Androgen Therapy for Acute Myeloid and Hairy Cell Leukemia

Opinion statement

The purpose of this paper is to review the preclinical and clinical rationale for androgen therapy of acute myeloid (AML) and hairy cell leukemia (HCL). A major recent positive study should renew interest in this therapy, which has been reported to be effective in these leukemias for more than 50 years. Hopefully, renewed interest in this approach, which seems promising, will lead to well-designed modern studies that will precisely define a role for androgens in these leukemias. A recent large prospective, randomized study has demonstrated enhanced survival for elderly AML patients who present with WBC counts < 30,000/μL have improved overall survival when androgens are given post-remission, and numerous case reports suggest that androgens frequently restore normal peripheral blood counts in severely pancytopenic patients with HCL. Well-designed prospective studies are needed to precisely define which patients are most likely to benefit from androgen therapy and where in the treatment plan they should be incorporated.

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Leptomeningeal Metastases

Opinion statement

Treatment options for leptomeningeal metastases are expanding with greater tolerability and efficacy than in the past. Improved knowledge of molecular subtypes of some cancers can guide in choosing more effective therapeutic options; however, physicians should be mindful that these molecular types can be different in the central nervous system compared to the rest of the body. This is particularly true in breast and lung cancer, in which some patients now can live for many months or even years after diagnosis of leptomeningeal metastases. Options for intrathecal therapies are expanding, but physicians should be mindful that this is a passive delivery system that relies on normal CSF flow, so therapies will not penetrate bulky or parenchymal disease sites, especially in the presence of abnormal CSF flow. When chemotherapeutic options are lacking or unsuccessful, focal radiosurgery which can provide symptomatic relief and proton craniospinal radiation remain effective options. Hopefully more formal studies will be conducted in the future to verify which treatments are indeed most effective for particular types of cancer.

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Androgen Therapy for Acute Myeloid and Hairy Cell Leukemia

Opinion statement

The purpose of this paper is to review the preclinical and clinical rationale for androgen therapy of acute myeloid (AML) and hairy cell leukemia (HCL). A major recent positive study should renew interest in this therapy, which has been reported to be effective in these leukemias for more than 50 years. Hopefully, renewed interest in this approach, which seems promising, will lead to well-designed modern studies that will precisely define a role for androgens in these leukemias. A recent large prospective, randomized study has demonstrated enhanced survival for elderly AML patients who present with WBC counts < 30,000/μL have improved overall survival when androgens are given post-remission, and numerous case reports suggest that androgens frequently restore normal peripheral blood counts in severely pancytopenic patients with HCL. Well-designed prospective studies are needed to precisely define which patients are most likely to benefit from androgen therapy and where in the treatment plan they should be incorporated.

http://ift.tt/2GaG1sU

Leptomeningeal Metastases

Opinion statement

Treatment options for leptomeningeal metastases are expanding with greater tolerability and efficacy than in the past. Improved knowledge of molecular subtypes of some cancers can guide in choosing more effective therapeutic options; however, physicians should be mindful that these molecular types can be different in the central nervous system compared to the rest of the body. This is particularly true in breast and lung cancer, in which some patients now can live for many months or even years after diagnosis of leptomeningeal metastases. Options for intrathecal therapies are expanding, but physicians should be mindful that this is a passive delivery system that relies on normal CSF flow, so therapies will not penetrate bulky or parenchymal disease sites, especially in the presence of abnormal CSF flow. When chemotherapeutic options are lacking or unsuccessful, focal radiosurgery which can provide symptomatic relief and proton craniospinal radiation remain effective options. Hopefully more formal studies will be conducted in the future to verify which treatments are indeed most effective for particular types of cancer.

http://ift.tt/2rxMr1J

Altered expression of HER-2 and the mismatch repair genes MLH1 and MSH2 predicts the outcome of T1 high-grade bladder cancer

Abstract

Purpose

The identification of factors predicting the outcome of stage T1 high-grade bladder cancer (BC) is a major clinical issue.

Methods

We performed immunohistochemistry to assess the role of human epidermal growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and progression of T1 high-grade BCs having undergone transurethral resection of bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus Calmette–Guerin (BCG).

Results

HER-2 overexpression was a significant predictor of disease-free survival (DFS) in the overall as well as in the two patients' population; as for progression-free survival (PFS), it was significant in the overall but not in the two patients' population. MLH1 was an independent predictor of PFS only in patients treated with BCG and MSH2 failed to predict DFS and PFS in all populations. Most importantly, the higher the number of altered markers the lowers the DFS and PFS. In multivariate Cox proportional-hazards regression analysis, the number of altered molecular markers and BCG treatment were significant predictors (p = 0.0004 and 0.0283, respectively) of DFS, whereas the number of altered molecular markers was the only significant predictor (p = 0.0054) of PFS.

Conclusions

Altered expression of the proto-oncogene HER-2 and the two molecular markers of genetic instability MLH1 and MSH2 predicted T1 high-grade BC outcome with the higher the number of altered markers the lower the DFS and PFS. These findings provide grounds for further testing them in predicting the outcome of this challenging disease.

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Altered expression of HER-2 and the mismatch repair genes MLH1 and MSH2 predicts the outcome of T1 high-grade bladder cancer

Abstract

Purpose

The identification of factors predicting the outcome of stage T1 high-grade bladder cancer (BC) is a major clinical issue.

Methods

We performed immunohistochemistry to assess the role of human epidermal growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and progression of T1 high-grade BCs having undergone transurethral resection of bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus Calmette–Guerin (BCG).

Results

HER-2 overexpression was a significant predictor of disease-free survival (DFS) in the overall as well as in the two patients' population; as for progression-free survival (PFS), it was significant in the overall but not in the two patients' population. MLH1 was an independent predictor of PFS only in patients treated with BCG and MSH2 failed to predict DFS and PFS in all populations. Most importantly, the higher the number of altered markers the lowers the DFS and PFS. In multivariate Cox proportional-hazards regression analysis, the number of altered molecular markers and BCG treatment were significant predictors (p = 0.0004 and 0.0283, respectively) of DFS, whereas the number of altered molecular markers was the only significant predictor (p = 0.0054) of PFS.

Conclusions

Altered expression of the proto-oncogene HER-2 and the two molecular markers of genetic instability MLH1 and MSH2 predicted T1 high-grade BC outcome with the higher the number of altered markers the lower the DFS and PFS. These findings provide grounds for further testing them in predicting the outcome of this challenging disease.

http://ift.tt/2DZZUlJ

Inherited thrombotic thrombocytopenic purpura mimicking immune thrombocytopenic purpura during pregnancy: a case report

Thrombotic thrombocytopenic purpura is a very rare hereditary blood deficiency disorder of ADAMTS13 (von Willebrand factor-cleaving protease) and a life-threatening thrombotic microangiopathy characterized by ...

http://ift.tt/2DvTL3u

Role of Chemotherapy in the Neoadjuvant/Adjuvant Setting for Patients With Rectal Adenocarcinoma Undergoing Chemoradiotherapy and Surgery or Radiotherapy and Surgery

Abstract

Rectal cancer has been successfully managed in the last couple of decades. In the USA, as the initial approach, neoadjuvant concurrent chemoradiation has been associated not only with decrease in tumor size and recurrence but also with higher resection rate with minimal side effects. Data support that addition of chemotherapy to radiotherapy is superior to radiotherapy alone in the neoadjuvant setting. Recent debates have addressed the question of administration of adjuvant chemotherapy following surgery. In this article, we discuss the role of chemotherapy in both the neoadjuvant and the adjuvant settings for locally advanced rectal cancer.

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Role of Chemotherapy in the Neoadjuvant/Adjuvant Setting for Patients With Rectal Adenocarcinoma Undergoing Chemoradiotherapy and Surgery or Radiotherapy and Surgery

Abstract

Rectal cancer has been successfully managed in the last couple of decades. In the USA, as the initial approach, neoadjuvant concurrent chemoradiation has been associated not only with decrease in tumor size and recurrence but also with higher resection rate with minimal side effects. Data support that addition of chemotherapy to radiotherapy is superior to radiotherapy alone in the neoadjuvant setting. Recent debates have addressed the question of administration of adjuvant chemotherapy following surgery. In this article, we discuss the role of chemotherapy in both the neoadjuvant and the adjuvant settings for locally advanced rectal cancer.

http://ift.tt/2Dtola2

Experiences of Care of Adolescents and Young Adults with Cancer in Australia

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Experiences of Care of Adolescents and Young Adults with Cancer in Australia

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Optimization of dose distributions of target volumes and organs at risk during stereotactic body radiation therapy for pancreatic cancer with dose-limiting auto-shells

To identify optimization of dose distributions of target volumes and decrease of radiation doses to normal tissues during stereotactic body radiation therapy (SBRT) for pancreatic cancer with dose-limiting aut...

http://ift.tt/2F5cj78

Modelling the immunosuppressive effect of liver SBRT by simulating the dose to circulating lymphocytes: an in-silico planning study

Tumor immune-evasion and associated failure of immunotherapy can potentially be overcome by radiotherapy, which however also has detrimental effects on tumor-infiltrating and circulating lymphocytes (CL). We t...

http://ift.tt/2DBbt4N

Children’s experiences and responses towards an intervention for psychological preparation for radiotherapy

Children can experience distress when undergoing radiotherapy as a reaction to being scared of and unfamiliar with the procedure. The aim was to evaluate children's experiences and responses towards an interve...

http://ift.tt/2F3rFJg

Comparison of the clinical efficacy between single-agent and dual-agent concurrent chemoradiotherapy in the treatment of unresectable esophageal squamous cell carcinoma: a multicenter retrospective analysis

Some Chinese patients with esophageal squamous cell carcinomaare often treated with single-agent concurrent chemoradiotherapy. However, no results have been reported from randomized controlled clinical trials ...

http://ift.tt/2DDCfd4

The Expanding World of N-MYC-Driven Tumors [Reviews]

Enhanced and deregulated expression of N-MYC, a member of the MYC family of transcription factors, drives the development of multiple tumors, including tumors of the nervous and hematologic systems and neuroendocrine tumors in other organs. This review summarizes the cell-of-origin, biological features, associated signaling pathways, and current treatment strategies for N-MYC–driven tumors. We also highlight biological differences within specific tumor types that are driven by the different MYC proteins.

Significance: N-MYC is a driver of multiple tumor types that are derived through a mechanism that involves direct differentiation within the same lineage (e.g., in the case of neuroblastoma, medulloblastoma, and acute myeloid leukemia) and is often associated with a poor prognosis. Emerging data suggest that N-MYC also drives other tumor types through a mechanism that promotes a lineage switch and that this switch may be exploited for therapeutic purposes. Cancer Discov; 8(2); 1–14. ©2018 AACR.

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Optimization of dose distributions of target volumes and organs at risk during stereotactic body radiation therapy for pancreatic cancer with dose-limiting auto-shells

To identify optimization of dose distributions of target volumes and decrease of radiation doses to normal tissues during stereotactic body radiation therapy (SBRT) for pancreatic cancer with dose-limiting aut...

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Modelling the immunosuppressive effect of liver SBRT by simulating the dose to circulating lymphocytes: an in-silico planning study

Tumor immune-evasion and associated failure of immunotherapy can potentially be overcome by radiotherapy, which however also has detrimental effects on tumor-infiltrating and circulating lymphocytes (CL). We t...

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Children’s experiences and responses towards an intervention for psychological preparation for radiotherapy

Children can experience distress when undergoing radiotherapy as a reaction to being scared of and unfamiliar with the procedure. The aim was to evaluate children's experiences and responses towards an interve...

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Comparison of the clinical efficacy between single-agent and dual-agent concurrent chemoradiotherapy in the treatment of unresectable esophageal squamous cell carcinoma: a multicenter retrospective analysis

Some Chinese patients with esophageal squamous cell carcinomaare often treated with single-agent concurrent chemoradiotherapy. However, no results have been reported from randomized controlled clinical trials ...

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Beyond Concurrent Chemoradiation: The Emerging Role of PD-1/PD-L1 Inhibitors in Stage III Lung Cancer

Concurrent chemoradiation (cCRT) with platinum-based chemotherapy is standard of care therapy for patients with Stage III unresectable non-small cell lung cancer (NSCLC). Though potentially curative, five-year overall survival has hovered around 20%, despite extensive efforts to improve outcomes with increasing doses of conformal radiation and intensification of systemic therapy with either induction or consolidation chemotherapy. PD-1/PD-L1 immune checkpoint inhibitors have demonstrated unprecedented efficacy in patients with Stage IV NSCLC.  Additionally, preclinical and early clinical evidence suggests that chemotherapy and radiation may work synergistically with anti-PD-1/PD-L1 therapy to promote anti-tumor immunity, which has led to the initiation of clinical trials testing these drugs in patients with Stage III NSCLC. A preliminary report of a randomized phase III trial, the PACIFIC trial, demonstrated an impressive increase in median progression-free survival with consolidative durvalumab, a PD-L1 inhibitor, compared to observation after cCRT. Here, we discuss the clinical and translational implications of integrating PD-1/PD-L1 inhibitors in the management of patients with unresectable Stage III NSCLC.

http://ift.tt/2Dx8IT1

Pembrolizumab plus pegylated interferon alfa-2b or ipilimumab for advanced melanoma or renal cell carcinoma: dose-finding results from the phase 1b KEYNOTE-029 study

Purpose: Pembrolizumab, ipilimumab, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase 1b KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg Q3W plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6/18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3-4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5/12 (42%) patients with melanoma and 3/10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2/14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2/3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3-4 treatment-related adverse events occurred in 10/17 (59%) patients. Responses occurred in 1/5 (20%) patients with melanoma and 2/12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population.

http://ift.tt/2n2ojz0

Glycogen phosphorylase: a novel biomarker in doxorubicin-induced cardiac injury

Extracellular vesicles (EVs) containing glycogen phosphorylase, brain/heart (PYGB) have been demonstrated as a sensitive biomarker for normal cardiac injuries for patients after chemotherapy. Oxidative stress was suggested to be the mechanism behind the chemotherapy-induced tissue damage and augmented with mitochondrial antioxidant could be an effective means of early intervention.

http://ift.tt/2DwYPor

Further investigation of the role of ACYP2 and WFS1 pharmacogenomic variants in the development of cisplatin-induced ototoxicity in testicular cancer patients

Purpose: Adverse drug reactions such as ototoxicity, which occurs in approximately one fifth of adult patients who receive cisplatin treatment, can incur large socio-economic burdens on testicular cancer patients who develop this cancer during early adulthood. Recent genome-wide association studies have identified genetic variants in ACYP2 and WFS1 that are associated with cisplatin-induced ototoxicity. We sought to explore the role of these genetic susceptibility factors to cisplatin-induced ototoxicity in testicular cancer patients. Experimental Design: Extensive clinical and demographic data were collected for 229 testicular cancer patients treated with cisplatin. Patients were genotyped for two variants, ACYP2 rs1872328 and WFS1 rs62283056, that have previously been associated with hearing loss in cisplatin-treated patients. Analyses were performed to investigate the association of these variants with ototoxicity in this cohort of adult testicular cancer patients. Results: Pharmacogenomic analyses revealed that ACYP2 rs1872328 was significantly associated with cisplatin-induced ototoxicity (P=2.83x10-3, OR[95%C]:14.7[2.6-84.2]). WFS1 rs62283056 was not significantly associated with ototoxicity caused by cisplatin (P=0.39); however, this variant was associated with hearing loss attributable to any cause (P=5.67x10-3, OR[95%CI]:3.2[1.4-7.7]). Conclusions: This study has provided the first evidence for the role of ACYP2 rs1872328 in cisplatin-induced ototoxicity in testicular cancer patients. These results support the use of this information to guide the development of strategies to prevent cisplatin-induced ototoxicity across cancers. Further, this study has highlighted the importance of phenotypic differences in replication studies and has provided further evidence for the role of WFS1 rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment.

http://ift.tt/2n2rTsZ

Safety, activity and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma

Purpose: The current management of advanced esophageal squamous cell carcinoma (ESCC) remains unsatisfactory. We investigated the safety, efficacy and biomarkers of SHR-1210, an anti-PD-1 antibody, in patients with recurrent or metastatic ESCC. Experimental Design: This study was a part of phase 1 trial in China. Patients with advanced ESCC who were refractory or intolerant to previous chemotherapy were enrolled. Eligible patients received intravenous SHR-1210 at a dose of 60 mg, with escalation to 200mg and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between candidate biomarkers (PD-L1 and somatic mutation load) and the efficacy of SHR-1210 were also explored. Results: Between May 11, 2016 and December 9, 2016, a total of 30 patients from one site in China were enrolled. Ten patients (33.3%) had an independently assessed objective response. Median progression free survival was 3.6 months (95% CI: 0-7.2). Three (10.0%) treatment-related grade 3 adverse events were reported: two (6.7%) pneumonitis and one (3.3%) increased cardiac troponin I. No grade 4 or grade 5 treatment-related adverse events were reported. The exome sequencing and analysis showed that the mutational burden and the potential mutation-associated neoantigen count were associated with better responses. An objective response was more common in patients with PD-L1-positive tumors as defined by >5% staining (7 of 15 patients) than in those with PD-L1-negative tumors (1 of 9 patients). Conclusion: In this population of ESCC patients, SHR-1210 had a manageable safety profile and promising antitumor activity.

http://ift.tt/2Dwud6j

Beyond Concurrent Chemoradiation: The Emerging Role of PD-1/PD-L1 Inhibitors in Stage III Lung Cancer

Concurrent chemoradiation (cCRT) with platinum-based chemotherapy is standard of care therapy for patients with Stage III unresectable non-small cell lung cancer (NSCLC). Though potentially curative, five-year overall survival has hovered around 20%, despite extensive efforts to improve outcomes with increasing doses of conformal radiation and intensification of systemic therapy with either induction or consolidation chemotherapy. PD-1/PD-L1 immune checkpoint inhibitors have demonstrated unprecedented efficacy in patients with Stage IV NSCLC.  Additionally, preclinical and early clinical evidence suggests that chemotherapy and radiation may work synergistically with anti-PD-1/PD-L1 therapy to promote anti-tumor immunity, which has led to the initiation of clinical trials testing these drugs in patients with Stage III NSCLC. A preliminary report of a randomized phase III trial, the PACIFIC trial, demonstrated an impressive increase in median progression-free survival with consolidative durvalumab, a PD-L1 inhibitor, compared to observation after cCRT. Here, we discuss the clinical and translational implications of integrating PD-1/PD-L1 inhibitors in the management of patients with unresectable Stage III NSCLC.

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Pembrolizumab plus pegylated interferon alfa-2b or ipilimumab for advanced melanoma or renal cell carcinoma: dose-finding results from the phase 1b KEYNOTE-029 study

Purpose: Pembrolizumab, ipilimumab, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase 1b KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg Q3W plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6/18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3-4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5/12 (42%) patients with melanoma and 3/10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2/14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2/3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3-4 treatment-related adverse events occurred in 10/17 (59%) patients. Responses occurred in 1/5 (20%) patients with melanoma and 2/12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population.

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via IFTTT

Glycogen phosphorylase: a novel biomarker in doxorubicin-induced cardiac injury

Extracellular vesicles (EVs) containing glycogen phosphorylase, brain/heart (PYGB) have been demonstrated as a sensitive biomarker for normal cardiac injuries for patients after chemotherapy. Oxidative stress was suggested to be the mechanism behind the chemotherapy-induced tissue damage and augmented with mitochondrial antioxidant could be an effective means of early intervention.

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

Further investigation of the role of ACYP2 and WFS1 pharmacogenomic variants in the development of cisplatin-induced ototoxicity in testicular cancer patients

Purpose: Adverse drug reactions such as ototoxicity, which occurs in approximately one fifth of adult patients who receive cisplatin treatment, can incur large socio-economic burdens on testicular cancer patients who develop this cancer during early adulthood. Recent genome-wide association studies have identified genetic variants in ACYP2 and WFS1 that are associated with cisplatin-induced ototoxicity. We sought to explore the role of these genetic susceptibility factors to cisplatin-induced ototoxicity in testicular cancer patients. Experimental Design: Extensive clinical and demographic data were collected for 229 testicular cancer patients treated with cisplatin. Patients were genotyped for two variants, ACYP2 rs1872328 and WFS1 rs62283056, that have previously been associated with hearing loss in cisplatin-treated patients. Analyses were performed to investigate the association of these variants with ototoxicity in this cohort of adult testicular cancer patients. Results: Pharmacogenomic analyses revealed that ACYP2 rs1872328 was significantly associated with cisplatin-induced ototoxicity (P=2.83x10-3, OR[95%C]:14.7[2.6-84.2]). WFS1 rs62283056 was not significantly associated with ototoxicity caused by cisplatin (P=0.39); however, this variant was associated with hearing loss attributable to any cause (P=5.67x10-3, OR[95%CI]:3.2[1.4-7.7]). Conclusions: This study has provided the first evidence for the role of ACYP2 rs1872328 in cisplatin-induced ototoxicity in testicular cancer patients. These results support the use of this information to guide the development of strategies to prevent cisplatin-induced ototoxicity across cancers. Further, this study has highlighted the importance of phenotypic differences in replication studies and has provided further evidence for the role of WFS1 rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/2n2rTsZ
via IFTTT

Safety, activity and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma

Purpose: The current management of advanced esophageal squamous cell carcinoma (ESCC) remains unsatisfactory. We investigated the safety, efficacy and biomarkers of SHR-1210, an anti-PD-1 antibody, in patients with recurrent or metastatic ESCC. Experimental Design: This study was a part of phase 1 trial in China. Patients with advanced ESCC who were refractory or intolerant to previous chemotherapy were enrolled. Eligible patients received intravenous SHR-1210 at a dose of 60 mg, with escalation to 200mg and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between candidate biomarkers (PD-L1 and somatic mutation load) and the efficacy of SHR-1210 were also explored. Results: Between May 11, 2016 and December 9, 2016, a total of 30 patients from one site in China were enrolled. Ten patients (33.3%) had an independently assessed objective response. Median progression free survival was 3.6 months (95% CI: 0-7.2). Three (10.0%) treatment-related grade 3 adverse events were reported: two (6.7%) pneumonitis and one (3.3%) increased cardiac troponin I. No grade 4 or grade 5 treatment-related adverse events were reported. The exome sequencing and analysis showed that the mutational burden and the potential mutation-associated neoantigen count were associated with better responses. An objective response was more common in patients with PD-L1-positive tumors as defined by >5% staining (7 of 15 patients) than in those with PD-L1-negative tumors (1 of 9 patients). Conclusion: In this population of ESCC patients, SHR-1210 had a manageable safety profile and promising antitumor activity.

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Selective mTORC2 inhibitor therapeutically blocks breast cancer cell growth and survival

Small molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date. Here we report the engineering of a nanoparticle-based RNAi therapeutic that can effectively silence the mTORC2 obligate cofactor Rictor. Nanoparticle-based Rictor ablation in HER2-amplified breast tumors was achieved following intra-tumoral and intra-venous delivery, decreasing Akt phosphorylation and increasing tumor cell killing. Selective mTORC2 inhibition in vivo, combined with the HER2 inhibitor lapatinib, decreased the growth of HER2-amplified breast cancers to a greater extent than either agent alone, suggesting that mTORC2 promotes lapatinib resistance but is overcome by mTORC2 inhibition. Importantly, selective mTORC2 inhibition was effective in a TNBC model, decreasing Akt phosphorylation and tumor growth, consistent with our findings that RICTOR mRNA correlates with worse outcome in patients with basal-like TNBC. Together, our results offer preclinical validation of a novel RNAi delivery platform for therapeutic gene ablation in breast cancer, and they show that mTORC2-selective targeting is feasible and efficacious in this disease setting.

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Small molecule activators of protein phosphatase 2A for the treatment of castration-resistant prostate cancer.

Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that is more difficult to treat nearly always occurs due to aberrant re-activation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth inhibitory effects of re-engineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable to enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment.

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2-hydroxyglutarate-mediated autophagy of the endoplasmic reticulum leads to an unusual downregulation of phospholipid biosynthesis in mutant IDH1 gliomas

Tumor metabolism is reprogrammed to meet the demands of proliferating cancer cells. In particular, cancer cells upregulate synthesis of the membrane phospholipids phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdE) in order to allow for rapid membrane turnover. Nonetheless, we show here that, in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas, which produce the oncometabolite 2-hydroxyglutarate (2-HG), PtdCho and PtdE biosynthesis is downregulated and results in lower levels of both phospholipids when compared to wild-type IDH1 cells. 2-HG inhibited collagen-4-prolyl hydroxylase activity, leading to accumulation of misfolded procollagen-IV in the endoplasmic reticulum (ER) of both genetically engineered and patient-derived IDHmut glioma models. The resulting ER stress triggered increased expression of FAM134b, which mediated autophagic degradation of the ER (ER-phagy) and a reduction in ER area. Because the ER is the site of phospholipid synthesis, ER-phagy led to reduced PtdCho and PtdE biosynthesis. Inhibition of ER-phagy via pharmacological or molecular approaches restored phospholipid biosynthesis in IDHmut glioma cells, triggered apoptotic cell death, inhibited tumor growth and prolonged the survival of orthotopic IDHmut glioma-bearing mice, pointing to a potential therapeutic opportunity. Glioma patient biopsies also exhibited increased ER-phagy and downregulation of PtdCho and PtdE levels in IDHmut samples compared to wild-type, clinically validating our observations. Collectively, this study provides detailed and clinically-relevant insights into the functional link between oncometabolite-driven ER-phagy and phospholipid biosynthesis in IDHmut gliomas.

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Selective mTORC2 inhibitor therapeutically blocks breast cancer cell growth and survival

Small molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date. Here we report the engineering of a nanoparticle-based RNAi therapeutic that can effectively silence the mTORC2 obligate cofactor Rictor. Nanoparticle-based Rictor ablation in HER2-amplified breast tumors was achieved following intra-tumoral and intra-venous delivery, decreasing Akt phosphorylation and increasing tumor cell killing. Selective mTORC2 inhibition in vivo, combined with the HER2 inhibitor lapatinib, decreased the growth of HER2-amplified breast cancers to a greater extent than either agent alone, suggesting that mTORC2 promotes lapatinib resistance but is overcome by mTORC2 inhibition. Importantly, selective mTORC2 inhibition was effective in a TNBC model, decreasing Akt phosphorylation and tumor growth, consistent with our findings that RICTOR mRNA correlates with worse outcome in patients with basal-like TNBC. Together, our results offer preclinical validation of a novel RNAi delivery platform for therapeutic gene ablation in breast cancer, and they show that mTORC2-selective targeting is feasible and efficacious in this disease setting.

http://ift.tt/2DsgOZb

Small molecule activators of protein phosphatase 2A for the treatment of castration-resistant prostate cancer.

Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that is more difficult to treat nearly always occurs due to aberrant re-activation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth inhibitory effects of re-engineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable to enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment.

http://ift.tt/2DYTEuk

2-hydroxyglutarate-mediated autophagy of the endoplasmic reticulum leads to an unusual downregulation of phospholipid biosynthesis in mutant IDH1 gliomas

Tumor metabolism is reprogrammed to meet the demands of proliferating cancer cells. In particular, cancer cells upregulate synthesis of the membrane phospholipids phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdE) in order to allow for rapid membrane turnover. Nonetheless, we show here that, in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas, which produce the oncometabolite 2-hydroxyglutarate (2-HG), PtdCho and PtdE biosynthesis is downregulated and results in lower levels of both phospholipids when compared to wild-type IDH1 cells. 2-HG inhibited collagen-4-prolyl hydroxylase activity, leading to accumulation of misfolded procollagen-IV in the endoplasmic reticulum (ER) of both genetically engineered and patient-derived IDHmut glioma models. The resulting ER stress triggered increased expression of FAM134b, which mediated autophagic degradation of the ER (ER-phagy) and a reduction in ER area. Because the ER is the site of phospholipid synthesis, ER-phagy led to reduced PtdCho and PtdE biosynthesis. Inhibition of ER-phagy via pharmacological or molecular approaches restored phospholipid biosynthesis in IDHmut glioma cells, triggered apoptotic cell death, inhibited tumor growth and prolonged the survival of orthotopic IDHmut glioma-bearing mice, pointing to a potential therapeutic opportunity. Glioma patient biopsies also exhibited increased ER-phagy and downregulation of PtdCho and PtdE levels in IDHmut samples compared to wild-type, clinically validating our observations. Collectively, this study provides detailed and clinically-relevant insights into the functional link between oncometabolite-driven ER-phagy and phospholipid biosynthesis in IDHmut gliomas.

http://ift.tt/2DroE58

Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Abstract

Early preclinical evidence provided the rationale for programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of cancer immunotherapy given that activation of the PD-1/PD-L1 axis putatively served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity. Early-phase studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved agents of this class is rapidly enlarging with indications for treatment spanning across a spectrum of malignancies. The purpose of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy to date. In particular, we focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and treatment beyond progression, immune-related toxicities, and clinical trial design are key concepts in need of further consideration to optimize the anticancer potential of this class of immunotherapy.

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Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Abstract

Early preclinical evidence provided the rationale for programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of cancer immunotherapy given that activation of the PD-1/PD-L1 axis putatively served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity. Early-phase studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved agents of this class is rapidly enlarging with indications for treatment spanning across a spectrum of malignancies. The purpose of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy to date. In particular, we focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and treatment beyond progression, immune-related toxicities, and clinical trial design are key concepts in need of further consideration to optimize the anticancer potential of this class of immunotherapy.

http://ift.tt/2rvRsbg

Preoperative imaging evaluation of pancreatic pathologies for the objective prediction of pancreatic fistula after pancreaticoduodenectomy

Abstract

In performing pancreaticoduodenectomy (PD) or when conducting clinical trials involving PD procedure, a universal platform for predicting the risk of postoperative pancreatic fistula (POPF) is indispensable. In this article, the most significant imaging studies that focused on the objective preoperative assessment of pancreatic pathologies in association with the occurrence of POPF after PD were reviewed. Several recently developed imaging modalities can objectively predict the occurrence of POPF after PD by assessing the elasticity, fibrosis, and fatty infiltration of the pancreas. These valuable imaging modalities include: (1) acoustic radiation force impulse ultrasound (US) electrography which provides information about the elastic properties of the pancreas; (2) contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) with/without contrast-enhancement which reflect the histological degree of pancreatic fibrosis; and (3) multi-detector row CT and/or MRI which reflects the microscopic fatty infiltration of the pancreas. The precise and objective preoperative risk assessment of POPF enables surgeons to customize appropriate management strategies for individual patients undergoing PD. This would be also beneficial for stratifying patients for enrolment in relevant studies that involve pancreatic head resection, as objective criteria could be set for the definitive evaluation of collected data related to surgical outcomes across different institutions and surgeons.

http://ift.tt/2G7bdsI

Preoperative imaging evaluation of pancreatic pathologies for the objective prediction of pancreatic fistula after pancreaticoduodenectomy

Abstract

In performing pancreaticoduodenectomy (PD) or when conducting clinical trials involving PD procedure, a universal platform for predicting the risk of postoperative pancreatic fistula (POPF) is indispensable. In this article, the most significant imaging studies that focused on the objective preoperative assessment of pancreatic pathologies in association with the occurrence of POPF after PD were reviewed. Several recently developed imaging modalities can objectively predict the occurrence of POPF after PD by assessing the elasticity, fibrosis, and fatty infiltration of the pancreas. These valuable imaging modalities include: (1) acoustic radiation force impulse ultrasound (US) electrography which provides information about the elastic properties of the pancreas; (2) contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) with/without contrast-enhancement which reflect the histological degree of pancreatic fibrosis; and (3) multi-detector row CT and/or MRI which reflects the microscopic fatty infiltration of the pancreas. The precise and objective preoperative risk assessment of POPF enables surgeons to customize appropriate management strategies for individual patients undergoing PD. This would be also beneficial for stratifying patients for enrolment in relevant studies that involve pancreatic head resection, as objective criteria could be set for the definitive evaluation of collected data related to surgical outcomes across different institutions and surgeons.

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Immunogenomics: A Negative Prostate Cancer Outcome Associated with TcR-γ/δ Recombinations

Abstract

We developed a scripted algorithm, based on previous, earlier editions of the algorithm, to mine prostate cancer exome files for T-cell receptor (TcR) recombination reads: Reads representing TcR gene recombinations were identified in 497 prostate cancer exome files from the cancer genome atlas (TCGA). As has been reported for melanoma, co-detection of productive TcR-α and TcR-β recombination reads correlated with an RNA expression signature representing T-cell exhaustion, particularly with high RNA levels for PD-1 and PD-L1, in comparison to several different control sets of samples. Co-detection of TcR-α and TcR-β recombination reads also correlated with high level expression of genes representing antigen presenting functions, further supporting the conclusion that co-detection of TcR-α and TcR-β recombination reads represents an immunologically relevant microenvironment. Finally, detection of unproductive TcR-δ recombinations, and unproductive and productive TcR-γ recombinations, strongly correlated with, and may represent a convenient biomarker for a poor clinical outcome. These results underscore the value of the genomics-based assessment of unproductive TcR recombinations and raise questions about the impact of tumor microenvironment lymphocytes in the absence of antigenicity.

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Immunogenomics: A Negative Prostate Cancer Outcome Associated with TcR-γ/δ Recombinations

Abstract

We developed a scripted algorithm, based on previous, earlier editions of the algorithm, to mine prostate cancer exome files for T-cell receptor (TcR) recombination reads: Reads representing TcR gene recombinations were identified in 497 prostate cancer exome files from the cancer genome atlas (TCGA). As has been reported for melanoma, co-detection of productive TcR-α and TcR-β recombination reads correlated with an RNA expression signature representing T-cell exhaustion, particularly with high RNA levels for PD-1 and PD-L1, in comparison to several different control sets of samples. Co-detection of TcR-α and TcR-β recombination reads also correlated with high level expression of genes representing antigen presenting functions, further supporting the conclusion that co-detection of TcR-α and TcR-β recombination reads represents an immunologically relevant microenvironment. Finally, detection of unproductive TcR-δ recombinations, and unproductive and productive TcR-γ recombinations, strongly correlated with, and may represent a convenient biomarker for a poor clinical outcome. These results underscore the value of the genomics-based assessment of unproductive TcR recombinations and raise questions about the impact of tumor microenvironment lymphocytes in the absence of antigenicity.

http://ift.tt/2mXKKoS

Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma

We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize th...

http://ift.tt/2DvKKYb

The 150 most important questions in cancer research and clinical oncology series: questions 86–93

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which spark diverse thoughts, interesting communications, and potenti...

http://ift.tt/2n0ypQY

Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma

We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize th...

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The 150 most important questions in cancer research and clinical oncology series: questions 86–93

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which spark diverse thoughts, interesting communications, and potenti...

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Optimized thoracoport design for the thoracoscopic procedure during minimally invasive esophagectomy

Minimally invasive esophagectomy has several benefits as an effective alternative treatment for esophageal cancer. The three-phase esophageal resection may be the most popular approach to esophagectomy. Numerous thoracoport designs are available for the thoracoscopic procedure. The present study aims to contribute a distinctive three-port technique that is designed to minimize surgical trauma and facilitate operation during the thoracoscopic procedure. In this paper, we describe and demonstrate the details of the port design and each operation step. Based on our practical experience, the rational combination of the port design and instrument usage of the three-port technique makes the thorascopic procedure more convenient.

http://ift.tt/2DpVweE

Comparison of long-term clinical outcomes among different vascularized lymph node transfers: 6-year experience of a single center's approach to the treatment of lymphedema

http://ift.tt/2E180KU

Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S-1 adjuvant chemotherapy

Background and Objectives

Limited information exists regarding beneficial effects of Helicobacter pylori. To examine the effect in advanced gastric cancer, we compared survival for patients treated with surgery-only or adjuvant chemotherapy on the basis of H. pylori infection status.

Methods

A cohort of 491 patients who underwent R0 resection for locally advanced gastric cancer between 2000 and 2009 at 12 institutions in northern Japan was included. H. pylori infection status, was assessed from paraffin-embedded formalin-fixed samples. Overall survival (OS) and disease-free survival (DFS) in surgery-only (Surgery) and adjuvant chemotherapy (S-1) groups were analyzed. A propensity score matching was employed to correct for confounding factors by indication.

Results

H. pylori infection was positive in 175 patients and negative in 316 patients. H. pylori-positive patients showed significantly better survival than H. pylori-negative patients in both OS (hazard ratio [HR] 0.593, 95% confidence interval [CI] 0.417-0.843; P = 0.003]) and DFS (HR 0.679, 95%CI 0.492-0.937; P = 0.018). Propensity score matching further confirmed that S-1 was virtually only effective when tumors were H. pylori-positive.

Conclusions

The favorable outcome of H. pylori-positive patients implies that the host immune system is modulated by H. pylori enhancing the chemotherapeutic efficacy.

http://ift.tt/2Dqcdqe

C-reactive protein as a marker of the surgical stress reduction within an ERAS protocol (Enhanced Recovery After Surgery) in colorectal surgery: A prospective cohort study

Background

The aim of this study is to evaluate the effectiveness of an Enhanced Recovery After Surgery Protocol (ERAS) in relation to reduce the Systemic Inflammatory Response (SIR) to surgery using C-reactive protein (CRP) in the first (POD1), second (POD2) and third (POD3) postoperative day.

Methods

We enrolled 121 patients (ERAS group) that underwent elective colorectal surgery with ERAS, and compared them with 135 patients (preERAS group) that had undergone surgery prior to the implementation. We made a univariate analysis to compare the CRP values in POD1, POD2, and POD3 between preERAS/ERAS group, laparoscopic/open surgery and the presence or not of Clavien Dindo complications. Multivariable lineal regression was used to assess if the ERAS had a decreasing effect on the CRP in POD1, POD2, and POD3, and was adjusted by age, male sex, use of laparoscopy, and complications.

Results

The presence of complications was independently associated with an increase in CRP values ​​in POD1, POD2, and POD3. Laparoscopy in POD1 and POD2, and ERAS in POD2 was independently associated with a decrease in CRP values.

Conclusion

The analysis shows an increase in SIR measured as a CRP value in those patients that had complications. The SIR decreased with laparoscopy in POD1 and POD2 and with ERAS in POD2.

http://ift.tt/2DpWojw

Cancers, Vol. 10, Pages 27: Analysis of Site-Specific Methylation of Tumor-Related Genes in Head and Neck Cancer: Potential Utility as Biomarkers for Prognosis

Cancers, Vol. 10, Pages 27: Analysis of Site-Specific Methylation of Tumor-Related Genes in Head and Neck Cancer: Potential Utility as Biomarkers for Prognosis

Cancers doi: 10.3390/cancers10010027

Authors: Kiyoshi Misawa Daiki Mochizuki Atsushi Imai Masato Mima Yuki Misawa Hiroyuki Mineta

Clarifying the epigenetic regulation of tumor-related genes (TRGs) can provide insights into the mechanisms of tumorigenesis and the risk for disease recurrence in HPV-negative head and neck cancers, originating in the hypopharynx, larynx, and oral cavity. We analyzed the methylation status of the promoters of 30 TRGs in 178 HPV-negative head and neck cancer patients using a quantitative methylation-specific PCR. Promoter methylation was correlated with various clinical characteristics and patient survival. The mean number of methylated TRGs was 14.2 (range, 2–25). In the multivariate Cox proportional hazards analysis, the methylation of COL1A2 and VEGFR1 was associated with poor survival for hypopharyngeal cancer, with hazard ratios: 3.19; p = 0.009 and 3.07; p = 0.014, respectively. The methylation of p16 and COL1A2 were independent prognostic factors for poor survival in laryngeal cancer (hazard ratio: 4.55; p = 0.013 and 3.12; p = 0.035, respectively). In patients with oral cancer, the methylation of TAC1 and SSTR1 best correlated with poor survival (hazard ratio: 4.29; p = 0.005 and 5.38; p = 0.029, respectively). Our findings suggest that methylation status of TRGs could serve as important site-specific biomarkers for prediction of clinical outcomes in patients with HPV-negative head and neck cancer.

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Cancers, Vol. 10, Pages 25: Localization Microscopy Analyses of MRE11 Clusters in 3D-Conserved Cell Nuclei of Different Cell Lines

Cancers, Vol. 10, Pages 25: Localization Microscopy Analyses of MRE11 Clusters in 3D-Conserved Cell Nuclei of Different Cell Lines

Cancers doi: 10.3390/cancers10010025

Authors: Marion Eryilmaz Eberhard Schmitt Matthias Krufczik Franziska Theda Jin-Ho Lee Christoph Cremer Felix Bestvater Wladimir Schaufler Michael Hausmann Georg Hildenbrand

In radiation biophysics, it is a subject of nowadays research to investigate DNA strand break repair in detail after damage induction by ionizing radiation. It is a subject of debate as to what makes up the cell's decision to use a certain repair pathway and how the repair machinery recruited in repair foci is spatially and temporarily organized. Single-molecule localization microscopy (SMLM) allows super-resolution analysis by precise localization of single fluorescent molecule tags, resulting in nuclear structure analysis with a spatial resolution in the 10 nm regime. Here, we used SMLM to study MRE11 foci. MRE11 is one of three proteins involved in the MRN-complex (MRE11-RAD50-NBS1 complex), a prominent DNA strand resection and broken end bridging component involved in homologous recombination repair (HRR) and alternative non-homologous end joining (a-NHEJ). We analyzed the spatial arrangements of antibody-labelled MRE11 proteins in the nuclei of a breast cancer and a skin fibroblast cell line along a time-course of repair (up to 48 h) after irradiation with a dose of 2 Gy. Different kinetics for cluster formation and relaxation were determined. Changes in the internal nano-scaled structure of the clusters were quantified and compared between the two cell types. The results indicate a cell type-dependent DNA damage response concerning MRE11 recruitment and cluster formation. The MRE11 data were compared to H2AX phosphorylation detected by γH2AX molecule distribution. These data suggested modulations of MRE11 signal frequencies that were not directly correlated to DNA damage induction. The application of SMLM in radiation biophysics offers new possibilities to investigate spatial foci organization after DNA damaging and during subsequent repair.

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Cancers, Vol. 10, Pages 27: Analysis of Site-Specific Methylation of Tumor-Related Genes in Head and Neck Cancer: Potential Utility as Biomarkers for Prognosis

Cancers, Vol. 10, Pages 27: Analysis of Site-Specific Methylation of Tumor-Related Genes in Head and Neck Cancer: Potential Utility as Biomarkers for Prognosis

Cancers doi: 10.3390/cancers10010027

Authors: Kiyoshi Misawa Daiki Mochizuki Atsushi Imai Masato Mima Yuki Misawa Hiroyuki Mineta

Clarifying the epigenetic regulation of tumor-related genes (TRGs) can provide insights into the mechanisms of tumorigenesis and the risk for disease recurrence in HPV-negative head and neck cancers, originating in the hypopharynx, larynx, and oral cavity. We analyzed the methylation status of the promoters of 30 TRGs in 178 HPV-negative head and neck cancer patients using a quantitative methylation-specific PCR. Promoter methylation was correlated with various clinical characteristics and patient survival. The mean number of methylated TRGs was 14.2 (range, 2–25). In the multivariate Cox proportional hazards analysis, the methylation of COL1A2 and VEGFR1 was associated with poor survival for hypopharyngeal cancer, with hazard ratios: 3.19; p = 0.009 and 3.07; p = 0.014, respectively. The methylation of p16 and COL1A2 were independent prognostic factors for poor survival in laryngeal cancer (hazard ratio: 4.55; p = 0.013 and 3.12; p = 0.035, respectively). In patients with oral cancer, the methylation of TAC1 and SSTR1 best correlated with poor survival (hazard ratio: 4.29; p = 0.005 and 5.38; p = 0.029, respectively). Our findings suggest that methylation status of TRGs could serve as important site-specific biomarkers for prediction of clinical outcomes in patients with HPV-negative head and neck cancer.

http://ift.tt/2DBGh5K

Cancers, Vol. 10, Pages 25: Localization Microscopy Analyses of MRE11 Clusters in 3D-Conserved Cell Nuclei of Different Cell Lines

Cancers, Vol. 10, Pages 25: Localization Microscopy Analyses of MRE11 Clusters in 3D-Conserved Cell Nuclei of Different Cell Lines

Cancers doi: 10.3390/cancers10010025

Authors: Marion Eryilmaz Eberhard Schmitt Matthias Krufczik Franziska Theda Jin-Ho Lee Christoph Cremer Felix Bestvater Wladimir Schaufler Michael Hausmann Georg Hildenbrand

In radiation biophysics, it is a subject of nowadays research to investigate DNA strand break repair in detail after damage induction by ionizing radiation. It is a subject of debate as to what makes up the cell's decision to use a certain repair pathway and how the repair machinery recruited in repair foci is spatially and temporarily organized. Single-molecule localization microscopy (SMLM) allows super-resolution analysis by precise localization of single fluorescent molecule tags, resulting in nuclear structure analysis with a spatial resolution in the 10 nm regime. Here, we used SMLM to study MRE11 foci. MRE11 is one of three proteins involved in the MRN-complex (MRE11-RAD50-NBS1 complex), a prominent DNA strand resection and broken end bridging component involved in homologous recombination repair (HRR) and alternative non-homologous end joining (a-NHEJ). We analyzed the spatial arrangements of antibody-labelled MRE11 proteins in the nuclei of a breast cancer and a skin fibroblast cell line along a time-course of repair (up to 48 h) after irradiation with a dose of 2 Gy. Different kinetics for cluster formation and relaxation were determined. Changes in the internal nano-scaled structure of the clusters were quantified and compared between the two cell types. The results indicate a cell type-dependent DNA damage response concerning MRE11 recruitment and cluster formation. The MRE11 data were compared to H2AX phosphorylation detected by γH2AX molecule distribution. These data suggested modulations of MRE11 signal frequencies that were not directly correlated to DNA damage induction. The application of SMLM in radiation biophysics offers new possibilities to investigate spatial foci organization after DNA damaging and during subsequent repair.

http://ift.tt/2DAdChe

Optimized thoracoport design for the thoracoscopic procedure during minimally invasive esophagectomy

Minimally invasive esophagectomy has several benefits as an effective alternative treatment for esophageal cancer. The three-phase esophageal resection may be the most popular approach to esophagectomy. Numerous thoracoport designs are available for the thoracoscopic procedure. The present study aims to contribute a distinctive three-port technique that is designed to minimize surgical trauma and facilitate operation during the thoracoscopic procedure. In this paper, we describe and demonstrate the details of the port design and each operation step. Based on our practical experience, the rational combination of the port design and instrument usage of the three-port technique makes the thorascopic procedure more convenient.

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Predictors for 30-day readmission after pulmonary resection for lung cancer

Background: The purpose of this study was to assess the rate, cause, and factors associated with readmissions following pulmonary resection for lung cancer and their relationship with 90-day mortality.

Methods: A prospective cohort study was conducted of 379 patients who underwent surgery for lung cancer at the university hospitals Granada, Spain between 2012 and 2016.

Results: The rate of readmissions within 30 postoperative days was 6.2%. The most common reason for readmission was subcutaneous emphysema (21.7%), pneumonia (13%), and pleural empyema (8.5%). A higher probability of requiring urgent readmission was associated with a higher Charlson index (OR 2.0,95% confidence interval 1.50-2.67, P = 0.001); peripheral arterial vasculopathy (OR 4.8, 95%CI 1.27-18.85, P = 0.021); a history of stroke (OR 8.2, 95%CI 1.08-62.37, P = 0.04); postoperative atelectasis (OR 4.7, 95%CI 1.21-18.64, P = 0.026); and air leaks (OR 12.6, 95%CI 4.10-38.91, P = 0.001).The prediction multivariable model for readmission represents an area under the curve (ROC) of 0.90. Mortality at 90 postoperative days in the group of readmitted patients was 13% versus 1.5 for the group of patients who did not require readmission (P < 0.001).

Conclusions: The factors predictive for readmission can help design individualized outpatient follow-up plans and programs for the reduction of readmissions.

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Comparison of long-term clinical outcomes among different vascularized lymph node transfers: 6-year experience of a single center's approach to the treatment of lymphedema

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Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S-1 adjuvant chemotherapy

Background and Objectives

Limited information exists regarding beneficial effects of Helicobacter pylori. To examine the effect in advanced gastric cancer, we compared survival for patients treated with surgery-only or adjuvant chemotherapy on the basis of H. pylori infection status.

Methods

A cohort of 491 patients who underwent R0 resection for locally advanced gastric cancer between 2000 and 2009 at 12 institutions in northern Japan was included. H. pylori infection status, was assessed from paraffin-embedded formalin-fixed samples. Overall survival (OS) and disease-free survival (DFS) in surgery-only (Surgery) and adjuvant chemotherapy (S-1) groups were analyzed. A propensity score matching was employed to correct for confounding factors by indication.

Results

H. pylori infection was positive in 175 patients and negative in 316 patients. H. pylori-positive patients showed significantly better survival than H. pylori-negative patients in both OS (hazard ratio [HR] 0.593, 95% confidence interval [CI] 0.417-0.843; P = 0.003]) and DFS (HR 0.679, 95%CI 0.492-0.937; P = 0.018). Propensity score matching further confirmed that S-1 was virtually only effective when tumors were H. pylori-positive.

Conclusions

The favorable outcome of H. pylori-positive patients implies that the host immune system is modulated by H. pylori enhancing the chemotherapeutic efficacy.

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Preoperative coagulation abnormalities as a risk factor for adverse events after pancreas surgery

Objective

To determine whether elevated INR or PTT values predicted 30-day postoperative adverse events following elective pancreatectomy.

Methods

The American college of surgeons national surgical quality improvement program (ACS-NSQIP) database was used to identify 14 747 patients undergoing elective pancreatectomy from 2005 to 2013. The association of elevated INR or PTT with 30-day postoperative outcomes of morbidity and mortality was examined using multivariate logistic regression analysis.

Results

The overall 30-day mortality rate increased from 1.8% to 3.3% from the control to the high INR or PTT group (P = <0.001). An elevated INR/PTT increased the odds for bleeding requiring transfusion, superficial SSI, sepsis, unplanned intubation or >48 h on a ventilator, cardiac arrest or myocardial infarction, acute renal failure, return to the OR, and prolonged length of stay. With the exception of superficial SSI, multivariate logistic regression models revealed that these same events remained statistically significant after controlling for potential confounders.

Conclusion

Prolonged bleeding times (high INR/PTT) is associated with increased mortality and adverse outcomes after pancreas surgery. A patient's coagulation profile may serve as a risk stratification tool to identify higher risk patients that require more resources.

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C-reactive protein as a marker of the surgical stress reduction within an ERAS protocol (Enhanced Recovery After Surgery) in colorectal surgery: A prospective cohort study

Background

The aim of this study is to evaluate the effectiveness of an Enhanced Recovery After Surgery Protocol (ERAS) in relation to reduce the Systemic Inflammatory Response (SIR) to surgery using C-reactive protein (CRP) in the first (POD1), second (POD2) and third (POD3) postoperative day.

Methods

We enrolled 121 patients (ERAS group) that underwent elective colorectal surgery with ERAS, and compared them with 135 patients (preERAS group) that had undergone surgery prior to the implementation. We made a univariate analysis to compare the CRP values in POD1, POD2, and POD3 between preERAS/ERAS group, laparoscopic/open surgery and the presence or not of Clavien Dindo complications. Multivariable lineal regression was used to assess if the ERAS had a decreasing effect on the CRP in POD1, POD2, and POD3, and was adjusted by age, male sex, use of laparoscopy, and complications.

Results

The presence of complications was independently associated with an increase in CRP values ​​in POD1, POD2, and POD3. Laparoscopy in POD1 and POD2, and ERAS in POD2 was independently associated with a decrease in CRP values.

Conclusion

The analysis shows an increase in SIR measured as a CRP value in those patients that had complications. The SIR decreased with laparoscopy in POD1 and POD2 and with ERAS in POD2.

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Primary liver sarcomas in the modern era: Resection or transplantation?

Background and Objectives

Primary liver sarcomas (PLS) are rare. Published series are limited by small numbers of patients.

Methods

We reviewed the National Cancer Database (2004-2014) for patients who underwent surgical resection of PLS.

Results

Of 237 patients identified, the majority were female (60.8%), with median age of 52 years. Histologies were: epithelioid hemangioendothelioma (n = 67), angiosarcoma (n = 64), leiomyosarcoma (n = 33), embryonal rhabdomyosarcoma (n = 31), carcinosarcoma (n = 16), giant cell sarcoma (n = 14), spindle cell sarcoma (n = 12). Ninety-seven (40.9%) patients underwent lobectomies or extended lobectomies, 41 patients (17.3%) underwent transplantation. Surgical margins were negative in 82.9%. Tumors were well differentiated in 11.3%. Histology type correlated with outcome with the best prognosis for epithelioid hemangioendothelioma (OS: not reached, similar for resection and transplantation) and the worst for angiosarcoma (OS:16.6 mo with resection; 6 mo with transplantation; P = 0.04). Resections with microscopically negative margins were associated with improved survival (58.7 vs 11.3 mo for positive margins; P < 0.001). Chemotherapy and radiation therapy were used in a minority of patients (32.9% and 4.3% respectively) with no improvement in outcomes.

Conclusions

Both hepatic resection and liver transplantation can be associated with long term survival for selected primary liver sarcomas such as epitheliod hemangioendotheliomas. Histology type and the ability to resect the tumor with negative margins correlate with outcomes and the decision to operate should be carefully weighed for subtypes with particularly dismal prognosis such as angiosarcomas.

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Staged surgical treatment of extremity lymphedema with dual gastroepiploic vascularized lymph node transfers followed by suction-assisted lipectomy—A prospective study

Background

Both physiologic and excisional procedures have been described for the treatment of lymphedema. However, there exist few reports that combine these procedures. The objective of this study was to evaluate the effectiveness of combining vascularized lymph node transfer (VLNT) with suction-assisted lipectomy (SAL) in a staged manner for the treatment of extremity lymphedema.

Methods

Patients with unilateral late stage II lymphedema (International Society of Lymphology), who consented to staged surgical treatment, were evaluated prospectively. Between 2014 and 2015, 12 female patients with upper (n = 6) or lower (n = 6) extremity lymphedema completed the treatment protocol. Primary outcomes evaluated included limb size and number of infectious episodes. In addition, compression garment usage was analyzed.

Results

The overall circumference reduction rate was on average 37.9% after VLNT and increased to 96.4% after SAL. While all patients had experienced at least one infectious episode prior to surgical treatment, only one patient did so after VLNT and none after SAL. All patients were able to eventually discontinue compression therapy.

Conclusion

VLNT followed by SAL can allow patients with late Stage II lymphedema achieve near normal limb size and eradication of infectious episodes. At follow-up, these desirable outcomes were maintained well after discontinuation of compression therapy.

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Optimized thoracoport design for the thoracoscopic procedure during minimally invasive esophagectomy

Minimally invasive esophagectomy has several benefits as an effective alternative treatment for esophageal cancer. The three-phase esophageal resection may be the most popular approach to esophagectomy. Numerous thoracoport designs are available for the thoracoscopic procedure. The present study aims to contribute a distinctive three-port technique that is designed to minimize surgical trauma and facilitate operation during the thoracoscopic procedure. In this paper, we describe and demonstrate the details of the port design and each operation step. Based on our practical experience, the rational combination of the port design and instrument usage of the three-port technique makes the thorascopic procedure more convenient.

http://ift.tt/2DpVweE

Alternative vascular constructs of lymph node flap transfer

Vascularized lymph node transfer is a quite innovative physiological surgical procedure for the lymphedema treatment. Although is gaining more popularity due to its promising results, there are some concerns regarding difficult to harvest it and the potential risk of iatrogenic lymphedema. Here, we present alternative vascular constructs of lymph node flap for the treatment of lymphedema, which provide the benefits of a technically easier dissection and physiological reconstruction of the damaged lymphatics. Furthermore, we introduce a classification based on the flap vascular supply including six types of flaps and we provide the details of the surgical technique.

http://ift.tt/2E0VL0A

Predictors for 30-day readmission after pulmonary resection for lung cancer

Background: The purpose of this study was to assess the rate, cause, and factors associated with readmissions following pulmonary resection for lung cancer and their relationship with 90-day mortality.

Methods: A prospective cohort study was conducted of 379 patients who underwent surgery for lung cancer at the university hospitals Granada, Spain between 2012 and 2016.

Results: The rate of readmissions within 30 postoperative days was 6.2%. The most common reason for readmission was subcutaneous emphysema (21.7%), pneumonia (13%), and pleural empyema (8.5%). A higher probability of requiring urgent readmission was associated with a higher Charlson index (OR 2.0,95% confidence interval 1.50-2.67, P = 0.001); peripheral arterial vasculopathy (OR 4.8, 95%CI 1.27-18.85, P = 0.021); a history of stroke (OR 8.2, 95%CI 1.08-62.37, P = 0.04); postoperative atelectasis (OR 4.7, 95%CI 1.21-18.64, P = 0.026); and air leaks (OR 12.6, 95%CI 4.10-38.91, P = 0.001).The prediction multivariable model for readmission represents an area under the curve (ROC) of 0.90. Mortality at 90 postoperative days in the group of readmitted patients was 13% versus 1.5 for the group of patients who did not require readmission (P < 0.001).

Conclusions: The factors predictive for readmission can help design individualized outpatient follow-up plans and programs for the reduction of readmissions.

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Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S-1 adjuvant chemotherapy

Background and Objectives

Limited information exists regarding beneficial effects of Helicobacter pylori. To examine the effect in advanced gastric cancer, we compared survival for patients treated with surgery-only or adjuvant chemotherapy on the basis of H. pylori infection status.

Methods

A cohort of 491 patients who underwent R0 resection for locally advanced gastric cancer between 2000 and 2009 at 12 institutions in northern Japan was included. H. pylori infection status, was assessed from paraffin-embedded formalin-fixed samples. Overall survival (OS) and disease-free survival (DFS) in surgery-only (Surgery) and adjuvant chemotherapy (S-1) groups were analyzed. A propensity score matching was employed to correct for confounding factors by indication.

Results

H. pylori infection was positive in 175 patients and negative in 316 patients. H. pylori-positive patients showed significantly better survival than H. pylori-negative patients in both OS (hazard ratio [HR] 0.593, 95% confidence interval [CI] 0.417-0.843; P = 0.003]) and DFS (HR 0.679, 95%CI 0.492-0.937; P = 0.018). Propensity score matching further confirmed that S-1 was virtually only effective when tumors were H. pylori-positive.

Conclusions

The favorable outcome of H. pylori-positive patients implies that the host immune system is modulated by H. pylori enhancing the chemotherapeutic efficacy.

http://ift.tt/2Dqcdqe

Preoperative coagulation abnormalities as a risk factor for adverse events after pancreas surgery

Objective

To determine whether elevated INR or PTT values predicted 30-day postoperative adverse events following elective pancreatectomy.

Methods

The American college of surgeons national surgical quality improvement program (ACS-NSQIP) database was used to identify 14 747 patients undergoing elective pancreatectomy from 2005 to 2013. The association of elevated INR or PTT with 30-day postoperative outcomes of morbidity and mortality was examined using multivariate logistic regression analysis.

Results

The overall 30-day mortality rate increased from 1.8% to 3.3% from the control to the high INR or PTT group (P = <0.001). An elevated INR/PTT increased the odds for bleeding requiring transfusion, superficial SSI, sepsis, unplanned intubation or >48 h on a ventilator, cardiac arrest or myocardial infarction, acute renal failure, return to the OR, and prolonged length of stay. With the exception of superficial SSI, multivariate logistic regression models revealed that these same events remained statistically significant after controlling for potential confounders.

Conclusion

Prolonged bleeding times (high INR/PTT) is associated with increased mortality and adverse outcomes after pancreas surgery. A patient's coagulation profile may serve as a risk stratification tool to identify higher risk patients that require more resources.

http://ift.tt/2DYaSIr

C-reactive protein as a marker of the surgical stress reduction within an ERAS protocol (Enhanced Recovery After Surgery) in colorectal surgery: A prospective cohort study

Background

The aim of this study is to evaluate the effectiveness of an Enhanced Recovery After Surgery Protocol (ERAS) in relation to reduce the Systemic Inflammatory Response (SIR) to surgery using C-reactive protein (CRP) in the first (POD1), second (POD2) and third (POD3) postoperative day.

Methods

We enrolled 121 patients (ERAS group) that underwent elective colorectal surgery with ERAS, and compared them with 135 patients (preERAS group) that had undergone surgery prior to the implementation. We made a univariate analysis to compare the CRP values in POD1, POD2, and POD3 between preERAS/ERAS group, laparoscopic/open surgery and the presence or not of Clavien Dindo complications. Multivariable lineal regression was used to assess if the ERAS had a decreasing effect on the CRP in POD1, POD2, and POD3, and was adjusted by age, male sex, use of laparoscopy, and complications.

Results

The presence of complications was independently associated with an increase in CRP values ​​in POD1, POD2, and POD3. Laparoscopy in POD1 and POD2, and ERAS in POD2 was independently associated with a decrease in CRP values.

Conclusion

The analysis shows an increase in SIR measured as a CRP value in those patients that had complications. The SIR decreased with laparoscopy in POD1 and POD2 and with ERAS in POD2.

http://ift.tt/2DpWojw

Primary liver sarcomas in the modern era: Resection or transplantation?

Background and Objectives

Primary liver sarcomas (PLS) are rare. Published series are limited by small numbers of patients.

Methods

We reviewed the National Cancer Database (2004-2014) for patients who underwent surgical resection of PLS.

Results

Of 237 patients identified, the majority were female (60.8%), with median age of 52 years. Histologies were: epithelioid hemangioendothelioma (n = 67), angiosarcoma (n = 64), leiomyosarcoma (n = 33), embryonal rhabdomyosarcoma (n = 31), carcinosarcoma (n = 16), giant cell sarcoma (n = 14), spindle cell sarcoma (n = 12). Ninety-seven (40.9%) patients underwent lobectomies or extended lobectomies, 41 patients (17.3%) underwent transplantation. Surgical margins were negative in 82.9%. Tumors were well differentiated in 11.3%. Histology type correlated with outcome with the best prognosis for epithelioid hemangioendothelioma (OS: not reached, similar for resection and transplantation) and the worst for angiosarcoma (OS:16.6 mo with resection; 6 mo with transplantation; P = 0.04). Resections with microscopically negative margins were associated with improved survival (58.7 vs 11.3 mo for positive margins; P < 0.001). Chemotherapy and radiation therapy were used in a minority of patients (32.9% and 4.3% respectively) with no improvement in outcomes.

Conclusions

Both hepatic resection and liver transplantation can be associated with long term survival for selected primary liver sarcomas such as epitheliod hemangioendotheliomas. Histology type and the ability to resect the tumor with negative margins correlate with outcomes and the decision to operate should be carefully weighed for subtypes with particularly dismal prognosis such as angiosarcomas.

http://ift.tt/2E0VsTu

Lymphatic vessel diameter in female pelvic cancer-related lower extremity lymphedematous limbs

Background

Lymphaticovenular anastomosis (LVA) has become one of the useful surgical treatments for compression-refractory lower extremity lymphedema (LEL). It is important to anastomose larger lymphatic vessels with abundant lymph flows in LVA surgery. This study aimed to clarify factors associated with lymphatic vessel diameter.

Methods

One hundred thirty-four LEL patients who underwent pre-operative indocyanine green (ICG) lymphography and LVA from June 2009 to August 2014 in a single institution were included in this retrospective observational study. Clinical, ICG lymphography, and intraoperative findings were collected from medical charts. A lymphatic vessel with external diameters of 0.5 mm or larger was defined as a large lymphatic vessel (LLV). Independent factors associated with LLV were identified using logistic regression analysis.

Results

Nine hundred sixty-two lymphatic vessels were identified, among which 438 (45.5%) were LLVs. Independent factors associated with LLV were older age (odds ration [OR], 1.408; 95% confidence interval [CI], 1.026-1.931; P = 0.034), positive history of radiation (OR, 1.634; 95%CI 1.228-2.173; P = 0.001), incision site in the thigh/lower leg compared with in the groin (OR, 1.617/1.685; 95%CI 1.076-2.432/1.148-2.473; P = 0.021/0.008). Inverse associations were observed in S-region/D-region on ICG lymphography compared with L-region (OR, 0.537/0.048; 95%CI, 0.397-0.726/0.006-0.371; P < 0.001/0.004).

Conclusions

D-region on ICG lymphography had the lowest OR to find LLV, representing that lymphatic vessels found in D-region on ICG lymphography would be significantly smaller than those in L-region. In LVA surgery, D-region should be avoided.

http://ift.tt/2DpWoQy

Staged surgical treatment of extremity lymphedema with dual gastroepiploic vascularized lymph node transfers followed by suction-assisted lipectomy—A prospective study

Background

Both physiologic and excisional procedures have been described for the treatment of lymphedema. However, there exist few reports that combine these procedures. The objective of this study was to evaluate the effectiveness of combining vascularized lymph node transfer (VLNT) with suction-assisted lipectomy (SAL) in a staged manner for the treatment of extremity lymphedema.

Methods

Patients with unilateral late stage II lymphedema (International Society of Lymphology), who consented to staged surgical treatment, were evaluated prospectively. Between 2014 and 2015, 12 female patients with upper (n = 6) or lower (n = 6) extremity lymphedema completed the treatment protocol. Primary outcomes evaluated included limb size and number of infectious episodes. In addition, compression garment usage was analyzed.

Results

The overall circumference reduction rate was on average 37.9% after VLNT and increased to 96.4% after SAL. While all patients had experienced at least one infectious episode prior to surgical treatment, only one patient did so after VLNT and none after SAL. All patients were able to eventually discontinue compression therapy.

Conclusion

VLNT followed by SAL can allow patients with late Stage II lymphedema achieve near normal limb size and eradication of infectious episodes. At follow-up, these desirable outcomes were maintained well after discontinuation of compression therapy.

http://ift.tt/2E1N5rb

Comparison of open and closed abdomen techniques for the delivery of intraperitoneal pemetrexed using a murine model

Background and Objectives

Pemetrexed is an appealing agent to use for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the optimal method of pemetrexed delivery still remains undefined. Using a murine model, we compared the use of open and closed abdomen techniques on the absorption of intraperitoneal (IP) pemetrexed in different compartments.

Methods

Eleven Sprague-Dawley rats were submitted to a fixed dose of IP pemetrexed (1000 mg/m²) at a perfusion temperature of 40°C during 25 min according to two techniques: open and closed. At the end of perfusion, samples in different compartments were harvested and the concentrations of pemetrexed were measured by high performance liquid chromatography.

Results

Absorption of IP pemetrexed in portal and systemic blood was significantly higher using the open compared to the closed abdomen technique (93.17 vs 52.50 µg/mL, P < 0.001) and (76.26 vs 51.65 µg/mL, P < 0.001), respectively. No difference was found between the two techniques on the peritoneal tissue concentration of pemetrexed (18.07 vs 19.17 µg/g, P = 0.51).

Conclusion

Peritoneal absorption of pemetrexed is not modified by the use of either technique. However, systemic concentrations of pemetrexed increased using the open technique, suggesting it could increase systemic toxicity.

http://ift.tt/2DryMLe

CCR5 governs DNA damage and breast cancer stem cell expansion

The functional significance of the chemokine receptor CCR5 in human breast cancer (BCa) epithelial cells is poorly understood. Here we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5+ BCa epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative BCa cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is re-expressed selectively on cancerous but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DDR-based treatments, allowing a dose reduction of standard chemotherapy and radiation.

http://ift.tt/2n2jjLo

CCR5 governs DNA damage and breast cancer stem cell expansion

The functional significance of the chemokine receptor CCR5 in human breast cancer (BCa) epithelial cells is poorly understood. Here we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5+ BCa epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative BCa cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is re-expressed selectively on cancerous but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DDR-based treatments, allowing a dose reduction of standard chemotherapy and radiation.

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Pediatric low-grade gliomas: a brave new world

See the article by Jones et al. on pages 160–173.

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The siren song of bevacizumab: swan song or clarion call?

Bevacizumab burst onto the neuro-oncology scene in 2005 based upon dramatic responses in recurrent glioblastoma patients receiving this agent with the ineffective drug irinotecan. Acceptable toxicity and superior radiographic response rates compared with standard salvage therapy, confirmed in pivotal uncontrolled phase II trials,^1,2 led to accelerated FDA approval in 2009. Moreover, many patients were able to reduce their corticosteroid dose, suggesting steroid-sparing properties.³ Nonetheless, these reports, which focused on progression-free survival (PFS) and radiographic response, did not suggest seismic improvement in overall survival (OS). Thus, concerns persisted that the agent's apparent activity might principally or wholly reflect anti–vascular endothelial growth factor mediated stabilization of the blood–brain barrier, creating a "pseudoresponse."

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Ritanserin, a novel agent targeting the mesenchymal subtype of glioblastomas

See the article by Olmez et al on pages 192–202.

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Highlights from the Literature

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Forthcoming Meetings

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Meeting Update—Society for Neuro-Oncology 2017 Annual Meeting

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Standard chemoradiation in combination with VEGF targeted therapy for glioblastoma results in progressive gray and white matter volume loss

brain atrophychemoradiationglioblastomaneuroimagingneurotoxicity

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Corrigendum

Corrigendum to Jones et al. Pediatric low-grade gliomas: next biologically driven steps. Neuro-Oncology, (https://doi.org/10.1093/neuonc/nox141) first published online August 02, 2017.

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Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy

Abstract

Background

Cabozantinib is a potent, multitarget inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2). This open-label, phase II trial evaluated cabozantinib in patients with recurrent or progressive glioblastoma (GBM).

Methods

Patients were initially enrolled to a starting cabozantinib dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of safety concerns. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, glucocorticoid use, and safety.

Results

Among 222 patients enrolled, 70 had received prior antiangiogenic therapy. Herein, we report results in this subset of 70 patients. The objective response rate was 4.3%, and the median duration of response was 4.2 months. The proportion of patients alive and progression free at 6 months was 8.5%. Median progression-free survival was 2.3 months, and median overall survival was 4.6 months. The most common adverse events reported in all patients, regardless of dose group, included fatigue (74.3%), diarrhea (47.1%), increased alanine aminotransferase (37.1%), headache (35.7%), hypertension (35.7%), and nausea (35.7%); overall, 34 (48.6%) patients experienced adverse events that resulted in dose reductions.

Conclusions

Cabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM.

Clinical Trials Registration Number

NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288)

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Is the blood–brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data

Abstract

The blood–brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.

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Identification of time-to-peak on dynamic 18F-FET-PET as a prognostic marker specifically in IDH1/2 mutant diffuse astrocytoma

Abstract

Background

Stratification of glioma according to isocitrate dehydrogenase 1/2 (IDH1/2) mutation and 1p/19q codeletion status has gained major importance in the new World Health Organization (WHO) classification. Parameters derived from uptake dynamics of ¹⁸F-fluoro-ethyl-tyrosine PET (¹⁸F-FET-PET) such as minimal time-to-peak (TTP_min) allow discrimination between different prognostic glioma subgroups, too. The present study is aimed at exploring whether TTP_min analysis provides prognostic information beyond the WHO classification.

Methods

Three hundred patients with newly diagnosed WHO 2007 grades II–IV gliomas with ¹⁸F-FET-PET imaging at diagnosis were grouped into 4 subgroups (IDH1/2 mut–1p/19q codel; IDH1/2 mut–1p/19q non-codel; IDH1/2 wildtype WHO grade II and III tumors; and glioblastoma). Clinical and imaging factors such as age, Karnofsky performance score, treatment, TTP_min, and maximal tumor-to-brain ratio (TBR_max) were analyzed with regard to progression-free and overall survival (PFS and OS) via univariate and multivariate regression analysis.

Results

PFS and OS were longest in the IDH1/2 mut–1p/19q codel subgroup, followed by IDH1/2 mut–1p/19q non-codel, IDH1/2 wildtype, and GBM (P < 0.001). Further, outcome stratified by TTP_min with a cutoff of 17.5 minutes revealed significantly longer PFS and OS in patients with TTP_min >17.5 minutes (P < 0.001 for PFS and OS). Lower TBR_max values or the absence of ¹⁸F-FET uptake was also associated with favorable outcome in the entire group. In the subgroup analyses, longer median TTP_min was associated with improved outcome specifically in the IDH1/2 mut–1p/19q non-codel group.

Conclusion

¹⁸F-FET-PET–derived dynamic analysis defines prognostically distinct subgroups of IDH1/2 mutant–1p/19q non-codel gliomas which cannot be distinguished as yet by molecular marker analysis.

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Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy

Abstract

Background

Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM).

Methods

Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety.

Results

Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome.

Conclusions

Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions.

Clinical Trials Registration Number

NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288)

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