying condition decreases morbidity and mortality. After treatment of the underlying metabolic disorders, lesions mostly disappear without leaving scars. We present a case with multiple yellowish, erythematous papules on the extremities suggestive of eruptive xanthomas admitted to our hospital with acute pancreatitis.

http://ift.tt/2g5M9u8

Ogilvies syndrome treated with an emergency laparotomy, right hemicolectomy and end ileostomy

Acute colonic pseudo-obstruction (ACPO), or Ogilvie's syndrome, is a rare clinical entity in which there is massive non-toxic colonic dilatation in the absence of a mechanically obstructing lesion. It is an important yet poorly recognised cause of surgical morbidity and mortality occurring typically in elderly patients with multiple comorbidities. ACPO can often be reversed conservatively with colonoscopic or nasogastric decompression. Surgical intervention is seldom necessary. We present a case of Ogilvie's syndrome in which a healthy 76-year-old man developed life-threatening pseudo-obstruction following rib polytrauma after a mechanical fall. Pneumatosis coli was evident radiologically, prompting emergency exploratory laparotomy. Operative findings of serosal tearing and ischaemic colitis necessitated treatment with right hemicolectomy and ileostomy formation. Microbiological and histopathological analyses proved negative for inflammatory, obstructive and infectious colitides. The case emphasises the importance of early recognition and timely intervention in the management of this rare yet potentially fatal cause of megacolon.

http://ift.tt/2hYaN0n

ANCA and IgA glomerulonephritis all in one: prognosis and complications

We present the case of a 75-year-old Hispanic woman with known stage 3 chronic kidney disease, long-standing hypertension and type 2 diabetes mellitus who presented with right-sided abdominal pain and acute kidney injury, nephrotic range proteinuria with positive antimyeloperoxidase antibody. A renal biopsy revealed IgA nephropathy with superimposed pauci-immune antineutrophilic cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. The patient was treated with pulse intravenous methylprednisolone, cyclophosphamide and plasmapheresis. One week after her second dose of cyclophosphamide, she was readmitted for infectious complications including influenza A respiratory infection, Rothia bacteraemia associated with diarrhoea and herpes zoster of the trunk. In this report, we review the prevalence, treatment and prognosis of coexistent IgA nephropathy and pauci-immune ANCA-associated crescentic glomerulonephritis. We propose that a reduced-dose treatment regimen should be considered in elderly patients due to their higher risk of infectious complications. Current literature suggests that this treatment approach may reduce infectious complications without compromising therapeutic efficacy.

http://ift.tt/2g74pTS

Knee upside down

We present a case of a 19-year-old woman with a forced hyperextension trauma of the knee causing a posteromedial fracture, a medial meniscus root tear and rupture of the posterior cruciate ligament. The posteromedial fracture of the tibial plateau was treated operatively with open reduction and internal fixation. Anatomical reconstruction was achieved. Postoperative treatment included unlimited flexion and minimal weight bearing. After 3 months, the patient had minimal pain after weight bearing and returned to preoperative range of motion.

http://ift.tt/2g7cRlZ

Value of a molecular screening program to support clinical trial enrollment in Asian cancer patients: The Integrated Molecular Analysis of Cancer (IMAC) Study

Abstract

The value of precision oncology initiatives in Asian contexts remains unresolved. Here we review the institutional implementation of prospective molecular screening to facilitate accrual of patients into biomarker-driven clinical trials, and to explore the mutational landscape of advanced tumors occurring in a prospective cohort of Asian patients (n = 396) with diverse cancer types. Next-generation sequencing (NGS) and routine clinicopathological assays such as immunohistochemistry, copy number analysis, and in situ hybridization tests were performed on tumor samples. Actionable biomarker results were used to identify eligibility for early-phase, biomarker-driven clinical trials. Overall, NGS was successful in 365 of 396 patients (92%), achieving a mean depth of 1,943× and coverage uniformity of 96%. The median turnaround time from sample receipt to return of genomic results was 26.0 days (IQR, 19.0-39.0 days). Reportable mutations were found in 300 of 365 patients (82%). Ninety-one percent of patients at study enrollment indicated consent to receive incidental findings and willingness to undergo genetic counseling if required. The most commonly mutated oncogenes included KRAS (19%), PIK3CA (16%), EGFR (5%), BRAF (3%), and KIT (3%); while the most frequently mutated tumor suppressor genes included TP53 (40%), SMARCB1 (12%), APC (8%), PTEN (6%), and SMAD4 (5%). Among 23 patients enrolled in genotype-matched trials, median progression-free survival was 2.9 months (IQR, 1.5 to 4.0 months). Nine of 20 evaluable patients (45%; 95% CI, 23.1% to 68.5%) derived clinical benefit, including 3 partial responses and 6 with stable disease lasting ≥ 8 weeks. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2y5eEPN
via IFTTT

FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma

Abstract

Glioblastoma (GBM) is characterized by the presence of hypoxia, stemness and local invasiveness. We have earlier demonstrated that FAT1 promotes invasiveness, inflammation and upregulates HIF-1α expression and its signalling in hypoxic GBM. Here, we have identified the role of FAT1 in regulating EMT (Epithelial-Mesenchymal Transition) and stemness characteristics in GBM. The expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/VEGF/PGK1/CA9) was upregulated in ≥39% of GBM tumors (n=31) with significant positive correlation (p≤0.05) of the expression of FAT1 with LOX/Vimentin/SOX2/HIF-1α/PGK1/VEGF/CA9. Furthermore, positive correlation (p≤0.01) of FAT1 with Vimentin/N-cad/SOX2/REST/HIF-1α has been observed in TCGA GBM-dataset (n=430). Analysis of cells (U87MG/A172) exposed to severe hypoxia (0.2%O₂) revealed elevated mRNA expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/PGK1/VEGF/CA9) as compared to their normoxic (20%O₂) counterparts. FAT1 knockdown in U87MG/A172 maintained in severe hypoxia and in normoxic primary glioma cultures led to significant reduction of EMT/stemness markers as compared to controls. HIF-1α knockdown in U87MG cells markedly reduced the expression of all the EMT/stemness markers studied except for nestin and SOX2 which were more under the influence of FAT1. This indicates FAT1 has a novel regulatory effect on EMT/stemness markers both via or independent of HIF-1α. The functional relevance of our study was corroborated by significant reduction in the number of soft-agar colonies formed in hypoxic-siFAT1 treated U87MG cells. Hence, this study for the first time reveals FAT1 as a novel regulator of EMT/stemness in hypoxic GBM and suggests FAT1 as a potential therapeutic candidate. This article is protected by copyright. All rights reserved.

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

Value of a molecular screening program to support clinical trial enrollment in Asian cancer patients: The Integrated Molecular Analysis of Cancer (IMAC) Study

Abstract

The value of precision oncology initiatives in Asian contexts remains unresolved. Here we review the institutional implementation of prospective molecular screening to facilitate accrual of patients into biomarker-driven clinical trials, and to explore the mutational landscape of advanced tumors occurring in a prospective cohort of Asian patients (n = 396) with diverse cancer types. Next-generation sequencing (NGS) and routine clinicopathological assays such as immunohistochemistry, copy number analysis, and in situ hybridization tests were performed on tumor samples. Actionable biomarker results were used to identify eligibility for early-phase, biomarker-driven clinical trials. Overall, NGS was successful in 365 of 396 patients (92%), achieving a mean depth of 1,943× and coverage uniformity of 96%. The median turnaround time from sample receipt to return of genomic results was 26.0 days (IQR, 19.0-39.0 days). Reportable mutations were found in 300 of 365 patients (82%). Ninety-one percent of patients at study enrollment indicated consent to receive incidental findings and willingness to undergo genetic counseling if required. The most commonly mutated oncogenes included KRAS (19%), PIK3CA (16%), EGFR (5%), BRAF (3%), and KIT (3%); while the most frequently mutated tumor suppressor genes included TP53 (40%), SMARCB1 (12%), APC (8%), PTEN (6%), and SMAD4 (5%). Among 23 patients enrolled in genotype-matched trials, median progression-free survival was 2.9 months (IQR, 1.5 to 4.0 months). Nine of 20 evaluable patients (45%; 95% CI, 23.1% to 68.5%) derived clinical benefit, including 3 partial responses and 6 with stable disease lasting ≥ 8 weeks. This article is protected by copyright. All rights reserved.

http://ift.tt/2y5eEPN

FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma

Abstract

Glioblastoma (GBM) is characterized by the presence of hypoxia, stemness and local invasiveness. We have earlier demonstrated that FAT1 promotes invasiveness, inflammation and upregulates HIF-1α expression and its signalling in hypoxic GBM. Here, we have identified the role of FAT1 in regulating EMT (Epithelial-Mesenchymal Transition) and stemness characteristics in GBM. The expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/VEGF/PGK1/CA9) was upregulated in ≥39% of GBM tumors (n=31) with significant positive correlation (p≤0.05) of the expression of FAT1 with LOX/Vimentin/SOX2/HIF-1α/PGK1/VEGF/CA9. Furthermore, positive correlation (p≤0.01) of FAT1 with Vimentin/N-cad/SOX2/REST/HIF-1α has been observed in TCGA GBM-dataset (n=430). Analysis of cells (U87MG/A172) exposed to severe hypoxia (0.2%O₂) revealed elevated mRNA expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/PGK1/VEGF/CA9) as compared to their normoxic (20%O₂) counterparts. FAT1 knockdown in U87MG/A172 maintained in severe hypoxia and in normoxic primary glioma cultures led to significant reduction of EMT/stemness markers as compared to controls. HIF-1α knockdown in U87MG cells markedly reduced the expression of all the EMT/stemness markers studied except for nestin and SOX2 which were more under the influence of FAT1. This indicates FAT1 has a novel regulatory effect on EMT/stemness markers both via or independent of HIF-1α. The functional relevance of our study was corroborated by significant reduction in the number of soft-agar colonies formed in hypoxic-siFAT1 treated U87MG cells. Hence, this study for the first time reveals FAT1 as a novel regulator of EMT/stemness in hypoxic GBM and suggests FAT1 as a potential therapeutic candidate. This article is protected by copyright. All rights reserved.

http://ift.tt/2fXyGAL

Issue Information

from Cancer via ola Kala on Inoreader http://ift.tt/2ybO5rL
via IFTTT

Issue Information

http://ift.tt/2ybO5rL

In vivo detection of HSP90 identifies breast cancers with aggressive behavior

Purpose: Heat shock protein 90 (Hsp90), a chaperone to numerous molecular pathways in malignant cells, is elevated in aggressive breast cancers (BC). We hypothesized that identifying breast cells with elevated Hsp90 activity in situ could result in early detection of aggressive BC. Experimental Design: We exploited the uptake of a Hsp90 inhibitor by malignant cells to create an imaging probe (HS131) of Hsp90 activity by linking it to a near infrared (nIR) dye. HS131 uptake into cells correlated with cell membrane expression of Hsp90 and was used to image molecular subtypes of murine and human BC in vitro and in murine models. Results: HS131 imaging was both sensitive and specific in detecting the murine 4T1 BC cell line, as well as subclones with differing metastatic potential. Highly metastatic subclones (4T07) had high HS131 uptake, but subclones with lower metastatic potential (67NR, 168FARN) had low HS131 uptake. We generated isogenic cell lines to demonstrate that overexpression of a variety of specific oncogenes resulted in high HS131 uptake and retention. Finally, we demonstrated that HS131 could be used to detect spontaneous tumors in MMTV-neu mice, as well as primary and metastatic human BC xenografts. HS131 could image invasive lobular BC, a histologic subtype of BC which is often undetectable by mammography. Conclusions: An HSP90-targeting nIR probe is sensitive and specific in imaging all molecular subtypes of murine and human BC, with higher uptake in aggressive and highly metastatic clones. Clinical studies with Hsp90-targeting nIR probes will be initiated shortly.

http://ift.tt/2ybESQ9

In vivo detection of HSP90 identifies breast cancers with aggressive behavior

Purpose: Heat shock protein 90 (Hsp90), a chaperone to numerous molecular pathways in malignant cells, is elevated in aggressive breast cancers (BC). We hypothesized that identifying breast cells with elevated Hsp90 activity in situ could result in early detection of aggressive BC. Experimental Design: We exploited the uptake of a Hsp90 inhibitor by malignant cells to create an imaging probe (HS131) of Hsp90 activity by linking it to a near infrared (nIR) dye. HS131 uptake into cells correlated with cell membrane expression of Hsp90 and was used to image molecular subtypes of murine and human BC in vitro and in murine models. Results: HS131 imaging was both sensitive and specific in detecting the murine 4T1 BC cell line, as well as subclones with differing metastatic potential. Highly metastatic subclones (4T07) had high HS131 uptake, but subclones with lower metastatic potential (67NR, 168FARN) had low HS131 uptake. We generated isogenic cell lines to demonstrate that overexpression of a variety of specific oncogenes resulted in high HS131 uptake and retention. Finally, we demonstrated that HS131 could be used to detect spontaneous tumors in MMTV-neu mice, as well as primary and metastatic human BC xenografts. HS131 could image invasive lobular BC, a histologic subtype of BC which is often undetectable by mammography. Conclusions: An HSP90-targeting nIR probe is sensitive and specific in imaging all molecular subtypes of murine and human BC, with higher uptake in aggressive and highly metastatic clones. Clinical studies with Hsp90-targeting nIR probes will be initiated shortly.

from Cancer via ola Kala on Inoreader http://ift.tt/2ybESQ9
via IFTTT

A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies

Preclinical studies using genetically engineered mouse models (GEMM) have the potential to expedite the development of effective new therapies; however, they are not routinely integrated into drug development pipelines. GEMMs may be particularly valuable for investigating treatments for less common cancers, which frequently lack alternative faithful models. Here, we describe a multicenter cooperative group that has successfully leveraged the expertise and resources from philanthropic foundations, academia, and industry to advance therapeutic discovery and translation using GEMMs as a preclinical platform. This effort, known as the Neurofibromatosis Preclinical Consortium (NFPC), was established to accelerate new treatments for tumors associated with neurofibromatosis type 1 (NF1). At its inception, there were no effective treatments for NF1 and few promising approaches on the horizon. Since 2008, participating laboratories have conducted 95 preclinical trials of 38 drugs or combinations through collaborations with 18 pharmaceutical companies. Importantly, these studies have identified 13 therapeutic targets, which have inspired 16 clinical trials. This review outlines the opportunities and challenges of building this type of consortium and highlights how it can accelerate clinical translation. We believe that this strategy of foundation–academic–industry partnering is generally applicable to many diseases and has the potential to markedly improve the success of therapeutic development. Cancer Res; 1–6. ©2017 AACR.

from Cancer via ola Kala on Inoreader http://ift.tt/2g71EC9
via IFTTT

Moonshot Acceleration Factor: Medical Imaging

Medical imaging is essential to screening, early diagnosis, and monitoring responses to cancer treatments and, when used with other diagnostics, provides guidance for clinicians in choosing the most effective patient management plan that maximizes survivorship and quality of life. At a gathering of agency officials, patient advocacy organizations, industry/professional stakeholder groups, and clinical/basic science academicians, recommendations were made on why and how one should build a "cancer knowledge network" that includes imaging. Steps to accelerate the translation and clinical adoption of cancer discoveries to meet the goals of the Cancer Moonshot include harnessing computational power and architectures, developing data sharing policies, and standardizing medical imaging and in vitro diagnostics. Cancer Res; 1–4. ©2017 AACR.

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

IL-10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer.

Ligation of PD-1 in the tumor microenvironment is known to inhibit effective adaptive anti-tumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow-derived DC with IL-10 led to increased PD-1 expression. Both groups of DC also responded to PD-1 blockade by increasing production of IL-10. Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody resulted in an increase in IL-10 levels in both serum and ascites. While PD-1 blockade or IL-10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented anti-tumor T and B cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL-10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti-PD-1 (or anti-PD-L1) monotherapies and prompts further studies aimed at identifying such resistance mechanisms.

from Cancer via ola Kala on Inoreader http://ift.tt/2g7IgF6
via IFTTT

MALT1 inhibition is efficacious in both naive and ibrutinib-resistant chronic lymphocytic leukemia.

The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity, reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV. Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease.

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

Sleeping Beauty insertional mutagenesis in mice identifies drivers of steatosis-associated hepatic tumor

Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis, and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis-associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance.

from Cancer via ola Kala on Inoreader http://ift.tt/2g6e25k
via IFTTT

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and how its growth inhibitory effects are mitigated and uncertain. Here we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3' untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced auto-activating process and a distinct intracellular routing that prevented its extracellular secretion. Together these events led to a dramatic increase in processing of the pro-growth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this pro-enzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. 

from Cancer via ola Kala on Inoreader http://ift.tt/2i056yW
via IFTTT

A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies

Preclinical studies using genetically engineered mouse models (GEMM) have the potential to expedite the development of effective new therapies; however, they are not routinely integrated into drug development pipelines. GEMMs may be particularly valuable for investigating treatments for less common cancers, which frequently lack alternative faithful models. Here, we describe a multicenter cooperative group that has successfully leveraged the expertise and resources from philanthropic foundations, academia, and industry to advance therapeutic discovery and translation using GEMMs as a preclinical platform. This effort, known as the Neurofibromatosis Preclinical Consortium (NFPC), was established to accelerate new treatments for tumors associated with neurofibromatosis type 1 (NF1). At its inception, there were no effective treatments for NF1 and few promising approaches on the horizon. Since 2008, participating laboratories have conducted 95 preclinical trials of 38 drugs or combinations through collaborations with 18 pharmaceutical companies. Importantly, these studies have identified 13 therapeutic targets, which have inspired 16 clinical trials. This review outlines the opportunities and challenges of building this type of consortium and highlights how it can accelerate clinical translation. We believe that this strategy of foundation–academic–industry partnering is generally applicable to many diseases and has the potential to markedly improve the success of therapeutic development. Cancer Res; 1–6. ©2017 AACR.

http://ift.tt/2g71EC9

Moonshot Acceleration Factor: Medical Imaging

Medical imaging is essential to screening, early diagnosis, and monitoring responses to cancer treatments and, when used with other diagnostics, provides guidance for clinicians in choosing the most effective patient management plan that maximizes survivorship and quality of life. At a gathering of agency officials, patient advocacy organizations, industry/professional stakeholder groups, and clinical/basic science academicians, recommendations were made on why and how one should build a "cancer knowledge network" that includes imaging. Steps to accelerate the translation and clinical adoption of cancer discoveries to meet the goals of the Cancer Moonshot include harnessing computational power and architectures, developing data sharing policies, and standardizing medical imaging and in vitro diagnostics. Cancer Res; 1–4. ©2017 AACR.

http://ift.tt/2hYCBlj

IL-10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer.

Ligation of PD-1 in the tumor microenvironment is known to inhibit effective adaptive anti-tumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow-derived DC with IL-10 led to increased PD-1 expression. Both groups of DC also responded to PD-1 blockade by increasing production of IL-10. Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody resulted in an increase in IL-10 levels in both serum and ascites. While PD-1 blockade or IL-10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented anti-tumor T and B cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL-10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti-PD-1 (or anti-PD-L1) monotherapies and prompts further studies aimed at identifying such resistance mechanisms.

http://ift.tt/2g7IgF6

MALT1 inhibition is efficacious in both naive and ibrutinib-resistant chronic lymphocytic leukemia.

The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity, reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV. Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease.

http://ift.tt/2hYCwOx

Sleeping Beauty insertional mutagenesis in mice identifies drivers of steatosis-associated hepatic tumor

Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis, and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis-associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance.

http://ift.tt/2g6e25k

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and how its growth inhibitory effects are mitigated and uncertain. Here we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3' untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced auto-activating process and a distinct intracellular routing that prevented its extracellular secretion. Together these events led to a dramatic increase in processing of the pro-growth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this pro-enzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. 

http://ift.tt/2i056yW

Checkpoint Inhibitors Spur Changes in Trial Design [News in Depth]

Adaptive studies, novel endpoints, new preclinical models address research challenges.

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

Atrial myxomas causing severe left and right ventricular dysfunction

Aanchal Dixit, Prabhat Tewari, Rashmi Soori, Surendra Kumar Agarwal

Annals of Cardiac Anaesthesia 2017 20(4):450-452

Myxomas are the most common cardiac tumors, accounting for about 50% of benign primary cardiac tumors, with the majority located in the left atrium, and 80% of which originate in the interatrial septum. We report two cases with severe cachexia, neurological sequelae, and severe biventricle dysfunction secondary to atrial myxomas with marked early improvement after tumor excision.

http://ift.tt/2kC9ViX

Think beyond right bundle branch block in atrial septal defect

Monish S Raut, Arvind Verma, Arun Maheshwari, Ganesh Shivnani

Annals of Cardiac Anaesthesia 2017 20(4):475-476



http://ift.tt/2yUXst5

Congenital syndromes affecting heart and airway alike

Rajinder Singh Rawat

Annals of Cardiac Anaesthesia 2017 20(4):393-394



http://ift.tt/2yUrZqE

The use of intravenous hydroxocobalamin as a rescue in methylene blue-resistant vasoplegic syndrome in cardiac surgery

Yi Cai, Anwar Mack, Beth L Ladlie, Archer Kilbourne Martin

Annals of Cardiac Anaesthesia 2017 20(4):462-464

Vasoplegic syndrome is a well-recognized complication during cardiopulmonary bypass (CPB) and is associated with increased morbidity and mortality, especially when refractory to conventional vasoconstrictor therapy. This is the first reported case of vasoplegia on CPB unresponsive to methylene blue whereas responsive to hydroxocobalamin, which indicates that the effect of hydroxocobalamin outside of the nitric oxide system is significant or that the two drugs have a synergistic effect in one or multiple mechanisms.

http://ift.tt/2kE3Y5c

Low-dose intravenous ketamine for postcardiac surgery pain: Effect on opioid consumption and the incidence of chronic pain

Jennifer Cogan, Geneviève Lalumière, Grisell Vargas-Schaffer, Alain Deschamps, Zeynep Yegin

Annals of Cardiac Anaesthesia 2017 20(4):395-398

Background: Recent meta-analyses have concluded that low-dose intravenous ketamine infusions (LDKIs) during the postoperative period may help to decrease acute and chronic postoperative pain after major surgery. Aims: This study aims to evaluate the level of pain at least 3 months after surgery for patients treated with a postoperative LDKI versus patients who were not treated with a postoperative LDKI. Methods: Administrative and Ethics Board approval were obtained for this study. We performed a retrospective chart review for all patients receiving LDKI, and equal number of age-, sex-, and surgery-matched patients who did not receive LDKI. Low-dose ketamine was prepared using 100 mg of ketamine in 100 ml of normal saline and run between 50 and 200 mcg/kg/h. Results: We reviewed 115 patients with LDKI and 115 without LDKI. The average age was 63.1 years, 73% of the patients were men and sex was evenly distributed between LDKI and non-LDKI. The average duration of the ketamine infusions was 26.8 h with the average dose being 169.9 mg. At an average of 9 months after surgery, 42% of the ketamine group and 38% of the nonketamine group stated that they had had pain on discharge. Of these patients, 30% of the ketamine group and 26% of the nonketamine group still had pain at the time of the phone call. Women in both groups had more acute and chronic pain than men. Conclusion: These results show that LDKI does not promote a decrease in long-term postoperative pain.

http://ift.tt/2yUrP2w

An uncommon intraoperative implantable cardiac device complication and subsequent troubleshooting

Rekha Suthar, Omar Viswanath, S Howard Wittels, Gerald P Rosen

Annals of Cardiac Anaesthesia 2017 20(4):483-484



http://ift.tt/2kCMc24

An innovative technique to improve safety of volatile anesthetics suction from the cardiopulmonary bypass circuit

Francesco De Simone, Luigi Cassarà, Salvatore Sardo, Elena Scarparo, Omar Saleh, Caetano Nigro Neto, Alberto Zangrillo, Giovanni Landoni

Annals of Cardiac Anaesthesia 2017 20(4):399-402

Context: Myocardial injury during cardiac surgery on cardiopulmonary bypass (CPB) is a major determinant of morbidity and mortality. Preclinical and clinical evidence of dose- and time-related cardioprotective effects of volatile anesthetic drugs exist and their use during the whole surgery duration could improve perioperative cardiac protection. Even if administering volatile agents during CPB are relatively easy, technical problems, such as waste gas scavenging, may prevent safe and manageable administration of halogenated vapors during CPB. Aims: The aim of this study is to improve the safe administration of volatile anesthesia during CPB. Settings and Design: Tertiary teaching hospital. Subjects and Methods: We describe an original device that collects and disposes of any volatile anesthetic vapors present in the exit stream of the oxygenator, hence preventing its dispersal into the operating theatre environment and adaptively regulates pressure of oxygenator chamber in the CPB circuit. Results: We have so far applied a prototype of this device in more than 1300 adult cardiac surgery patients who received volatile anesthetics during the CPB phase. Conclusions: Widespread implementation of scavenging system like the one we designed may facilitate the perfusionist and the anesthesiologist in delivering these cardioprotective drugs with beneficial impact on patients' outcome without compromising on safety.

http://ift.tt/2kBPId0

Lutembacher syndrome: Dilemma of doing a tricuspid annuloplasty

AV Varsha, Gladdy George, Raj Sahajanandan

Annals of Cardiac Anaesthesia 2017 20(4):456-458

We discuss the case of a 24-year-old woman with Lutembacher syndrome and severe tricuspid regurgitation (TR) who underwent surgical closure of atrial septal defect and mitral valve replacement without tricuspid annuloplasty despite a severe TR and a large tricuspid annulus on preoperative echo. The pathophysiology of Lutembacher syndrome is discussed below. The utility of perioperative echocardiography in assessing the annular diameter, tenting area and coaptation depth and thus providing insights into the functioning of the tricuspid valve will also be emphasized.

http://ift.tt/2yT3hXK

Relationship between perioperative left atrial appendage doppler velocity estimates and new-onset atrial fibrillation in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass

Kunal Sarin, Sandeep Chauhan, Akshay K Bisoi, Poonam Malhotra Kapoor, Parag Gharde, Arindam Choudhury

Annals of Cardiac Anaesthesia 2017 20(4):403-407

Background: Literature search reveals that postoperative atrial fibrillation (POAF) occurs in 15%–40% of coronary artery bypass graft (CABG) patients. Although several risk models exist for predicting the development of POAF, few have studied left atrial appendage (LAA) velocity. We hypothesize that an association between LAA velocity and development of POAF exists. Design and Methods: Single institution university hospital prospective observational clinical study performed between May 2016 and November 2016 in 96 adult patients undergoing CABG surgery utilizing cardiopulmonary bypass (CPB). Transesophageal echocardiography was performed perioperatively to measure LAA velocity and left atrial (LA) size after anesthetic induction, post-CPB and during the postoperative period before extubation. Student's t-test was used for inter-group comparisons. Data are expressed as mean ± (standard deviation). The value of P < 0.05 was considered statistically significant. Results: A total of 95 patients (69 males and 26 females) completed the study and were included in the final analysis. Of these, 21 (22%) (15 males and 5 females) developed POAF. The patient group which developed POAF was compared with the group that did not develop POAF. On comparing mean age of patients in each group (59 years in patients with no POAF and 63.71 years in patients with POAF, P = 0.04). LA volume indexed in POAF group (34.13 ml/m2) compared with that in group with no POAF (34.82 ml/m2) resulted in P = 0.04. Mean LAA velocities (pre-CPB, post-CPB, postoperative Intensive Care Unit) in group with no POAF were 41.06, 56.33, and 60.44 cm/s, respectively, whereas in the other group with POAF the values were 39.68, 55.04, and 58.09 cm/s, respectively. No statistical significance was noted (P > 0.05). Comparison of comorbidities also did not yield any significant results (P > 0.05). Conclusions: Decreasing LAA velocity does not appear to independently predict the development of POAF in patients undergoing CABG surgery with the use of CPB. There is, however, a positive correlation of POAF with age and LA volume.

http://ift.tt/2kBPDWK

Perioperative management of a patient with glanzmann's thrombasthenia for mitral valve repair under cardiopulmonary bypass

Parimala Prasanna Simha, Prasanna Simha Mohan Rao, Deepak Arakalgud, Rakesh Rajashekharappa, Manjunath Narasimhaih

Annals of Cardiac Anaesthesia 2017 20(4):468-471

A 30-year-old male patient presented with Glanzmann's thrombasthenia and mitral valve prolapse. He was in acute decompensated congestive heart failure due to severe mitral and tricuspid regurgitation. After his cardiac failure had been stabilized, the patient was subjected to mitral and tricuspid valve repair. His transfusion requirements were guided by thrombelastography and his bleeding disorder was managed by infusing single donor plasmapheresed platelet transfusions in the perioperative period. The patient underwent surgery uneventfully.

http://ift.tt/2yUrzR6

Comparison of the renoprotective effect of dexmedetomidine and dopamine in high-risk renal patients undergoing cardiac surgery: A double-blind randomized study

Rabie Soliman, Mohamed Hussien

Annals of Cardiac Anaesthesia 2017 20(4):408-415

Objective: The purpose of the current study was to compare the renoprotective effects of continuous infusion of dexmedetomidine and dopamine in high-risk renal patients undergoing cardiac surgery. Design: A double-blind randomized study. Setting: Cardiac Centers. Patients: One hundred and fifty patients with baseline serum creatinine level ≥1.4 mg/dl were scheduled for cardiac surgery with cardiopulmonary bypass. Intervention: The patients were classified into two groups (each = 75): Group Dex – the patients received a continuous infusion of dexmedetomidine 0.4 μg/kg/h without loading dose during the procedure and the first 24 postoperative hours and Group Dopa – the patients received a continuous infusion of dopamine 3 μg/kg/min during the procedure and the first 24 postoperative hours. Measurements: The monitors included serum creatinine, creatinine clearance, blood urea nitrogen, and urine output. Main Results: The creatinine levels and blood urea nitrogen decreased at days 1, 2, 3, 4, and 5 in Dex group and increased in patients of Dopa group (P < 0.05). The creatinine clearance increased at days 1, 2, 3, 4, and 5 in Dex group and decreased in patients of Dopa group (P < 0.05). The amount of urine output was too much higher in the Dex group than the Dopa group (P < 0.05). Conclusions: The continuous infusion of dexmedetomidine during cardiac surgery has a renoprotective effect and decreased the deterioration in the renal function in high-risk renal patients compared to the continuous infusion of dopamine.

http://ift.tt/2kBPzGu

Bifid epiglottis: What perioperative physician should know about it?

Rupesh Yadav, Sohan Lal Solanki, Jeson R Doctor

Annals of Cardiac Anaesthesia 2017 20(4):479-480



http://ift.tt/2yUrsFa

Does bilevel positive airway pressure improve outcome of acute respiratory failure after open-heart surgery?

Ahmed Said Elgebaly

Annals of Cardiac Anaesthesia 2017 20(4):416-421

Background: Respiratory failure is of concern in the postoperative period after cardiac surgeries. Invasive ventilation (intermittent positive pressure ventilation [IPPV]) carries the risks and complications of intubation and mechanical ventilation (MV). Aims: Noninvasive positive pressure ventilation (NIPPV) is an alternative method and as effective as IPPV in treating insufficiency of respiration with less complications and minimal effects on respiratory and hemodynamic parameters next to open-heart surgery. Design: This is a prospective, randomized and controlled study. Materials and Methods: Forty-four patients scheduled for cardiac surgery were divided into two equal groups: Group I (IPPV) and Group II (NIPPV). Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), oxygen saturation (SpO2), arterial blood gas, weaning time, reintubation, tracheotomy rate, MV time, postoperative hospital stay, and ventilator-associated pneumonia during the period of hospital stay were recorded. Results: There was statistically significant difference in HR between groups with higher in Group I at 30 and 60 min and at 12 and 24 h. According to MAP, it started to increase significantly at hypoxemia, 15 min, 30 min, 4 h, 12 h, and at 24 h which was higher in Group I also. RR, PaO2, and PaCO2showed significant higher in Group II at 15, 30, and 60 min and 4 h. According to pH, there was a significant difference between groups at 15, 30, and 60 min and at 4, 12, and 24 h postoperatively. SpO2showed higher significant values in Group I at 15 and 30 min and at 12 h postoperatively. Duration of postoperative supportive ventilation was higher in Group I than that of Group II with statistically significant difference. Complications were statistically insignificant between Group I and Group II. Conclusion: Our study showed superiority of invasive over noninvasive mode of ventilator support. However, NIPPV (bilevel positive airway pressure) was proved to be a safe method.

http://ift.tt/2yTPZtX

Atmospheric pollution in cardiac operating rooms

Mukul Chandra Kapoor

Annals of Cardiac Anaesthesia 2017 20(4):391-392



http://ift.tt/2kE3V9w

Comparison of dexmedetomidine and ketamine versus propofol and ketamine for procedural sedation in children undergoing minor cardiac procedures in cardiac catheterization laboratory

Vidya Sagar Joshi, Sandeep S Kollu, Ram Murti Sharma

Annals of Cardiac Anaesthesia 2017 20(4):422-426

Background: The ideal anaesthetic technique for management of paediatric patients scheduled to undergo cardiac catheterisation is still not standardised. Aim: To compare the effects of ketamine-propofol and ketamine-dexmedetomidine combinations on hemodynamic parameters and recovery time in paediatric patients undergoing minor procedures and cardiac catheterisation under sedation for various congenital heart diseases. Material and Methods: 60 children of either sex undergoing cardiac catheterisation were randomly assigned into two groups Dexmedetomidine-ketamine group (DK) and Propofol-ketamine (PK) of 30 patients each. All patients were premedicated with glycopyrrolate and midazolam (0.05mg/kg) intravenously 5-10 min before anaesthetic induction. Group 'DK'received dexmedetomidineiv infusion 1 μg/kg over 10 min + ketamine1mg/kg bolus, followed by iv infusion of dexmedetomidine 0.5μg/kg/hr and of ketamine1 mg/kg/hr. Group 'PK' received propofol 1mg/kg and ketamine 1mg/kg/hr for induction followed by iv infusion of propofol 100 μg/kg/hr and ketamine 1 mg/kg/hr for maintenance. Haemodynamic parameters and recovery time was recorded postoperatively. Statistical Analysis: Independent sample t test was used to compare the statistical significance of continuous variables of both the groups.Chi square test was used for numerical data like gender.Fischer exact test was applied for non parametric data like ketamine consumption. Results: We observed that heart rate in dexmedetomidine (DK) group was significantly lower during the initial 25 mins after induction compared to the propofol (PK) group. Recovery was prolonged in the DK group compared to the PK group (40.88 vs. 22.28 min). Even ketamine boluses consumption was higher in DK group. Conclusion: Use of dexmedetomidine-ketamine combination is a safe alternative, without any hemodynamic orrespiratory effects during the cardiac catheterization procedure but with some delayed recovery.

http://ift.tt/2yUlbJL

Rhabdomyolysis and compartment syndrome in a bodybuilder undergoing minimally invasive cardiac surgery

Sebastian John Baxter, Madhusudan Rao Puchakayala, Vinayak N Bapat

Annals of Cardiac Anaesthesia 2017 20(4):453-455

Rhabdomyolysis is the result of skeletal muscle tissue injury and is characterized by elevated creatine kinase levels, muscle pain, and myoglobinuria. It is caused by crush injuries, hyperthermia, drugs, toxins, and abnormal metabolic states. This is often difficult to diagnose perioperatively and can result in renal failure and compartment syndrome if not promptly treated. We report a rare case of inadvertent rhabdomyolysis and compartment syndrome in a bodybuilder undergoing minimally invasive cardiac surgery. The presentation, differential diagnoses, and management are discussed. Hyperkalemia may be the first presenting sign. Early recognition and management are essential to prevent life-threatening complications.

http://ift.tt/2kBtsQv

Evaluation of the effect of metformin and insulin in hyperglycemia treatment after coronary artery bypass surgery in nondiabetic patients

Kamran Ghods, Hossein Davari, Abbasali Ebrahimian

Annals of Cardiac Anaesthesia 2017 20(4):427-431

Introduction: Insulin therapy is the most commonly used treatment for controlling hyperglycemia after coronary artery bypass surgery in both diabetic and nondiabetic patients. Metformin has been indicated for critically ill patients as an alternate for the treatment of hyperglycemia. This study evaluated the effect of metformin and insulin in hyperglycemia treatment after coronary artery bypass surgery in nondiabetic patients. Settings and Design: This study was a clinical trial comprising nondiabetic patients who had undergone coronary artery bypass surgery. Patients were randomly divided into the insulin group and the metformin group. Methods: Patients in the insulin group received continuous infusion of insulin while those in the metformin group received 500 mg metformin tablets twice daily. All the patients were followed up for 3 days after stabilization of blood glucose levels. Statistical Analysis: Data were analyzed using Chi-square test and Mann–Whitney U-test. Results: This study included a total of 56 patients. During the study period, the mean blood glucose levels decreased from 225.24 to 112.36 mg/dl (↓112.88 mg/dl) in the insulin group and from 221.80 to 121.92 mg/dl in the metformin group (↓99.88 mg/dl). There was no significant difference in the blood glucose levels of the patients between the two groups at any measurement times (P > 0.05). Conclusion: Using 500 mg metformin twice daily is similar to using insulin in nondiabetic patients undergoing coronary artery bypass graft. Therefore, the use of metformin can be considered as a treatment strategy for controlling hyperglycemia in this group of patients.

http://ift.tt/2yTFHdw

Two episodes of cardiac tamponade in the same patient from removing pacing wires and a pericardial drain: A case report

Rekha Suthar, Osman Nawazish Salaria, Carolina De La Cuesta, Omar Viswanath

Annals of Cardiac Anaesthesia 2017 20(4):459-461

A patient presented for an elective transcatheter aortic valve replacement with temporary transvenous pacing (TVP) wires placement per protocol. On postoperative day 1, the patient remained stable, so the wires were subsequently removed, after which the patient acutely decompensated, with transthoracic echocardiography revealing pericardial effusion. Emergent pericardiocentesis was performed, and a pericardial drain was placed. Three days later, the drain was removed; again, the patient acutely decompensated, requiring another emergent pericardiocentesis. Despite the relatively benign nature of TVP wires and pericardial drains, the possibility of cardiac tamponade should be kept in mind as a potential complication when they are being removed.

http://ift.tt/2kCM42A

Ischemic mitral regurgitation

Praveen Kerala Varma, Neethu Krishna, Reshmi Liza Jose, Ashish Narayan Madkaiker

Annals of Cardiac Anaesthesia 2017 20(4):432-439

Ischemic mitral regurgitation (IMR) is a frequent complication of left ventricular (LV) global or regional pathological remodeling due to chronic coronary artery disease. It is not a valve disease but represents the valvular consequences of increased tethering forces and reduced closing forces. IMR is defined as mitral regurgitation caused by chronic changes of LV structure and function due to ischemic heart disease and it worsens the prognosis. In this review, we discuss on etiology, pathophysiology, and mechanisms of IMR, its classification, evaluation, and therapeutic corrective methods of IMR.

http://ift.tt/2yTyNEU

A case report of combined radical pericardiectomy and beating heart coronary artery bypass grafting in a patient with tubercular chronic constrictive pericarditis with coronary artery disease

Gauranga Majumdar, Surendra Kumar Agarwal, Shantanu Pande, Bipin Chandra, Prabhat Tewari

Annals of Cardiac Anaesthesia 2017 20(4):465-467

We here report a successful midterm outcome following combined off-pump radical pericardiectomy and coronary artery bypass surgery (CABG) in a 65-year-old male patient who was suffering from chronic constrictive calcified tubercular pericarditis with coronary artery disease. Simultaneous off-pump CABG and radical pericardiectomy for nonsurgical constrictive pericarditis is reported very rarely in English literature.

http://ift.tt/2kBt0BN

Late-occurring nivolumab-induced cryptogenic organising pneumonia mimicking lung progression in a patient with metastatic non–small cell lung cancer

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): Linda Mahjoubi, Anas Gazzah, Aurélien Marabelle, François Le Roy Ladurie, Olivier Lambotte, Caroline Caramella, Julien Adam, Benjamin Besse, Jean-Charles Soria




from Cancer via ola Kala on Inoreader http://ift.tt/2yC7Rh9
via IFTTT

A systematic review of economic evaluation in pancreatic ductal adenocarcinoma

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Claire Gérard, Philippe Fagnoni, Angélique Vienot, Christophe Borg, Samuel Limat, Franck Daval, François Calais, Julie Vardanega, Marine Jary, Virginie Nerich
ObjectivesThe economic evaluation (EE) of healthcare interventions has become a necessity. However, high quality needs to be ensured in order to achieve validated results and help making informed decisions. Thus, the objective of the present study was to systematically identify and review published pancreatic ductal adenocarcinoma-related EEs and to assess their quality.MethodsSystematic literature research was conducted in PubMed and Cochrane to identify published EEs between 2000 and 2015. The quality of each selected EE was assessed by two independent reviewers, using the Drummond's checklist.ResultsOur systematic review was based on 32 EEs and showed a wide variety of methodological approaches, including different perspectives, time horizon, and cost effectiveness analyses. Nearly two-thirds of EEs are full EEs (n = 21), and about one-third of EEs had a Drummond score ≥7, synonymous with 'high quality'. Close to 50% of full EEs had a Drummond score ≥7, whereas all of partial EEs had a Drummond score <7 (n = 11).ConclusionsOver the past 15 years, a lot of interest has been evinced over the EE of pancreatic ductal adenocarcinoma (PDAC) and its direct impact on therapeutic advances in PDAC. To provide a framework for health care decision-making, to facilitate transferability and to lend credibility to health EEs, their quality must be improved. For the last 4 years, a tendency towards a quality improvement of these studies has been observed, probably coupled with a context of rational decision-making in health care, a better and wider spread of recommendations and thus, medical practitioners' full endorsement.



from Cancer via ola Kala on Inoreader http://ift.tt/2y6USRs
via IFTTT

Accuracy of screening women at familial risk of breast cancer without a known gene mutation: Individual patient data meta-analysis

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): Xuan-Anh Phi, Nehmat Houssami, Maartje J. Hooning, Christopher C. Riedl, Martin O. Leach, Francesco Sardanelli, Ellen Warner, Isabelle Trop, Sepideh Saadatmand, Madeleine M.A. Tilanus-Linthorst, Thomas H. Helbich, Edwin R. van den Heuvel, Harry J. de Koning, Inge-Marie Obdeijn, Geertruida H. de Bock
IntroductionWomen with a strong family history of breast cancer (BC) and without a known gene mutation have an increased risk of developing BC. We aimed to investigate the accuracy of screening using annual mammography with or without magnetic resonance imaging (MRI) for these women outside the general population screening program.MethodsAn individual patient data (IPD) meta-analysis was conducted using IPD from six prospective screening trials that had included women at increased risk for BC: only women with a strong familial risk for BC and without a known gene mutation were included in this analysis. A generalised linear mixed model was applied to estimate and compare screening accuracy (sensitivity, specificity and predictive values) for annual mammography with or without MRI.ResultsThere were 2226 women (median age: 41 years, interquartile range 35–47) with 7478 woman-years of follow-up, with a BC rate of 12 (95% confidence interval 9.3–14) in 1000 woman-years. Mammography screening had a sensitivity of 55% (standard error of mean [SE] 7.0) and a specificity of 94% (SE 1.3). Screening with MRI alone had a sensitivity of 89% (SE 4.6) and a specificity of 83% (SE 2.8). Adding MRI to mammography increased sensitivity to 98% (SE 1.8, P < 0.01 compared to mammography alone) but lowered specificity to 79% (SE 2.7, P < 0.01 compared with mammography alone).ConclusionIn this population of women with strong familial BC risk but without a known gene mutation, in whom BC incidence was high both before and after age 50, adding MRI to mammography substantially increased screening sensitivity but also decreased its specificity.



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

A Case of Peripheral Ulcerative Keratitis Associated with Autoimmune Hepatitis

Purpose. To describe a case of peripheral ulcerative keratitis in the setting of autoimmune hepatitis and possible overlap syndrome with primary sclerosing cholangitis. Case Report. A 48-year-old African American female with autoimmune hepatitis with possible overlap syndrome with primary sclerosing cholangitis presented with tearing, irritation, and injection of the left eye that was determined to be peripheral ulcerative keratitis. The patient was treated with topical and systemic steroids, immunosuppressant drugs (azathioprine and mycophenolate mofetil), a biologic (rituximab), and surgery (conjunctival resection), and the peripheral ulcerative keratitis epithelialized but ultimately led to corneal perforation. Conclusion. In this unique case, a patient with peripheral ulcerative keratitis who underwent treatment ultimately had a corneal perforation. This case may suggest a possible relationship between autoimmune hepatitis and peripheral ulcerative keratitis.

http://ift.tt/2kxjaki

A rare case of extra-adrenal bilateral perirenal and periureteric myelolipoma

A 30-year-old immunocompetent female presented with right flank pain since 3 years. MRI revealed a large well-defined T1 and T2 hypointense mildly enhancing lesion in the right anterior pararenal space displacing the right kidney and encasing the right ureter with T2 hyperintense wall thickening of the left renal pelvis and ureter. A provisional diagnosis of solitary fibrous tumour was kept. Bilateral double J stenting was done for hydronephrosis. Surgical debulking of the lesion was done with biopsy from the left periureteral wall thickening and was found to be myelolipoma on histopathological examination. This case is a novel variety of myelolipoma which is lipid poor, extra-adrenal and in bilateral perirenal and periureteric location.

http://ift.tt/2fWBu1j

Spontaneous bilateral carpopedal spasm in a bulimic patient

Description

A 36-year-old woman presented to the emergency department after she woke up with painful spasm of bilateral hands. She had been vomiting 10–15 times daily for the past few days. She denied any laxative or diuretic abuse. She had 18-year history of bulimia nervosa, primarily involving self-induced vomiting and excessive exercising. Her body mass index was 20.7 kg/m². Vital signs and physical examination were unremarkable except for dry oral mucosa, poor oral dentition and classic bilateral carpopedal spasm (figure 1). Labs revealed hypocalcaemia (ionised calcium 0.88 mmol/L), hypokalaemia (potassium 2.8 mEq/L), hypomagnesaemia (magnesium 1.6 mEq/L), metabolic alkalosis (serum bicarbonate 34.5 mEq/L), hypochloraemia (chloride 78 mEq/L), hypophosphataemia (phosphorus 1.6 mg/dL), acute kidney injury (serum creatinine 2.49 mg/dL, baseline of 0.9), leucocytosis (white blood cells 15 700  x10⁹/L mm³) and normal serum albumin 4 g/dL. ECG showed normal sinus rhythm with prolonged QTc of 550 ms (figure 2). Urine drug screen was positive...

http://ift.tt/2hX1BcG

Delayed spinal cord infarction following anterior cervical surgical decompression

Anterior cervical discectomy and fusion (ACDF) for cord compression is a safe and effective procedure with good outcomes. However, worsening of myelopathy is the most feared adverse event of the surgery. We report the case of a 36-year-old male patient who presented with an acute non-traumatic C5–6 cervical disc herniation causing incomplete quadriparesis. He underwent an uncomplicated ACDF at C5–6, and after an initial period of improvement, he developed a delayed onset of an anterior cord syndrome on day 3, without any discerning cause. We have reviewed similar cases reported in the literature and believe that our patient's postsurgical course is consistent with a delayed ischaemic/reperfusion injury to the cord following surgical decompression and restoration of blood flow through the anterior spinal artery and we make suggestions for management of such clinical events.

http://ift.tt/2fVzTbX

Videoscopic-assisted removal of a left ventricular mass in an octogenarian

Description

An 85-year-old female with history of hypertension, diabetes, coronary artery disease and emphysema presented with episodes of confusion. MRI demonstrated bilateral acute infarcts. She had non-ST elevation myocardial infarction and underwent percutaneous intervention with drug-elating stent for left anterior descending artery stenosis. Transthoracic echocardiography (TTE) (see online ) and transoesophageal echocardiography (TEE) demonstrated calcified left ventricular mass (LVM) (see online ), severe mitral annular calcification and moderate mitral stenosis (figure 1). Forced expiratory volume in one second 0.89 (85% of predicted), forced vital capacity 1.01 (69% of predicted) and frail body habitus. Multidisciplinary discussions (MDD) with family and they agreed to video-assisted LVM removal.1 2 Double lung ventilation was initiated, peripheral cardiopulmonary bypass (CPB) instituted through femoral vessels, ventilation stopped and resumed at the end of CPB. A 4 cm right intercostal incision performed and 10 mm videoscope inserted through separate 12 mm port. After cross-clamp, induction antegrade cardioplegia administrated...

http://ift.tt/2hXIkYk

Aspirin safety in glucose-6-phosphate dehydrogenase deficiency patients with acute coronary syndrome undergoing percutaneous coronary intervention

The use of aspirin, as part of a dual antiplatelet therapy regimen, is an established standard following coronary stenting in patients suffering from acute coronary syndrome (ACS). However, in glucose-6-phosphate dehydrogenase (G6PD) deficient patients, precaution is always taken with aspirin use, due to the risk of haemolysis. We reviewed all previous cases of G6PD deficient patients with ACS, in addition to a review of the available literature, to better understand the safety of aspirin use in this population. To date, there are no reported cases of haemolysis following aspirin use in this patient group and no guideline is established to date.

http://ift.tt/2z8tItx

Hoarseness as a presentation of mycosis fungoides infiltrating the larynx

Laryngeal involvement is a rare manifestation of mycosis fungoides (MF), with only nine reported cases of cutaneous T cell lymphoma with laryngeal or vocal cord involvement. Herein, we report the case of a patient with a 7-year history of MF who presented to the emergency department with hoarseness, throat tightness and cough, as well as erythroderma and skin tumours. Laryngoscopy and CT imaging were concerning for lymphomatous involvement of the left false vocal cord. A biopsy was taken of the false vocal cord lesion, which revealed an aberrant immunophenotype consistent with MF. The patient was started on doxorubicin with initial rapid improvement in symptoms. Within 2 months, her respiratory status and skin involvement worsened. Subsequent studies showed bone marrow involvement. The patient expired 4 months after original presentation. This report describes the patient's presentation and clinical course, and reviews the literature on vocal cord and laryngeal involvement of MF.

http://ift.tt/2y2XXEq

Nodular fasciitis of soft tissue over the mandible

Nodular fasciitis (NF) is an unusual, benign condition which can mimic more sinister, sarcomatous lesions both clinically and histologically. This case report presents a 35-year-old male, with a rapidly growing mass on the border of his left mandible, referred to a specialist head and neck unit. The initial presentation, radiology and cytology were initially inconclusive and the possibility of a malignant process was considered. Final histology was that of NF, the treatment of which is complete surgical excision. Therefore, NF is an important differential to consider when assessing similar clinical presentations, as highlighted in this case report.

http://ift.tt/2z9RrJN

Rare postoperative complication: Clostridium perfringens septic shock following elective abdominal surgery

Postoperative infections are one of the most common complications in general surgery, and while rates have reduced with the routine administration of perioperative antibiotics, around 5% of patients undergoing a surgical procedure will develop an infective complication.¹ The Gram-positive, obligate anaerobe, Clostridium perfringens, is a well-known pathogen that forms part of both the environmental and gastrointestinal flora.² While more commonly associated with food poisoning, anaerobic cellulitis and traumatic gas gangrene, rare cases of spontaneous non-traumatic gas gangrene of abdominal viscera have also been recorded.³ Although potentially treatable with appropriate antibiotic cover, cases of C. perfringens can rapidly progress into fulminant and fatal sepsis.⁴ Moreover, the timing of symptom onset postoperatively can vary significantly, reports ranging from hours to days.^{5 6} We report a case of C. perfringens-induced septic shock following elective bowel resection.

http://ift.tt/2y2XVMO

Haematuria in ADPKD: not always benign. Be aware!

Haematuria in patients with autosomal dominant polycystic kidney disease (ADPKD) is a very common manifestation. The cause of haematuria is often benign with the most common cause being haemorrhage within the renal cyst. But haematuria may also be caused by a coincident malignancy, the diagnosis of which may be missed if not investigated thoroughly. Herein, we present a case of ADPKD who presented to us with haematuria and was later found to have bladder cancer.

http://ift.tt/2za07Qs

Isolated adductor myocysticercosis in a 6-year-old girl

Description

A 6-year-old girl presented with asymptomatic right thigh swelling over medial aspect for 6 weeks. Examination revealed a 5 cmx4 cm, non-tender, mobile swelling, not fixed to the skin or underlying structures. The rest of the examination was within normal limits. There was no history of seizures, headache or ophthalmic complaints. Ultrasonography of the right thigh revealed a well-defined cystic lesion measuring 11.5 cmx4.3 cm seen in the adductor muscle of the thigh with eccentric echogenic focus within (figure 1). No perilesional oedema was seen. Stool examination was negative for Taenia solium eggs. Serological testing could not be done due to affordability issues. A diagnosis of vesicular stage of isolated adductor myocysticercosis was made. Neuroimaging and ophthalmic assessment were unremarkable. Patient was treated with oral albendazole as an outpatient basis and had uneventful recovery at 1 month of follow-up with thigh swelling got completely resolved. However, we could not repeat an ultrasonography a few months...

http://ift.tt/2y4EwLo

Delays in diagnosis and treatment of extrapulmonary tuberculosis in Guatemala

A 23-year-old indigenous Guatemalan man presented in 2016 to our clinic in Sololá, Guatemala, with 10 months of recurrent neck swelling, fevers, night sweats and weight loss. Previously, he had sought care in three different medical settings, including a private physician-run clinic, a tertiary private cancer treatment centre and, finally, a rural government health post. With assistance from our institution's accompaniment staff, the patient was admitted to a public tertiary care hospital for work-up. Rifampin-susceptible tuberculosis was diagnosed, and appropriate treatment was begun. The case illustrates how low tuberculosis recognition among community health workers and health system segmentation creates obstacles to appropriate care, especially for patients with limited means. As a result, significant diagnostic and treatment delays can occur, increasing the public health burden of tuberculosis.

http://ift.tt/2z9YodF

Interrupted aortic arch complicated with takotsubo cardiomyopathy mimicking aortic dissection

A 50-year-old man presented to the emergency department with interscapular pain, diaphoresis and restlessness. Initial examination raised the possibility of aortic dissection; however, the CT scan did not concur with the diagnosis. An ECG showed ST segment elevation in leads V1–V6 and echocardiography showed severe left ventricular systolic dysfunction. Coronary angiography through the right femoral artery was attempted but the diagnostic catheter could not be advanced to the ascending aorta. Radiocontrast injection showed complete obstruction of the descending aorta. Coronary angiography through right radial approach showed mild left anterior descending disease. The aortogram showed complete interruption of the ascending aorta with extensive collateral network. Left ventricle gram was consistent with stress-induced cardiomyopathy. We noticed intermittent confusion and agitation. MRI of the brain showed areas of deep white matter ischaemia as well as microhaemorrhages, suggesting posterior reversible leucoencephalopathy syndrome. He unfortunately went into cardiac arrest and could not be revived.

http://ift.tt/2y4Ukhq

Lipoedematous scalp: is there an association with fatty infiltration of the parotid?

Lipoedematous scalp (LS) is an extremely rare condition characterised by a soft and boggy consistency in the scalp due to an increased layer of subcutaneous tissue.

In this report, we present a case of LS in a 64-year-old Indian woman. Clinical examination revealed only vague boggy lumpiness involving the whole of occipital scalp extending to parietal scalp. MRI scalp showed diffuse fatty infiltration of the scalp, particularly at the posterior parietal and occipital convexity extending to both lateral aspects of the cranium, with homogeneous signal in keeping with fat. Incidentally MRI also found diffuse fatty infiltration of the parotids.

The aethiopathogenesis of LS is still unknown, however it is believed that the hormone leptin could be the key hormone in the dysregulation of fat deposition and distribution. This case report highlights the subtle features with which these cases can present and explores the literature on reported cases of LS.

http://ift.tt/2za033a

Pertussis manifesting as recurrent cough and wheezing in an incompletely vaccinated 8-month-old infant

Pertussis is an acute respiratory illness caused by Bordetella pertussis, showing a re-emergence in developed countries. However, it is probably under-recognised and, as a consequence, its burden is underestimated. Here, we report the clinical case of an infant diagnosed with pertussis, despite a regular schedule of vaccination, thanks to a careful clinical evaluation, including personal and family history. In addition to pointing the attention on a precocious diagnosis of atypical cases of pertussis, this case report further raised the issue of modifying and/or implementing the immunisation strategy, considering the ongoing changes of social (eg, immigration) and sanitary (eg, vaccine coverage) background in Italy and all over the Europe.

http://ift.tt/2y2XSk6

Endoscopic shaving of hair in a gastric bypass patient with a large bezoar

Trichotillomania can be associated with the formation of trichobezoars (hair ball) usually located in the stomach. Trichobezoars may lead to complications including bowel obstruction, and perforation. Patients with a history of diabetes, certain psychiatric disorders, prior gastric surgery and poor mastication ability are at an increased risk of developing bezoars. We are presenting a case of patient who suffered from a large, recurrent trichobezoar, who had a history of gastric bypass surgery as well as trichotillophagia. The endoscopic method used to remove the large bezoar will also be discussed. We have reviewed the cases published, in which patients developed bezoars after undergoing gastric bypass surgery. The purpose of this study is to raise awareness among clinicians that patients with certain psychiatric issues who had prior gastric surgeries, are at eminent risk of bezoar formation. A multidisciplinary approach including cognitive behavioural therapy, dietary education and pharmacotherapy should be taken to prevent complications.

http://ift.tt/2z9xEdi

Unusual case of urethral steinstrasse following laser cystolitholapaxy

Urethral steinstrasse is a rare finding. This case describes a 35-year-old man presenting with urethral steinstrasse 4 weeks following laser cystolitholapaxy of a large bladder stone.

http://ift.tt/2y2XQbY

Bilateral fungal keratitis with ring infiltrates: a rare scenario

A 12-year-old boy presented to the emergency department with chief complaints of pain, redness, discharge and diminution of vision in both eyes over the previous 20 days. There was no history of preceding trauma, contact lens use, any eye drop usage or ocular surgery. Systemic history was not significant. Presenting uncorrected visual acuity in his right eye was counting fingers at 1 m and 20/200 in the left eye, with accurate projection of rays in both eyes. Slit lamp biomicroscopy showed the presence of bilateral diffuse conjunctival congestion, corneal ring infiltrates and epithelial defect with corneal oedema. Potassium hydroxide wet mount showed the presence of septate fungal hyphae. The patient was treated with topical 5% natamycin and 1% voriconazole over a period of 6 weeks. Best-corrected visual acuity was 20/600 in the right eye and 20/20 in the left eye at 6-month follow-up.

http://ift.tt/2z9ZZQY

Durable complete remission with combination chemotherapy and bortezomib in HIV-associated plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is an aggressive form of non-Hodgkin's lymphoma (NHL) classically seen in patients infected with the human immunodeficiency virus, but can also be seen in other immunocompromised states such as transplant recipients, autoimmune diseases and the elderly. PBL is generally associated with a poor prognosis despite chemotherapy. There is evidence supporting the use of bortezomib in combination with standard chemotherapy to achieve durable responses in patients with PBL. We describe a patient with acquired immunodeficiency syndrome who presented with rectal pain and bright red blood per rectum. He was diagnosed with stage IVA PBL with anorectal, nodal, calvarial and hepatic involvement. Along with highly active antiretroviral therapy, he was treated with six cycles of dose adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH) plus bortezomib resulting in durable complete remission 30 months after diagnosis.

http://ift.tt/2y2XOAS

Life-threatening parapharyngeal and retropharyngeal abscess in an infant

Severe extensive deep neck abscess in an infant is uncommon. We share the case of a previously well 4-month old infant who was referred for a 4-day history of fever, lethargy and left lateral neck swelling. Contrast-enhanced CT scan revealed a large 5.3x8 cm collection involving the left parapharyngeal and retropharyngeal space, causing significant airway narrowing. 40 mL of frank pus was drained via intraoral incision and drainage with the aid of endoscope, and undesirable complications from an external approach were averted. The infant was extubated 48 hours postsurgery and was discharged home well after completion of 1 week of intravenous antibiotics. The child was discharged well from our follow-up at 1 month review. We discuss the pathophysiology of deep neck space abscesses, its incidence in the paediatric population and the various management options.

http://ift.tt/2z9ZVAI

Mitral valve prosthesis implanted in the atrial position in a patient with extensive calcification extending from epicardium to mitral annulus

Description

A 72-year-old woman with progressive dyspnoea underwent transoesophageal echocardiography demonstrating mixed mitral stenosis and regurgitation, extensive mitral annular calcification (MAC), left atrial appendage clot and mass on aortic valve. Laboratory work-up revealed normal serum calcium. Left heart catheterisation did not reveal any significant coronary artery disease. Right heart catheterisation demonstrated severe pulmonary artery hypertension. Chest CT scan showed extensive calcification extending from left ventricular epicardium to mitral annulus (see online ).1 Median sternotomy revealed epicardial calcification but none on pericardial (figure 1). Aortic right coronary cusp mass was identified and excised through aortotomy. Left atrial appendage clot was evacuated and AtriClip (AtriCure, Cincinnati, Ohio, USA) 45 mm was applied. Mitral valve was exposed through the left atriotomy. Extensive MAC extending to the atrial wall was observed (figure 2). Anterior mitral leaflet was excised and the posterior leaflet was debrided. A 2 cm wide patch (CorMatrix Cardiovascular, Roswell, Georgia, USA) was sutured to the atrial wall next to the posterior mitral...

http://ift.tt/2y53k5S

Notch signaling controls sprouting angiogenesis of endometriotic lesions

Abstract

Angiogenesis is essential for the engraftment and growth of endometriotic lesions. In this study, we analyzed whether this process is regulated by Notch signaling. Endometriotic lesions were induced by endometrial tissue transplantation into dorsal skinfold chambers of C57BL/6 mice, which were treated with the γ-secretase inhibitor DAPT or vehicle. Vascularization, morphology, and proliferation of the newly developing lesions were analyzed using intravital fluorescence microscopy, histology, and immunohistochemistry over 14 days. Inhibition of Notch signaling by DAPT significantly increased the number of angiogenic sprouts within the endometrial grafts during the first days after transplantation when compared to vehicle-treated controls. This was associated with an accelerated vascularization, as indicated by a higher functional microvessel density of DAPT-treated lesions on day 6. However, inhibition of Notch signaling did not affect the morphology and proliferating activity of the lesions, as previously described for tumors. Both DAPT- and vehicle-treated lesions finally consisted of cyst-like dilated glands, which were surrounded by a well-vascularized stroma and contained comparable numbers of proliferating cell nuclear antigen-positive cells. These findings demonstrate that sprouting angiogenesis in endometriotic lesions is controlled by Notch signaling. However, inhibition of Notch signaling does not have beneficial therapeutic effects on lesion development.

http://ift.tt/2yaAQHp

Notch signaling controls sprouting angiogenesis of endometriotic lesions

Abstract

Angiogenesis is essential for the engraftment and growth of endometriotic lesions. In this study, we analyzed whether this process is regulated by Notch signaling. Endometriotic lesions were induced by endometrial tissue transplantation into dorsal skinfold chambers of C57BL/6 mice, which were treated with the γ-secretase inhibitor DAPT or vehicle. Vascularization, morphology, and proliferation of the newly developing lesions were analyzed using intravital fluorescence microscopy, histology, and immunohistochemistry over 14 days. Inhibition of Notch signaling by DAPT significantly increased the number of angiogenic sprouts within the endometrial grafts during the first days after transplantation when compared to vehicle-treated controls. This was associated with an accelerated vascularization, as indicated by a higher functional microvessel density of DAPT-treated lesions on day 6. However, inhibition of Notch signaling did not affect the morphology and proliferating activity of the lesions, as previously described for tumors. Both DAPT- and vehicle-treated lesions finally consisted of cyst-like dilated glands, which were surrounded by a well-vascularized stroma and contained comparable numbers of proliferating cell nuclear antigen-positive cells. These findings demonstrate that sprouting angiogenesis in endometriotic lesions is controlled by Notch signaling. However, inhibition of Notch signaling does not have beneficial therapeutic effects on lesion development.

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

Advantages of 18 F FDG-PET/CT over Conventional Staging for Sarcoma Patients

Abstract

The effective management of patients with sarcomas requires accurate diagnosis and staging. Imaging, such as ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI) are the most freqently used methods for the detection of the lesion location, size, morphology and structural changes to adjacent tissues; however, these modalities provide little information about tumour biology. MRI is a robust and useful modality in tumour staging of sarcomas, however metabolic-fluorodeoxyglucose positron emission tomography/ computer tomography (¹⁸F–FDG PET/CT) provides greater accuracy to overall staging in combination with MRI [1]. The advantages of ¹⁸F–FDG PET/CT method compared with CT and MRI is that it provides a whole body imaging, maps the viability of the tumour or the metabolic activity of the tissue. Additionally, PET detects the most agressive part of the tumour, demonstrates the biological behaviour of the tumour and therefore has a predictive value. Little data ara available on the role of ¹⁸F–FDG PET/CT in the management of sarcomas. The present manuscript aims to provide a review of the major indications of ¹⁸F–FDG PET/CT for diagnosis, staging, restaging and monitoring response to therapy and to compare its usefulness with the conventional imaging modalities in the management of patients with sarcomas.

http://ift.tt/2g79vzv

Cannabinoid receptor 2 as a novel target for promotion of renal cell carcinoma prognosis and progression

Abstract

Purpose

Renal cell carcinoma (RCC) is the most common malignancy of urogenital system, and patients with RCC may face a poor prognosis. However, limited curable therapeutic options are currently available. The aim of this study is to investigate the role of Cannabinoid receptor 2 (CB2) in RCC progression.

Methods

Immunohistochemistry was to investigate the expression pattern of CB2 in 418 RCC tissues and explore its prognostic function in RCC patients. Furthermore, the role of used CB2 si-RNA knockdown and inhibited by AM630, a CB2 inverse agonist, on cell proliferation, migration, and cell cycle of RCC cell lines in vitro was also investigated.

Results

We observed that CB2 was up-regulated in RCC tissues, and presented as an independent prognostic factor for overall survival of RCC patients and higher CB2 expression tends to have poor clinical outcomes in survival analyses. Moreover, we also observed that CB2, incorporated with pN stage, pathological grade, and recurrence or distant metastasis after surgery, could obviously enhance their prognostic accuracy in a predictive nomogram analysis. In addition, knockdown or inhibition by AM630 for the expression of CB2 in vitro could significantly decreased cell proliferation and migration, and obviously induced cell cycle arrest in G2/M of RCC cells.

Conclusions

CB2 expression is functionally related to cellular proliferation, migration, and cell cycle of RCC cells. Our data suggest that CB2 might be a potential therapeutic target for RCC.

http://ift.tt/2wHkOS3

Crizotinib, a MET inhibitor, inhibits growth, migration, and invasion of breast cancer cells in vitro and synergizes with chemotherapeutic agents

http://ift.tt/2golsxU

Cannabinoid receptor 2 as a novel target for promotion of renal cell carcinoma prognosis and progression

Abstract

Purpose

Renal cell carcinoma (RCC) is the most common malignancy of urogenital system, and patients with RCC may face a poor prognosis. However, limited curable therapeutic options are currently available. The aim of this study is to investigate the role of Cannabinoid receptor 2 (CB2) in RCC progression.

Methods

Immunohistochemistry was to investigate the expression pattern of CB2 in 418 RCC tissues and explore its prognostic function in RCC patients. Furthermore, the role of used CB2 si-RNA knockdown and inhibited by AM630, a CB2 inverse agonist, on cell proliferation, migration, and cell cycle of RCC cell lines in vitro was also investigated.

Results

We observed that CB2 was up-regulated in RCC tissues, and presented as an independent prognostic factor for overall survival of RCC patients and higher CB2 expression tends to have poor clinical outcomes in survival analyses. Moreover, we also observed that CB2, incorporated with pN stage, pathological grade, and recurrence or distant metastasis after surgery, could obviously enhance their prognostic accuracy in a predictive nomogram analysis. In addition, knockdown or inhibition by AM630 for the expression of CB2 in vitro could significantly decreased cell proliferation and migration, and obviously induced cell cycle arrest in G2/M of RCC cells.

Conclusions

CB2 expression is functionally related to cellular proliferation, migration, and cell cycle of RCC cells. Our data suggest that CB2 might be a potential therapeutic target for RCC.

from Cancer via ola Kala on Inoreader http://ift.tt/2wHkOS3
via IFTTT

Advantages of 18 F FDG-PET/CT over Conventional Staging for Sarcoma Patients

Abstract

The effective management of patients with sarcomas requires accurate diagnosis and staging. Imaging, such as ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI) are the most freqently used methods for the detection of the lesion location, size, morphology and structural changes to adjacent tissues; however, these modalities provide little information about tumour biology. MRI is a robust and useful modality in tumour staging of sarcomas, however metabolic-fluorodeoxyglucose positron emission tomography/ computer tomography (¹⁸F–FDG PET/CT) provides greater accuracy to overall staging in combination with MRI [1]. The advantages of ¹⁸F–FDG PET/CT method compared with CT and MRI is that it provides a whole body imaging, maps the viability of the tumour or the metabolic activity of the tissue. Additionally, PET detects the most agressive part of the tumour, demonstrates the biological behaviour of the tumour and therefore has a predictive value. Little data ara available on the role of ¹⁸F–FDG PET/CT in the management of sarcomas. The present manuscript aims to provide a review of the major indications of ¹⁸F–FDG PET/CT for diagnosis, staging, restaging and monitoring response to therapy and to compare its usefulness with the conventional imaging modalities in the management of patients with sarcomas.

http://ift.tt/2g79vzv

10-Year-Old Female with Acute Abdominal Pain with Pancreatic Mass

A previously healthy 10-year-old female presented to a local emergency department following three days of nausea and vomiting diagnosed with a solid pseudopapillary tumor. Solid pseudopapillary neoplasms are a rare form of pancreatic cystic neoplasm that typically presents in young females in their 20–30s and are very rare in children. These neoplasms often present as an asymptomatic tumor found on incidental imaging. When symptomatic they most commonly present with abdominal pain and can also cause a palpable abdominal mass, weight loss, gastrointestinal obstruction, and nausea and vomiting. Timely diagnosis of this rare neoplasm is very important because complete resection of the tumor is the definitive treatment and leads to an excellent long-term survival.

http://ift.tt/2kA3aOH

Antiangiogenesis and medical therapy failure in intracranial atherosclerosis

Abstract

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide and the one with the worst prognosis. In this study, we assessed the hypothesis that the balance of circulating pro- and antiangiogenic factors plays a role in the evolution of the disease and can be used as a potential marker for the disease course and a target for treatment. Seventy-four patients with severe ICAD were enrolled in this prospective observational study, medically optimized, and followed for 6 months. Thirteen pro- and eight antiangiogenic factors were measured in the participants' serum using a sandwich multiplex ELISA. Angiogenic profiles were calculated using principal component analysis. We tested the association between angiogenic profiles and recurring cerebrovascular events despite intensive medical therapy, disability at 6 months after enrollment, and angiographic neovascularization in patients who failed medical treatment and underwent indirect revascularization surgery. There is a strong association between a functionally antiangiogenic profile and recurrent stroke or TIA in patients with ICAD (OR = 7.2, CI 2.4–34.4). Multivariable regression analysis showed that this antiangiogenic profile was also associated with poor functional status after 6 months (p = 0.002), independent from other clinical features such as history of previous stroke, diabetes, and age. In patients who failed medical management and underwent indirect revascularization surgery, high endostatin and angiostatin levels were also associated with low angiographic neovascularization (p = 0.02). The results of this study point to the striking importance of antiangiogenesis as a determinant of ICAD patient prognosis and suggest a possible new target for therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2y6qy9s
via IFTTT

Antiangiogenesis and medical therapy failure in intracranial atherosclerosis

Abstract

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide and the one with the worst prognosis. In this study, we assessed the hypothesis that the balance of circulating pro- and antiangiogenic factors plays a role in the evolution of the disease and can be used as a potential marker for the disease course and a target for treatment. Seventy-four patients with severe ICAD were enrolled in this prospective observational study, medically optimized, and followed for 6 months. Thirteen pro- and eight antiangiogenic factors were measured in the participants' serum using a sandwich multiplex ELISA. Angiogenic profiles were calculated using principal component analysis. We tested the association between angiogenic profiles and recurring cerebrovascular events despite intensive medical therapy, disability at 6 months after enrollment, and angiographic neovascularization in patients who failed medical treatment and underwent indirect revascularization surgery. There is a strong association between a functionally antiangiogenic profile and recurrent stroke or TIA in patients with ICAD (OR = 7.2, CI 2.4–34.4). Multivariable regression analysis showed that this antiangiogenic profile was also associated with poor functional status after 6 months (p = 0.002), independent from other clinical features such as history of previous stroke, diabetes, and age. In patients who failed medical management and underwent indirect revascularization surgery, high endostatin and angiostatin levels were also associated with low angiographic neovascularization (p = 0.02). The results of this study point to the striking importance of antiangiogenesis as a determinant of ICAD patient prognosis and suggest a possible new target for therapy.

http://ift.tt/2y6qy9s

Intraoperative oliguria predicts acute kidney injury after major abdominal surgery

Abstract

Background

The threshold of intraoperative urine output below which the risk of acute kidney injury (AKI) increases is unclear. The aim of this retrospective cohort study was to investigate the relationship between intraoperative urine output during major abdominal surgery and the development of postoperative AKI and to identify an optimal threshold for predicting the differential risk of AKI.

Methods

Perioperative data were collected retrospectively on 3560 patients undergoing major abdominal surgery (liver, colorectal, gastric, pancreatic, or oesophageal resection) at Kyoto University Hospital. We evaluated the relationship between intraoperative urine output and the development of postoperative AKI as defined by recent guidelines. Logistic regression analysis was performed to adjust for patient and operative variables, and the minimum P-value approach was used to determine the threshold of intraoperative urine output that independently altered the risk of AKI.

Results

The overall incidence of AKI in the study population was 6.3%. Using the minimum P-value approach, a threshold of 0.3 ml kg⁻¹ h⁻¹ was identified, below which there was an increased risk of AKI (adjusted odds ratio, 2.65; 95% confidence interval, 1.77–3.97; P<0.001). The addition of oliguria <0.3 ml kg⁻¹ h⁻¹ to a model with conventional risk factors significantly improved risk stratification for AKI (net reclassification improvement, 0.159; 95% confidence interval, 0.049–0.270; P=0.005).

Conclusions

Among patients undergoing major abdominal surgery, intraoperative oliguria <0.3 ml kg⁻¹ h⁻¹ was significantly associated with increased risk of postoperative AKI.

http://ift.tt/2yaT5wl

Detection of PD-L1 in circulating tumor cells and white blood cells from patients with advanced non-small cell lung cancer

Abstract

Background

Expression of PD-L1 in tumor cells and tumor-infiltrating immune cells has been associated with improved efficacy to anti-PD-1/PD-L1 inhibitors in patients with advanced-stage non-small cell lung cancer (NSCLC) and emerged as potential biomarker for the selection of patients to cancer immunotherapies. We investigated the utility of circulating tumor cells (CTCs) and circulating white blood cells (WBCs) as a non-invasive method to evaluate PD-L1 status in advanced NSCLC patients.

Patients and Methods

CTCs and circulating WBCs were enriched from peripheral blood samples (ISET® platform, Rarecells) from 106 NSCLC patients. PD-L1 expression on ISET filters and matched-tumor tissue was evaluated by automated immunostaining (SP142 antibody, Ventana), and quantified in tumor cells and WBCs.

Results

CTCs were detected in 80 (75%) patients, with levels ranging from 2 to 256 CTCs/4ml, and median of 60 CTCs/4ml. Among 71 evaluable samples with matched-tissue and CTCs, 6 patients (8%) showed ≥ 1 PD-L1 positive CTCs, and 11 patients (15%) showed ≥ 1% PD-L1 positive tumor cells in tumor tissue with 93% concordance between tissue and CTCs (Sensitivity=55%; Specificity=100%). From 74 samples with matched-tissue and circulating WBCs, 40 patients (54%) showed ≥ 1% PD-L1 positive immune infiltrates in tumor tissue, and 39 patients (53%) showed ≥ 1% PD-L1 positive in circulating WBCs, with 80% concordance between blood and tissue (Sensitivity=82%; Specificity=79%).We found a trend for worse survival in patients receiving first-line cisplatin-based chemotherapy treatments, whose tumors express PD-L1 in circulating tumor or immune cells (PFS and OS), similar to the effects of PD-L1 expression in matched-patient tumors.

Conclusions

These results demonstrated that PD-L1 status in CTCs and circulating WBCs correlate with PD-L1 status in tumor tissue, revealing the potential of CTCs assessment as a non-invasive real-time biopsy to evaluate PD-L1 expression in patients with advanced-stage NSCLC.

from Cancer via ola Kala on Inoreader http://ift.tt/2hYY9hL
via IFTTT

The use of antidepressants in oncology: a review and practical tips for oncologists

Abstract

Background.

The use of psychotropic drugs, namely those with an antidepressant profile (ADs), is a mandatory part of an integrated treatment of psychiatric disorders among cancer patients. We aimed to synthetize the most relevant data emerging from published studies to provide tips about the use of ADs in oncology.

Design

A search was made of the major databases over the last 30 years (Embase/Medline (PsycLIT, PsycINFO, the Cochrane Library), including narrative reviews, systematic reviews and meta-analyses summarizing the results from observational studies and randomized clinical trials assessing effectiveness, safety profile, interactions, contraindications, and use of ADs in oncology with regard to both psychiatric (depressive spectrum, stress-related, anxiety disorders), and cancer-related symptoms (e.g. pain, hot flashes, fatigue).

Results

The weight of evidence supports the efficacy of ADs for more severe major depression in individuals with cancer and as an adjuvant treatment in cancer-related symptoms, although the methodological limitations of reported randomized controlled trials do not permit definite conclusions. Data also indicate that there should be caution in the use of ADs in cancer patients in terms of their safety profile and potential clinically significant interactions with other prescribed medications Practical recommendations that have been made for the use of ADs in cancer patients, in the context of a multimodal approach to depression treatment, have been summarized here.

Conclusions

ADs are a relatively safe and effective treatment for more severe major depression in cancer patients. However, more research is urgently needed regarding the efficacy of ADs in different cancer types and cancer settings, their interactions with anti-cancer agents, and their additive benefit when integrated with psychosocial interventions.

from Cancer via ola Kala on Inoreader http://ift.tt/2g46qjU
via IFTTT