Issue Information ‐ TOC

Journal of Surgical Oncology, Volume 117, Issue 4, Page 540-544, March 15, 2018.


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Cover Image, Volume 117, Number 4, March 15, 2018

Journal of Surgical Oncology, Volume 117, Issue 4, Page i-i, March 15, 2018.


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Totally minimally invasive esophagectomy after neoadjuvant chemoradiotherapy: Long‐term oncologic outcomes

Journal of Surgical Oncology, Volume 117, Issue 4, Page 651-658, March 15, 2018.


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Issue Information ‐ TOC

Journal of Surgical Oncology, Volume 117, Issue 4, Page 540-544, March 15, 2018.


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Issue Information ‐ Ed Board

Journal of Surgical Oncology, Volume 117, Issue 4, Page 539-539, March 15, 2018.


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Cover Image, Volume 117, Number 4, March 15, 2018

Journal of Surgical Oncology, Volume 117, Issue 4, Page i-i, March 15, 2018.


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Totally minimally invasive esophagectomy after neoadjuvant chemoradiotherapy: Long‐term oncologic outcomes

Journal of Surgical Oncology, Volume 117, Issue 4, Page 651-658, March 15, 2018.


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Anti‐thymocyte globulin improves survival free from relapse and graft‐versus‐host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia‐negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT

Cancer, EarlyView.


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The pot dealer state harms patients with cancer

Cancer, EarlyView.


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Reply to The pot dealer state harms patients with cancer

Cancer, EarlyView.


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HOTAIR gene polymorphisms contribute to increased neuroblastoma susceptibility in Chinese children

Cancer, EarlyView.


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Anti‐thymocyte globulin improves survival free from relapse and graft‐versus‐host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia‐negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT

Cancer, EarlyView.


https://ift.tt/2IkuIyz

The pot dealer state harms patients with cancer

Cancer, EarlyView.


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Reply to The pot dealer state harms patients with cancer

Cancer, EarlyView.


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HOTAIR gene polymorphisms contribute to increased neuroblastoma susceptibility in Chinese children

Cancer, EarlyView.


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Precision medicine becomes reality—tumor type-agnostic therapy

Abstract

Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy. These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated, and therefore established a precedent for tumor type-agnostic therapy. In the 2017 American Society for Clinical Oncology annual meeting, larotrectinib (LOXO-101), Loxooncology's oral, potent, and selective inhibitor of tropomyosin receptor kinases (TRK), demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion proteins in adult and pediatric patients. Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features: (a) biomarker-based, well-defined rare patient population; (b) exceptionally high clinical efficacy, e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor types with MSI-H/dMMR and 75% ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins; (c) durable responses lasting at least 6 months with complete responses observed; and (d) parallel development in adult and pediatric populations. With increasing accessibility to genetic analysis tools such as next-generation sequencing, tumor type-agnostic therapy has become a reality, both during clinical development and in clinical practice. Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.

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Selection of candidates for surgery as local therapy among early-stage small cell lung cancer patients: a population-based analysis

Abstract

Background

Surgery and radiotherapy are considered local therapies for small cell lung cancer (SCLC). The present study aimed to select candidates for surgery as local therapy among patients with stage I or II SCLC, based on the eighth edition of the TNM classification for lung cancer.

Methods

Patients diagnosed with SCLC between 2004 and 2013 were selected from the Surveillance, Epidemiology, And End Results database. The TNM stage of SCLC in these patients was re-classified according to the eighth edition of the TNM classification for lung cancer. Patients with stage I or II SCLC were included in the present study. Overall survival (OS) and lung cancer-specific survival (LCSS) were separately compared in the different TNM stages between patients who received surgery and radiotherapy as local therapy. Multivariate analysis was applied to evaluate multiple factors associated with survival.

Results

Among the 2129 patients included in the present study, 387 (18.2%) received surgery, 1032 (48.5%) underwent radiotherapy as local therapy, 154 (7.2%) underwent surgery and radiotherapy, and 556 (26.1%) did not undergo either surgery or radiotherapy. Among patients with T1-2N0 (tumor size ≤ 50 mm without positive lymph nodes) disease, patients who underwent surgery had higher 5-year OS and LCSS rates than patients who received radiotherapy (T1N0: 46.0% vs. 23.8%, P < 0.001, and 58.4% vs. 36.4%, P < 0.001, respectively; T2N0: 42.6% vs. 24.7%, P = 0.004, and 48.8% vs. 31.3%, P = 0.011, respectively). Multivariate analysis results revealed that surgery was associated with low risk of death. However, among T3N0 or T1-2N1 (stage IIB) SCLC patients, patients who underwent surgery did not have higher 5-year OS and LCSS rates than patients who received radiotherapy (T3N0: 16.2% vs. 26.5%, P = 0.085, and 28.7% vs. 30.9%, P = 0.372, respectively; T1-2N1: 20.3% vs. 29.0%, P = 0.146, and 25.6% vs. 35.5%, P = 0.064, respectively).

Conclusions

Based on the assumption that the overwhelming majority of stage I or II SCLC patients who underwent surgery or radiotherapy also received certain types of systemic therapy, only patients with T1-2N0 SCLC may benefit from surgery as local therapy. Patients with T3N0 or T1-2N1 SCLC may consider radiotherapy as local therapy.

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Precision medicine becomes reality—tumor type-agnostic therapy

Abstract

Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy. These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated, and therefore established a precedent for tumor type-agnostic therapy. In the 2017 American Society for Clinical Oncology annual meeting, larotrectinib (LOXO-101), Loxooncology's oral, potent, and selective inhibitor of tropomyosin receptor kinases (TRK), demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion proteins in adult and pediatric patients. Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features: (a) biomarker-based, well-defined rare patient population; (b) exceptionally high clinical efficacy, e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor types with MSI-H/dMMR and 75% ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins; (c) durable responses lasting at least 6 months with complete responses observed; and (d) parallel development in adult and pediatric populations. With increasing accessibility to genetic analysis tools such as next-generation sequencing, tumor type-agnostic therapy has become a reality, both during clinical development and in clinical practice. Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.

https://ift.tt/2GHadyD

Selection of candidates for surgery as local therapy among early-stage small cell lung cancer patients: a population-based analysis

Abstract

Background

Surgery and radiotherapy are considered local therapies for small cell lung cancer (SCLC). The present study aimed to select candidates for surgery as local therapy among patients with stage I or II SCLC, based on the eighth edition of the TNM classification for lung cancer.

Methods

Patients diagnosed with SCLC between 2004 and 2013 were selected from the Surveillance, Epidemiology, And End Results database. The TNM stage of SCLC in these patients was re-classified according to the eighth edition of the TNM classification for lung cancer. Patients with stage I or II SCLC were included in the present study. Overall survival (OS) and lung cancer-specific survival (LCSS) were separately compared in the different TNM stages between patients who received surgery and radiotherapy as local therapy. Multivariate analysis was applied to evaluate multiple factors associated with survival.

Results

Among the 2129 patients included in the present study, 387 (18.2%) received surgery, 1032 (48.5%) underwent radiotherapy as local therapy, 154 (7.2%) underwent surgery and radiotherapy, and 556 (26.1%) did not undergo either surgery or radiotherapy. Among patients with T1-2N0 (tumor size ≤ 50 mm without positive lymph nodes) disease, patients who underwent surgery had higher 5-year OS and LCSS rates than patients who received radiotherapy (T1N0: 46.0% vs. 23.8%, P < 0.001, and 58.4% vs. 36.4%, P < 0.001, respectively; T2N0: 42.6% vs. 24.7%, P = 0.004, and 48.8% vs. 31.3%, P = 0.011, respectively). Multivariate analysis results revealed that surgery was associated with low risk of death. However, among T3N0 or T1-2N1 (stage IIB) SCLC patients, patients who underwent surgery did not have higher 5-year OS and LCSS rates than patients who received radiotherapy (T3N0: 16.2% vs. 26.5%, P = 0.085, and 28.7% vs. 30.9%, P = 0.372, respectively; T1-2N1: 20.3% vs. 29.0%, P = 0.146, and 25.6% vs. 35.5%, P = 0.064, respectively).

Conclusions

Based on the assumption that the overwhelming majority of stage I or II SCLC patients who underwent surgery or radiotherapy also received certain types of systemic therapy, only patients with T1-2N0 SCLC may benefit from surgery as local therapy. Patients with T3N0 or T1-2N1 SCLC may consider radiotherapy as local therapy.

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Loss of NF-{kappa}B1 Promotes Inflammation and Immune Checkpoint Regulators [Research Watch]

Polymorphisms that reduce NF-B1 in epithelial and hematopoietic cells promote gastric cancer.

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Increasing Fc{gamma}R Binding Activity May Enhance Anti-CTLA4 Efficacy [Research Watch]

Anti-CTLA4 antibodies induce an FcR-dependent depletion of Tregs to promote tumor rejection.

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Inhibiting PTPN12-Regulated RTKs May Be Therapeutic in TNBC [Research Watch]

PTPN12 deficiency may confer sensitivity to tyrosine kinase inhibitor combinations in TNBC.

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LHPP Is a Histidine Phosphatase and a Tumor Suppressor [Research Watch]

Deregulated histidine phosphorylation may promote tumorigenesis in hepatocellular carcinoma (HCC).

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Machine Learning Improves Diagnosis of CNS Cancers [News in Brief]

Algorithm spots patterns in genome-wide methylation profiles to help classify brain and spinal cord tumors.

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A Review of Promising Natural Chemopreventive Agents for Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) accounts for 300,000 deaths per year worldwide and overall survival rates have shown little improvement over the past three decades. Current treatment methods including surgery, chemotherapy, and radiotherapy leave patients with secondary morbidities. Thus, treatment of HNSCC may benefit from exploration of natural compounds as chemopreventive agents. With excellent safety profiles, reduced toxicities, antioxidant properties, and general acceptance for use as dietary supplements, natural compounds are viewed as a desirable area of investigation for chemoprevention. Though most of the field is early in development, numerous studies display the potential utility of natural compounds against HNSCC. These compounds face additional challenges such as low bioavailability for systemic delivery, potential toxicities when consumed in pharmacological doses, and acquired resistance. However, novel delivery vehicles and synthetic analogs have shown overcome some of these challenges. This review covers eleven promising natural compounds in the chemoprevention of HNSCC including vitamin A, curcumin, isothiocyanate, green tea, luteolin, resveratrol, genistein, lycopene, bitter melon, withaferin A, and guggulsterone. The review discusses the therapeutic potential and associated challenges of these agents in the chemopreventive efforts against HNSCC.

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Tumour-derived GM-CSF promotes granulocyte immunosuppression in mesothelioma patients

Purpose: The cross talk between tumour cells, myeloid cells, and T cells play a critical role in tumour pathogenesis and response to immunotherapies. Although the aetiology of mesothelioma is well understood the impact of mesothelioma on the surrounding immune microenvironment is less well studied. In this study the effect of the mesothelioma microenvironment on circulating and infiltrating granulocytes and T cells is investigated. Experimental Design: Tumour and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T cell suppression. Co-cultures of granulocytes, mesothelioma cells, T cells were used to identify the mechanism of T cell inhibition. Results: Analysis of tumours showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T cell proliferation and activation. Characterisation of the blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR- granulocytes at increased frequency compared to healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of Reactive Oxygen Species (ROS) from granulocytes, resulting in T cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumours express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralising antibody, or ROS inhibition, restored T cell proliferation suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients. Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma and the immune micro-environment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy.

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SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy

Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy. Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by Flow Cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-L-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells. Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples. Conclusions:Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy.

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Tumour-derived GM-CSF promotes granulocyte immunosuppression in mesothelioma patients

Purpose: The cross talk between tumour cells, myeloid cells, and T cells play a critical role in tumour pathogenesis and response to immunotherapies. Although the aetiology of mesothelioma is well understood the impact of mesothelioma on the surrounding immune microenvironment is less well studied. In this study the effect of the mesothelioma microenvironment on circulating and infiltrating granulocytes and T cells is investigated. Experimental Design: Tumour and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T cell suppression. Co-cultures of granulocytes, mesothelioma cells, T cells were used to identify the mechanism of T cell inhibition. Results: Analysis of tumours showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T cell proliferation and activation. Characterisation of the blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR- granulocytes at increased frequency compared to healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of Reactive Oxygen Species (ROS) from granulocytes, resulting in T cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumours express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralising antibody, or ROS inhibition, restored T cell proliferation suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients. Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma and the immune micro-environment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy.

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Renal failure in pediatric Castleman disease: Four French cases with thrombotic microangiopathy

Pediatric Blood &Cancer, EarlyView.


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Parent understanding of the risk of future limitations secondary to pediatric cancer treatment

Pediatric Blood &Cancer, EarlyView.


https://ift.tt/2Ih3bOm

Comment on: Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia

Pediatric Blood &Cancer, EarlyView.


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Funerals

Pediatric Blood &Cancer, EarlyView.


https://ift.tt/2uAVG2M

Renal failure in pediatric Castleman disease: Four French cases with thrombotic microangiopathy

Pediatric Blood &Cancer, EarlyView.


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Parent understanding of the risk of future limitations secondary to pediatric cancer treatment

Pediatric Blood &Cancer, EarlyView.


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Funerals

Pediatric Blood &Cancer, EarlyView.


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Phase I trial of the mTOR inhibitor everolimus in combination with multi‐agent chemotherapy in relapsed childhood acute lymphoblastic leukemia

Pediatric Blood &Cancer, EarlyView.


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Three-dimensional cluster formation and structure in heterogeneous dose distribution of intensity modulated radiation therapy

To investigate three-dimensional cluster structure and its correlation to clinical endpoint in heterogeneous dose distributions from intensity modulated radiation therapy.

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Programmed death‐ligand 1 (PD‐L1) expression in pleomorphic carcinoma of the lung

Journal of Surgical Oncology, EarlyView.


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Intraoperative identification and definition of “functional” lymphatic collecting vessels for supermicrosurgical lymphatico‐venous anastomosis in treating lymphedema patients

Journal of Surgical Oncology, EarlyView.


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In response to: Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities

Journal of Surgical Oncology, EarlyView.


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Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities

Journal of Surgical Oncology, EarlyView.


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Intraoperative identification and definition of “functional” lymphatic collecting vessels for supermicrosurgical lymphatico‐venous anastomosis in treating lymphedema patients

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2pRIfqm

Programmed death‐ligand 1 (PD‐L1) expression in pleomorphic carcinoma of the lung

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2IgcrlL

Breast cancer subtypes and local recurrence rate after surgery for bone metastasis to the extremities

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2pRyPeE

In response to: Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2uBTzvL

Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2pRScnP

Adiponectin Reverses the Proliferative Effects of Estradiol and IGF-1 in Human Epithelial Ovarian Cancer Cells by Downregulating the Expression of Their Receptors

Abstract

The expression of adiponectin receptors AdipoR1 and AdipoR2 has been reported in the human ovary and ovarian cancer tissues. Moreover, adiponectin has been reported to act as an anti-tumor factor by inhibiting cancer cell proliferation. Thus, we investigate whether adiponectin and its receptors influence ovarian cancer development. In the present study, we found that adiponectin was not expressed in the granulosa cell line (COV434), and epithelial ovarian cancer cell lines (OVCAR-3, SKOV-3, and Caov-3). Additionally, we found that AdipoR1 and AdipoR2 expression is lower in epithelial ovarian cancer cells than in granulosa tumor cells. Endogenous 17β-estradiol as well as exogenous estrogens, such as bisphenol A and its chlorinated and brominated analogs do not affect adiponectin receptor expression. We found that adiponectin inhibited the growth of OVCAR-3 and SKOV-3 cells, and that this effect was independent of apoptosis. Moreover, adiponectin reverses the stimulatory effects of 17β-estradiol and insulin-like growth factor 1 on cell proliferation by downregulating the expression of their receptors, whereas progesterone increased the sensitivity of cancer cells to adiponectin by upregulating AdipoR1 and AdipoR2 expression. These results suggest interactions between adiponectin and various ovarian steroid hormone and growth factor pathways in ovarian cancer cells.

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Adiponectin Reverses the Proliferative Effects of Estradiol and IGF-1 in Human Epithelial Ovarian Cancer Cells by Downregulating the Expression of Their Receptors

Abstract

The expression of adiponectin receptors AdipoR1 and AdipoR2 has been reported in the human ovary and ovarian cancer tissues. Moreover, adiponectin has been reported to act as an anti-tumor factor by inhibiting cancer cell proliferation. Thus, we investigate whether adiponectin and its receptors influence ovarian cancer development. In the present study, we found that adiponectin was not expressed in the granulosa cell line (COV434), and epithelial ovarian cancer cell lines (OVCAR-3, SKOV-3, and Caov-3). Additionally, we found that AdipoR1 and AdipoR2 expression is lower in epithelial ovarian cancer cells than in granulosa tumor cells. Endogenous 17β-estradiol as well as exogenous estrogens, such as bisphenol A and its chlorinated and brominated analogs do not affect adiponectin receptor expression. We found that adiponectin inhibited the growth of OVCAR-3 and SKOV-3 cells, and that this effect was independent of apoptosis. Moreover, adiponectin reverses the stimulatory effects of 17β-estradiol and insulin-like growth factor 1 on cell proliferation by downregulating the expression of their receptors, whereas progesterone increased the sensitivity of cancer cells to adiponectin by upregulating AdipoR1 and AdipoR2 expression. These results suggest interactions between adiponectin and various ovarian steroid hormone and growth factor pathways in ovarian cancer cells.

https://ift.tt/2GGtlg8

Intraoperative identification and definition of “functional” lymphatic collecting vessels for supermicrosurgical lymphatico‐venous anastomosis in treating lymphedema patients

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2pRIfqm

Programmed death‐ligand 1 (PD‐L1) expression in pleomorphic carcinoma of the lung

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2IgcrlL

Breast cancer subtypes and local recurrence rate after surgery for bone metastasis to the extremities

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2pRyPeE

In response to: Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2uBTzvL

Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities

Journal of Surgical Oncology, EarlyView.


https://ift.tt/2pRScnP

Trps1 is associated with the multidrug resistance of lung cancer cell by regulating MGMT gene expression

Cancer Medicine, EarlyView.


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Trps1 is associated with the multidrug resistance of lung cancer cell by regulating MGMT gene expression

Cancer Medicine, EarlyView.


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Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies

Abstract

Purpose

The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.

Methods

In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.

Results

A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib C_max, were − 0.529 ms (90% CI − 6.621, 5.562) on day 1 and − 9.202 ms (90% CI − 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI − 1.343, 2.412) and 1.16 (90% CI − 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.

Conclusions

Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.

Registration

The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.

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Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies

Abstract

Purpose

The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.

Methods

In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.

Results

A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib C_max, were − 0.529 ms (90% CI − 6.621, 5.562) on day 1 and − 9.202 ms (90% CI − 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI − 1.343, 2.412) and 1.16 (90% CI − 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.

Conclusions

Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.

Registration

The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.

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Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies

Abstract

Purpose

The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.

Methods

In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.

Results

A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib C_max, were − 0.529 ms (90% CI − 6.621, 5.562) on day 1 and − 9.202 ms (90% CI − 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI − 1.343, 2.412) and 1.16 (90% CI − 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.

Conclusions

Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.

Registration

The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.

https://ift.tt/2pUJaFJ

Clinical importance of DNA repair in sporadic colorectal cancer

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Gustavo A. Laporte, Natalia M. Leguisamo, Antonio N. Kalil, Jenifer Saffi
Colorectal cancer (CRC) is the third major cause of cancer-related deaths worldwide. However, despite the scientific efforts to provide a molecular classification to improve CRC clinical practice management, prognosis and therapeutic decision are still strongly dependent on the TNM staging system. Mismatch repair system deficiencies can occur in many organs, but it is mainly a hallmark of CRC influencing clinical outcomes and response to therapy. This review will discuss the effect of the modulation of other DNA repair pathways (direct, excision and double strand break repairs) in the clinical and pathological aspects of colorectal cancer and its potential as prognostic and predictive biomarkers.



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Targeting the tumor promoting effects of adenosine in chronic lymphocytic leukemia

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Yiqing Cai, Lili Feng, Xin Wang
Chronic lymphocytic leukemia (CLL) is a hematological malignancy which is characterized by progressive accumulation of functionally deficient B cells in blood, bone marrow, and lymphatic tissue. The tumor microenvironment (TME) appears to play a critical role in genesis and progression of CLL. High levels of extracellular adenosine (ADO) are detected in CLL as a consequence of expression of ecto-enzymes, such as CD39 and CD73. Extracellular ADO exhibits a broad range of effects on cell cycle control, immunoregulation, angiogenesis and cytokine regulation through both direct and indirect mechanisms. In this review, we focused on the multiple functions and related mechanisms of ADO signaling in CLL generation and progression.



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Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Hani M Babiker, Ali McBride, Michael Newton, Leigh M. Boehmer, Adrienne Goeller Drucker, Mollie Gowan, Manouchkathe Cassagnol, Todd D. Camenisch, Faiz Anwer, James M. Hollands
Cardiotoxic effects of chemotherapy and targeted drugs are ubiquitous and challenging in the field of oncology therapeutics. The broad spectrum of toxicities ranging from ischemic, hypertensive, cardiomyopathic, and arrhythmic complications can present as a significant challenge for clinicians treating cancer patients. If early diagnosis and intervention of cardiotoxic complications is missed, this can lead to delay or abrogation of planned treatment, which can potentially culminate to significant morbidity due to not only the cardiotoxic complications but also the progression of cancer. Hence, full knowledge of cardiovascular complications of chemotherapeutic agents, essential diagnostics tests to order, and appropriate management is paramount to oncologist, oncology pharmacists, and scientific clinical investigators. The aforementioned is particularly true in the current oncology era of plenteous early clinical trials studying several pathway/molecular-targeting agents with an increased cardiotoxic potential and the rapid expedited approval of those drugs by the FDA. Herein, we present a review discussing cardiotoxic effects of drugs and guidelines for management of the toxicities to assist the medical field in general managing patients with cancer.



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Going the distance: are we losing patients along the multiple myeloma treatment pathway?

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Evangelos Terpos, Florence Suzan, Hartmut Goldschmidt
Despite data suggesting that individuals with multiple myeloma can benefit from receiving several lines of therapy, and guidelines recommending treatment after relapse, a recent European patient chart review found that only 61% of patients receive second-line treatment. The review found that factors such as old age and previous adverse events lead to physicians deciding not to treat after relapse. However, given the large number of regimens available, treatment can be tailored to individual patients' needs and supportive care measures can help with the management of adverse effects. If approved therapies are not suitable for a patient, guidelines recommend registration in a clinical trial, yet only 7% of patients in the review were participating in such studies. A need for better education on the range of treatments available and their risk–benefit profiles is suggested. Access to new drugs should be examined to maximise the number of patients benefitting from them.



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Role of Bevacizumab in Uterine Leiomyosarcoma

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Giorgio Bogani, Antonino Ditto, Fabio Martineli, Mauro Signorelli, Valentina Chiappa, Caterina Fonatella, Roberta Sanfilippo, Umberto Leone Roberti Maggiore, Simone Ferrero, Domenica Lorusso, Francesco Raspagliesi
In the recent years, angiogenetic inhibitors have emerged for the treatment of several malignancies. In particular, bevacizumab has proved to be effective in many types of cancers (including sarcoma), but the limitations of antiangiogenic therapy have been shown in practice. Here, we sought to review the current evidence on the role and efficacy of bevacizumab in patients affected by uterine leiomyosarcoma. On April 2017, Literature was searched in order to identify studies reporting outcomes of patients affected either by early stage or advanced/recurred uterine leiomyosarcoma undergoing treatment with bevacizumab, alone or in combination with other chemotherapeutic regimens. Searching the literature data of 69 patients affected by metastatic, unresectable uterine leiomyosarcoma were retrieved; on the contrary, no data regarding the use of bevacizumab in patients with early-stage uterine leiomyosarcoma was published. Current evidence suggested that the addiction of bevacizumab to standard treatment modality does not increase grade 3 or worse toxicity (assessed by CTCAE). Pooled data regarding response rate suggested that 35%, 28%, 26% and 11% of patients experienced objective cure (complete + partial response), stable disease, progressive disease and unknown response, respectively. Data from the only one randomized controlled trial suggested that objective cure rate does not differ from standard chemotherapy treatment, thus limiting the indication to add bevacizumab in patients affected by metastatic, unresectable uterine leiomyosarcoma. The current evidence does not justify the use of bevacizumab into clinical practice. Further randomized studies testing the role of bevacizumab are warranted.



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Genetic alterations crossing the borders of distinct hematopoetic lineages and solid tumors: Diagnostic challenges in the era of high-throughput sequencing in hemato-oncology

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Evgenii Shumilov, Johanna Flach, Thomas Pabst, Martin Fiedler, Anne Angelillo-Scherrer, Lorenz Trümper, Raphael Joncourt, Alexander Kohlmann, Ulrike Bacher
Owing to the introduction of next-generation sequencing (NGS) new challenges for diagnostic algorithms and the interpretation of the results for therapeutic decision making in hemato-oncology have arisen. Recurrent somatic mutations crossing the borders between different hematological entities and solid neoplasms have been detected. In analogy to mutant TP53, the same mutation type may occur in myeloid, B- or T-lymphatic malignancies or solid neoplasms. At the same time, a certain mutation can show different prognostic outcomes in different entities and co-existence of certain mutations may change the prognostic relevance. These insights may spark the investigation of targeted therapies with the same substances across different disease entities. This review article summarizes mutations that can emerge in different hematologic and solid malignancies and summarizes other obstacles in the era of modern molecular diagnostics, such as the phenomenon of "clonal hematopoiesis of indeterminate potential" being difficult to interpret in the individual patient.



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Prognostic and Predictive Factors in Patients with Brain Metastases from Solid Tumors: A Review of Published Nomograms

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Carsten Nieder, Minesh P. Mehta, Hans Geinitz, Anca L. Grosu
ObjectiveTo review published nomograms that predict endpoints such as overall survival (OS) or risk of intracranial relapse in patients with brain metastases from solid tumors.MethodsThe methods and results of nomogram studies identified by a systematic search were extracted and compared, stratified by endpoint predicted by the respective nomograms. In particular, validation strategies (external/internal), concordance indices (cut-off 0.75) and comparisons to older models were analyzed.ResultsSix publications reported on prediction of OS. Most of these analyses focused on one particular primary tumor site, e.g., breast cancer or hepatocellular carcinoma, while the largest study included different primary tumor sites. The median number of patients was 244. Three of six studies included external validation cohorts. With few exceptions, concordance indices <0.75 were reported. In all studies reporting this endpoint, the nomogram outperformed older prognostic scores. Two nomograms focused on development of new brain metastases after radiosurgery (one externally validated), one on survival free from salvage whole brain radiotherapy (WBRT) after radiosurgery, and one on neurologic and non-neurologic death in patients receiving radiosurgery after WBRT failure. All concordance indices of these 4 nomograms were <0.70.ConclusionTaking into account concordance indices and comparisons to older prognostic models, the most promising, externally validated nomograms are the breast cancer and the non-small cell lung cancer nomogram predicting OS, and the distant brain failure after radiosurgery nomogram. Additional validation studies as well as continuous monitoring of the models' performance appear necessary to ensure their clinical applicability in the present era of rapidly changing treatment paradigms.



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Sarcoma–The Standard-bearer in cancer discovery

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Jared W. Potter, Kevin B. Jones, Jared J. Barrott
Sarcoma is a rare tumor type that occurs most frequently in connective tissue. Despite its uncommon occurrence, sarcoma research has provided the means for groundbreaking research that has advanced our understanding of general cancer mechanisms. It is through sarcoma research that the pioneering efforts of cancer immunotherapy were explored, that we understand the inherent genetic nature of cancer mutations, and that we appreciate the subclassification of general cancer types to make more accurate prognoses. This review explores the brief history of sarcoma research and what sarcomas can still teach us about the future of cancer research, especially in regard to novel immunotherapy targets, the role of epigenetics in disease progression and chemoresistance, and the benefits of more focused clinical trials.



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Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Hani M Babiker, Ali McBride, Michael Newton, Leigh M. Boehmer, Adrienne Goeller Drucker, Mollie Gowan, Manouchkathe Cassagnol, Todd D. Camenisch, Faiz Anwer, James M. Hollands
Cardiotoxic effects of chemotherapy and targeted drugs are ubiquitous and challenging in the field of oncology therapeutics. The broad spectrum of toxicities ranging from ischemic, hypertensive, cardiomyopathic, and arrhythmic complications can present as a significant challenge for clinicians treating cancer patients. If early diagnosis and intervention of cardiotoxic complications is missed, this can lead to delay or abrogation of planned treatment, which can potentially culminate to significant morbidity due to not only the cardiotoxic complications but also the progression of cancer. Hence, full knowledge of cardiovascular complications of chemotherapeutic agents, essential diagnostics tests to order, and appropriate management is paramount to oncologist, oncology pharmacists, and scientific clinical investigators. The aforementioned is particularly true in the current oncology era of plenteous early clinical trials studying several pathway/molecular-targeting agents with an increased cardiotoxic potential and the rapid expedited approval of those drugs by the FDA. Herein, we present a review discussing cardiotoxic effects of drugs and guidelines for management of the toxicities to assist the medical field in general managing patients with cancer.



https://ift.tt/2E9vmfS

Going the distance: are we losing patients along the multiple myeloma treatment pathway?

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Evangelos Terpos, Florence Suzan, Hartmut Goldschmidt
Despite data suggesting that individuals with multiple myeloma can benefit from receiving several lines of therapy, and guidelines recommending treatment after relapse, a recent European patient chart review found that only 61% of patients receive second-line treatment. The review found that factors such as old age and previous adverse events lead to physicians deciding not to treat after relapse. However, given the large number of regimens available, treatment can be tailored to individual patients' needs and supportive care measures can help with the management of adverse effects. If approved therapies are not suitable for a patient, guidelines recommend registration in a clinical trial, yet only 7% of patients in the review were participating in such studies. A need for better education on the range of treatments available and their risk–benefit profiles is suggested. Access to new drugs should be examined to maximise the number of patients benefitting from them.



https://ift.tt/2uvFuA0

Clinical importance of DNA repair in sporadic colorectal cancer

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Gustavo A. Laporte, Natalia M. Leguisamo, Antonio N. Kalil, Jenifer Saffi
Colorectal cancer (CRC) is the third major cause of cancer-related deaths worldwide. However, despite the scientific efforts to provide a molecular classification to improve CRC clinical practice management, prognosis and therapeutic decision are still strongly dependent on the TNM staging system. Mismatch repair system deficiencies can occur in many organs, but it is mainly a hallmark of CRC influencing clinical outcomes and response to therapy. This review will discuss the effect of the modulation of other DNA repair pathways (direct, excision and double strand break repairs) in the clinical and pathological aspects of colorectal cancer and its potential as prognostic and predictive biomarkers.



https://ift.tt/2pQyWWY

Role of Bevacizumab in Uterine Leiomyosarcoma

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Giorgio Bogani, Antonino Ditto, Fabio Martineli, Mauro Signorelli, Valentina Chiappa, Caterina Fonatella, Roberta Sanfilippo, Umberto Leone Roberti Maggiore, Simone Ferrero, Domenica Lorusso, Francesco Raspagliesi
In the recent years, angiogenetic inhibitors have emerged for the treatment of several malignancies. In particular, bevacizumab has proved to be effective in many types of cancers (including sarcoma), but the limitations of antiangiogenic therapy have been shown in practice. Here, we sought to review the current evidence on the role and efficacy of bevacizumab in patients affected by uterine leiomyosarcoma. On April 2017, Literature was searched in order to identify studies reporting outcomes of patients affected either by early stage or advanced/recurred uterine leiomyosarcoma undergoing treatment with bevacizumab, alone or in combination with other chemotherapeutic regimens. Searching the literature data of 69 patients affected by metastatic, unresectable uterine leiomyosarcoma were retrieved; on the contrary, no data regarding the use of bevacizumab in patients with early-stage uterine leiomyosarcoma was published. Current evidence suggested that the addiction of bevacizumab to standard treatment modality does not increase grade 3 or worse toxicity (assessed by CTCAE). Pooled data regarding response rate suggested that 35%, 28%, 26% and 11% of patients experienced objective cure (complete + partial response), stable disease, progressive disease and unknown response, respectively. Data from the only one randomized controlled trial suggested that objective cure rate does not differ from standard chemotherapy treatment, thus limiting the indication to add bevacizumab in patients affected by metastatic, unresectable uterine leiomyosarcoma. The current evidence does not justify the use of bevacizumab into clinical practice. Further randomized studies testing the role of bevacizumab are warranted.



https://ift.tt/2GnZFp2

Targeting the tumor promoting effects of adenosine in chronic lymphocytic leukemia

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Yiqing Cai, Lili Feng, Xin Wang
Chronic lymphocytic leukemia (CLL) is a hematological malignancy which is characterized by progressive accumulation of functionally deficient B cells in blood, bone marrow, and lymphatic tissue. The tumor microenvironment (TME) appears to play a critical role in genesis and progression of CLL. High levels of extracellular adenosine (ADO) are detected in CLL as a consequence of expression of ecto-enzymes, such as CD39 and CD73. Extracellular ADO exhibits a broad range of effects on cell cycle control, immunoregulation, angiogenesis and cytokine regulation through both direct and indirect mechanisms. In this review, we focused on the multiple functions and related mechanisms of ADO signaling in CLL generation and progression.



https://ift.tt/2J5SaAH

Genetic alterations crossing the borders of distinct hematopoetic lineages and solid tumors: Diagnostic challenges in the era of high-throughput sequencing in hemato-oncology

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Evgenii Shumilov, Johanna Flach, Thomas Pabst, Martin Fiedler, Anne Angelillo-Scherrer, Lorenz Trümper, Raphael Joncourt, Alexander Kohlmann, Ulrike Bacher
Owing to the introduction of next-generation sequencing (NGS) new challenges for diagnostic algorithms and the interpretation of the results for therapeutic decision making in hemato-oncology have arisen. Recurrent somatic mutations crossing the borders between different hematological entities and solid neoplasms have been detected. In analogy to mutant TP53, the same mutation type may occur in myeloid, B- or T-lymphatic malignancies or solid neoplasms. At the same time, a certain mutation can show different prognostic outcomes in different entities and co-existence of certain mutations may change the prognostic relevance. These insights may spark the investigation of targeted therapies with the same substances across different disease entities. This review article summarizes mutations that can emerge in different hematologic and solid malignancies and summarizes other obstacles in the era of modern molecular diagnostics, such as the phenomenon of "clonal hematopoiesis of indeterminate potential" being difficult to interpret in the individual patient.



https://ift.tt/2uvFbVS

Prognostic and Predictive Factors in Patients with Brain Metastases from Solid Tumors: A Review of Published Nomograms

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Carsten Nieder, Minesh P. Mehta, Hans Geinitz, Anca L. Grosu
ObjectiveTo review published nomograms that predict endpoints such as overall survival (OS) or risk of intracranial relapse in patients with brain metastases from solid tumors.MethodsThe methods and results of nomogram studies identified by a systematic search were extracted and compared, stratified by endpoint predicted by the respective nomograms. In particular, validation strategies (external/internal), concordance indices (cut-off 0.75) and comparisons to older models were analyzed.ResultsSix publications reported on prediction of OS. Most of these analyses focused on one particular primary tumor site, e.g., breast cancer or hepatocellular carcinoma, while the largest study included different primary tumor sites. The median number of patients was 244. Three of six studies included external validation cohorts. With few exceptions, concordance indices <0.75 were reported. In all studies reporting this endpoint, the nomogram outperformed older prognostic scores. Two nomograms focused on development of new brain metastases after radiosurgery (one externally validated), one on survival free from salvage whole brain radiotherapy (WBRT) after radiosurgery, and one on neurologic and non-neurologic death in patients receiving radiosurgery after WBRT failure. All concordance indices of these 4 nomograms were <0.70.ConclusionTaking into account concordance indices and comparisons to older prognostic models, the most promising, externally validated nomograms are the breast cancer and the non-small cell lung cancer nomogram predicting OS, and the distant brain failure after radiosurgery nomogram. Additional validation studies as well as continuous monitoring of the models' performance appear necessary to ensure their clinical applicability in the present era of rapidly changing treatment paradigms.



https://ift.tt/2GnZlqk

Sarcoma–The Standard-bearer in cancer discovery

Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Jared W. Potter, Kevin B. Jones, Jared J. Barrott
Sarcoma is a rare tumor type that occurs most frequently in connective tissue. Despite its uncommon occurrence, sarcoma research has provided the means for groundbreaking research that has advanced our understanding of general cancer mechanisms. It is through sarcoma research that the pioneering efforts of cancer immunotherapy were explored, that we understand the inherent genetic nature of cancer mutations, and that we appreciate the subclassification of general cancer types to make more accurate prognoses. This review explores the brief history of sarcoma research and what sarcomas can still teach us about the future of cancer research, especially in regard to novel immunotherapy targets, the role of epigenetics in disease progression and chemoresistance, and the benefits of more focused clinical trials.



https://ift.tt/2E7QIKl

Cancers, Vol. 10, Pages 99: Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond

Cancers, Vol. 10, Pages 99: Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond

Cancers doi: 10.3390/cancers10040099

Authors: Nina Prokoph Hugo Larose Megan Lim G. Burke Suzanne Turner

Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65–90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification of combination chemotherapy regimens and employing stem cell transplantation for chemotherapy-resistant patients. More recently, several new and 'renewed' agents have offered the opportunity for a change in the paradigm for the management of both chemo-sensitive and chemo-resistant forms of ALCL. The development of ALK inhibitors following the identification of the EML4-ALK fusion gene in Non-Small Cell Lung Cancer (NSCLC) has opened new possibilities for ALK-positive ALCL. The uniform expression of CD30 on the cell surface of ALCL has given the opportunity for anti-CD30 antibody therapy. The re-evaluation of vinblastine, which has shown remarkable activity as a single agent even in the face of relapsed disease, has led to the consideration of a revised approach to frontline therapy. The advent of immune therapies such as checkpoint inhibition has provided another option for the treatment of ALCL. In fact, the number of potential new agents now presents a real challenge to the clinical community that must prioritise those thought to offer the most promise for the future. In this review, we will focus on the current status of paediatric ALCL therapy, explore how new and 'renewed' agents are re-shaping the therapeutic landscape for ALCL, and identify the strategies being employed in the next generation of clinical trials.

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Cancers, Vol. 10, Pages 99: Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond

Cancers, Vol. 10, Pages 99: Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond

Cancers doi: 10.3390/cancers10040099

Authors: Nina Prokoph Hugo Larose Megan Lim G. Burke Suzanne Turner

Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65–90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification of combination chemotherapy regimens and employing stem cell transplantation for chemotherapy-resistant patients. More recently, several new and 'renewed' agents have offered the opportunity for a change in the paradigm for the management of both chemo-sensitive and chemo-resistant forms of ALCL. The development of ALK inhibitors following the identification of the EML4-ALK fusion gene in Non-Small Cell Lung Cancer (NSCLC) has opened new possibilities for ALK-positive ALCL. The uniform expression of CD30 on the cell surface of ALCL has given the opportunity for anti-CD30 antibody therapy. The re-evaluation of vinblastine, which has shown remarkable activity as a single agent even in the face of relapsed disease, has led to the consideration of a revised approach to frontline therapy. The advent of immune therapies such as checkpoint inhibition has provided another option for the treatment of ALCL. In fact, the number of potential new agents now presents a real challenge to the clinical community that must prioritise those thought to offer the most promise for the future. In this review, we will focus on the current status of paediatric ALCL therapy, explore how new and 'renewed' agents are re-shaping the therapeutic landscape for ALCL, and identify the strategies being employed in the next generation of clinical trials.

https://ift.tt/2pSTBd4

Proton beam therapy for the management of mediastinal Hodgkin lymphoma in a young female patient

Publication date: Available online 30 March 2018
Source:Cancer/Radiothérapie
Author(s): E. Meyer, F. Goudjil, J. Tamburini, R. Dendale, Y. Kirova




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Proton beam therapy for the management of mediastinal Hodgkin lymphoma in a young female patient

Publication date: Available online 30 March 2018
Source:Cancer/Radiothérapie
Author(s): E. Meyer, F. Goudjil, J. Tamburini, R. Dendale, Y. Kirova




https://ift.tt/2Gm5tzd

Impact of formulation on the iontophoretic delivery of the FOLFIRINOX regimen for the treatment of pancreatic cancer

Abstract

Purpose

Effective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti-cancer effects of these therapies while sparing unwanted toxicity. The objective of this study was to investigate the impact of formulation on the electro-transport of the FOLFIRINOX regimen for the development of a new treatment for pancreatic cancer.

Methods

Three formulations of the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were generated at a fixed pH of 6.0 and were referred to as formulation A (single drug solution with all four drugs combined), formulation B (two drug solutions with two drugs per solution), and formulation C (four individual drug solutions). Anodic iontophoresis of the three different formulations was evaluated in orthotopic patient-derived xenografts of pancreatic cancer.

Results

Iontophoretic transport of the FOLFIRINOX drugs was characterized according to organ exposure after a single device treatment in vivo. We report that the co-iontophoresis of two drug solutions, leucovorin + oxaliplatin and 5-fluorouracil + irinotecan, resulted in the highest levels of cytotoxic drugs in the tumor compared to drugs delivered individually or combined into one solution. There was no significant difference in plasma, pancreas, kidney, and liver exposure to the cytotoxic drugs delivered by the three different formulations. In addition, we found that reducing the duration of iontophoretic treatment from 10 to 5 min per solution resulted in a significant decrease in drug concentrations.

Conclusions

Underlying the difference in drug transport of the formulations was electrolyte concentrations, which includes both active and inactive components. Electrolyte concentrations can hinder or improve drug electro-transport. Overall, balancing electrolyte concentration is needed for optimal electro-transport.

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Impact of formulation on the iontophoretic delivery of the FOLFIRINOX regimen for the treatment of pancreatic cancer

Abstract

Purpose

Effective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti-cancer effects of these therapies while sparing unwanted toxicity. The objective of this study was to investigate the impact of formulation on the electro-transport of the FOLFIRINOX regimen for the development of a new treatment for pancreatic cancer.

Methods

Three formulations of the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were generated at a fixed pH of 6.0 and were referred to as formulation A (single drug solution with all four drugs combined), formulation B (two drug solutions with two drugs per solution), and formulation C (four individual drug solutions). Anodic iontophoresis of the three different formulations was evaluated in orthotopic patient-derived xenografts of pancreatic cancer.

Results

Iontophoretic transport of the FOLFIRINOX drugs was characterized according to organ exposure after a single device treatment in vivo. We report that the co-iontophoresis of two drug solutions, leucovorin + oxaliplatin and 5-fluorouracil + irinotecan, resulted in the highest levels of cytotoxic drugs in the tumor compared to drugs delivered individually or combined into one solution. There was no significant difference in plasma, pancreas, kidney, and liver exposure to the cytotoxic drugs delivered by the three different formulations. In addition, we found that reducing the duration of iontophoretic treatment from 10 to 5 min per solution resulted in a significant decrease in drug concentrations.

Conclusions

Underlying the difference in drug transport of the formulations was electrolyte concentrations, which includes both active and inactive components. Electrolyte concentrations can hinder or improve drug electro-transport. Overall, balancing electrolyte concentration is needed for optimal electro-transport.

https://ift.tt/2pTCUho

Impact of formulation on the iontophoretic delivery of the FOLFIRINOX regimen for the treatment of pancreatic cancer

Abstract

Purpose

Effective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti-cancer effects of these therapies while sparing unwanted toxicity. The objective of this study was to investigate the impact of formulation on the electro-transport of the FOLFIRINOX regimen for the development of a new treatment for pancreatic cancer.

Methods

Three formulations of the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were generated at a fixed pH of 6.0 and were referred to as formulation A (single drug solution with all four drugs combined), formulation B (two drug solutions with two drugs per solution), and formulation C (four individual drug solutions). Anodic iontophoresis of the three different formulations was evaluated in orthotopic patient-derived xenografts of pancreatic cancer.

Results

Iontophoretic transport of the FOLFIRINOX drugs was characterized according to organ exposure after a single device treatment in vivo. We report that the co-iontophoresis of two drug solutions, leucovorin + oxaliplatin and 5-fluorouracil + irinotecan, resulted in the highest levels of cytotoxic drugs in the tumor compared to drugs delivered individually or combined into one solution. There was no significant difference in plasma, pancreas, kidney, and liver exposure to the cytotoxic drugs delivered by the three different formulations. In addition, we found that reducing the duration of iontophoretic treatment from 10 to 5 min per solution resulted in a significant decrease in drug concentrations.

Conclusions

Underlying the difference in drug transport of the formulations was electrolyte concentrations, which includes both active and inactive components. Electrolyte concentrations can hinder or improve drug electro-transport. Overall, balancing electrolyte concentration is needed for optimal electro-transport.

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Striking Racial/Ethnic Disparities in Liver Cancer Incidence Rates and Temporal Trends in California, 1988–2012

Abstract

Background

Hepatocellular carcinoma (HCC) is characterized by disparate risk patterns by race/ethnicity. We examined HCC incidence patterns and temporal trends among detailed racial/ethnic populations, including disaggregated Asian-American subgroups.

Methods

Using data from the population-based California Cancer Registry, we identified 41 929 invasive HCC cases diagnosed during 1988–2012. Patients were grouped into mutually exclusive racial/ethnic groups of non-Hispanic (NH) white, NH black, Hispanic, and NH Asian/Pacific Islander (API), as well as Asian subgroups of Chinese, Filipino, Japanese, Korean, Vietnamese, Cambodian, Laotian, and South Asian. Age-adjusted and age-specific incidence rates by sex, race/ethnicity, and time period were calculated. The average annual percent change (AAPC) in incidence rates was estimated using joinpoint regression. All estimates were provided with the 95% confidence intervals (CIs).

Results

Aggregated NH API had higher HCC risk than NH whites, NH blacks, and Hispanics. When disaggregated, Southeast Asians (Vietnamese, Cambodians, and Laotians) had overall HCC incidence rates eight to nine times higher than NH whites and more than twice that of other ethnic Asians. Statistically significant rising temporal trends of HCC were found in NH whites, NH blacks, and Hispanics, especially those older than age 50 years. Overall HCC risk declined in Chinese males (AAPC = –1.3%, 95% CI = –2.0 to –0.6), but rose in Filipino (AAPC = +1.2%, 95% CI = 0.3 to 2.1) and Japanese males (AAPC = +3.0%, 95% CI = 0.4 to 5.6) and Vietnamese (AAPC = +4.5%, 95% CI = 0.7 to 8.5) and Laotian (+3.4%, 95% CI = 0.1 to 6.8) females.

Conclusions

Our findings provide valuable information for the identification of at-risk ethnic subgroups of Asian Americans while underscoring the importance of disaggregating ethnic populations in cancer research.

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High-dose thiamine and essential tremor

Essential tremor is a common neurological disease. The medical treatment of this affection currently involves the use of propranolol, primidone and other drugs. These drugs, however, are often not effective in reducing tremor and cause side effects in a large share of the patients treated. The treatment with intramuscular high-dose thiamine has led to a rapid, remarkable and persistent improvement of the symptoms in two patients with essential tremor. This result suggests the possibility that high doses of intramuscular thiamine may be an affordable alternative, highly effective and long-lasting medical treatment that has shown no relevant side effect.

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Acute brainstem compression

Description

A 34-year-old African woman, whose medical history was unremarkable, presented to the emergency room with severe headache and vomiting. Temperature, blood cells count, plasma electrolytes and chest X-ray were normal. Clinical conditions were rapidly deteriorating and neurological exam disclosed drowsiness, opisthotonus and decerebrate response to pain. Brain CT scan showed a 'full' posterior fossa, mild supratentorial hydrocephalus and herniation of cerebellar tonsils: after contrast, a nodule with ring enhancement and conspicuous perilesional oedema was disclosed in the right cerebellar hemisphere.

The patient was given diuretics and steroids with no success. Since the neurological conditions were worsening, a neurosurgical operation was then performed in emergency: posterior fossa was decompressed, the cerebellar nodular lesion was removed en bloc with microsurgical technique and a transient ventricular drain was placed. Neurological conditions promptly recovered after surgery.

Possible differential diagnosis:

Metastasis

Pyogenic abscess

Primitive brain tumour

Abscess from non-pyogenic agents.

...

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Rapid onset of multiple concurrent squamous cell carcinomas associated with the use of an arsenic-containing traditional medicine for chronic plaque psoriasis

We report a case of a 46-year-old Vietnamese man who developed widespread, numerous and concurrent cutaneous squamous cell carcinomas (SCCs) in non-sun exposed skin areas after taking a traditional medicine (TM) formulation for chronic plaque psoriasis. The SCC lesions began to develop within 12–15 months after beginning the arsenic-containing TM. The patient experienced both acute and chronic symptoms consistent with arsenic exposure. Laboratory investigation of a collected hair sample showed a significant arsenic level. The TM formulation used by the patient was tested and demonstrated an extremely high concentration of arsenic.

https://ift.tt/2IgXikm

Beckwith-Weidemann syndrome with IC2 (KvDMR1) hypomethylation defect: a novel mutation

The Beckwith-Wiedemann syndrome (BWS) is a rare genetic syndrome. However, this is one of the most common overgrowth syndromes. This is a genetically and clinically heterogeneous syndrome. Here, we report a case of Beckwith-Weidemann syndrome without macrosomia, visceromegaly and hemihyperplasia but having macroglossia, omphalocele and anterior linear ear lobe creases. The diagnosis was confirmed by gene analysis suggestive of imprinting centre 2 (KvDMR1) hypomethylation defect.

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Proximal tibiofibular joint dislocation treated using flexible and permanent syndesmosis fixation

We present the case of a 40-year-old man who suffered an isolated proximal tibiofibular dislocation of the left knee after a trauma during a soccer game. Physical examination and radiographic imaging revealed an anterolateral dislocation of the proximal fibula. The diagnosis was confirmed by MRI. The treatment choice was open reduction and internal fixation under direct visualisation using flexible and permanent internal fixation. Postoperative treatment includes knee immobilisation during the first week, and partial weight was allowed for 2 weeks progressing to full weight bearing over 4 weeks. The patient started a gradual and progressive physical therapy programme with range of motion exercises, muscle strengthening and gait training. Full knee range of motion was achieved after 4 weeks. No complaint of pain or hardware discomfort was reported, and the patient is back to daily life and sports activities after 6 months of surgical treatment.

https://ift.tt/2IeLIWM

Childhood obesity in Mexico: social determinants of health and other risk factors

Approximately 50 million children and adolescents in Latin America are affected by the childhood obesity pandemic. We present the case of a 5-year-old Mexican girl with obesity and gastro-oesophageal reflux disease (GORD), in whom prenatal, lifestyle and environmental risk factors were identified. Here, we demonstrate how childhood obesity is rooted since pregnancy and the perinatal stage, and how the social determinants of health like unsafe outdoor conditions, lack of infrastructure to exercise and a suboptimal physical activity curriculum in government schools strongly influence the development and maintenance of childhood obesity and complicate management.

https://ift.tt/2pQA65y

Pseudotumor cerebri as the presentation of Lyme disease in a non-endemic area

Intracranial hypertension is a rare entity in prepubertal children, and its differential diagnosis includes a number of systemic diseases, drugs, vitamin deficiencies and excesses, and hereditary conditions. Infectious aetiology is rare. The case of a 9-year-old boy with intracranial hypertension secondary to acute neuroborreliosis is described. He presented with daily pulsatile frontotemporal headache, pallor, photophobia and phonophobia. His neurological examination revealed papilledema with no nuchal rigidity. The lumbar puncture showed increased pressure (50 cm H₂O) and lymphocytic pleocytosis. Serum and cerebrospinal fluid (CSF) Borrelia burgdorferi antibodies were positive. This kind of infection is rare in Portugal but a trip to an endemic area was identified. A careful history, considering the exposure to rural areas together with the intracranial hypertension and inflammatory CSF, are important clues to the diagnosis, allowing the institution to select appropriate treatment.

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Essential thrombocytosis 40 years after splenectomy

Description

A 69-year-old man presented at our Department of Neurology in December 2016 with acute aphasia. His medical history was notable of splenectomy after a spleen rupture due to a car accident at the age of 25, a subarachnoidal haemorrhage (SAH) without evidence of cerebral aneurysm at the age of 35 and a non-ST elevation myocardial infarction at the age of 63. For this vascular event, a drug-eluting stent was placed into the ramus interventricularis anterior, followed by combined antiplatelet treatment for 2 years, and up to admission acetylsalicylic acid was given at a dose of 100 mg per day.

Now MRI revealed a left hemispheric ischaemic stroke (figure 1A). No major vascular risk factors were found. The only pathological finding was a thrombocytosis of 1700x10³ per µL, reference value 150–450x10³ per µL. A post-splenectomy syndrome was suspected. However, previous thrombocyte levels as documented during the SAH...

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Adult scurvy associated with psychiatric disorders and breast feeding

Scurvy is a nutritional disease caused by ascorbic acid deficiency and is potentially fatal. It was originally described in the 18th century by James Lind and associated with long sea voyages and insufficient citrus consumption. Its prevalence has declined markedly over the years but has still been described sporadically in certain countries. A 22-year-old woman with an anxiety disorder and anorexia nervosa, recent pregnancy and ongoing breast feeding, presented with a 10-day history of spontaneous haematomas in the lower limbs, gingivorrhagia and fatigue. The examination was remarkable for signs of minor bleeding without haemodynamic compromise, gonalgia and pale skin. Work-up studies revealed the presence of anaemia. Direct anamnesis identified a diet based solely of tea and carbohydrates due to distorted body image. With the working diagnosis of scurvy, nutritional support and oral vitamin C supplementation was initiated. Her symptoms and anaemia resolved in 30 days and the diagnosis was confirmed biochemically.

https://ift.tt/2Goj2u2

Apixaban-induced subdural bleeding: case presentation and literature review

Apixaban is a factor Xa inhibitor which is a non-vitamin K dependent oral anticoagulant known tocause the lowest rate of intracranial bleeding among the same kind of inibitors. In this paper, we report a rare case in a 60-year-old man with a history of hypertension and oligodendroglioma on apixaban for deep venous thrombosis who presented to our hospital with decreased level of consciousness and slurred speech with rapid deterioration. We highlight the risk of subdural bleeding requiring immediate neurosurgical intervention due to apixaban, with literature review.

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Synovial sarcoma of the transverse colon: a rare cause of intussusception

We report a third case of a primary intramural synovial sarcoma of the lower gastrointestinal tract. A 50-year-old woman presented with hematochezia, dizziness and shortness of breath. CT imaging revealed a transverse colo-colonic intussusception with a colonic mass serving as a lead point. A subtotal colectomy was performed with oncologic resection of a sausage-like mass in the mid-transverse colon. Pathological assessment showed a biphasic synovial sarcoma. The postoperative hospital course was without complications and the patient was discharged home with plans for postoperative surveillance.

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In Reply to Cihan

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Tyler M. Seibert, Jona A. Hattangadi-Gluth




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In Regard to Seibert et al

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Yasemin Benderli Cihan




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In Regard to Rao et al

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Melis Gultekin, Sezin Yuce Sari, Mustafa Cengiz




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Meetings

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1





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Genomics Reloaded: Rise of the Expression Profiles

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Gregory N. Gan, Randall J. Kimple




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Small Cells, Big Problems

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Hanbo Chen




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Consolidative Thoracic Radiation and Serial Central Nervous System Imaging

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Megan E. Daly




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In Regard to Pasquier et al

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Sanaa El Majjaoui, Nabil Ismaili, Noureddine Benjaafar




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Select Patients With “Limited” Extensive-Stage Small Cell Lung Cancer Should Be Treated Aggressively

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Elizabeth M. Gore




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A Small Window of Opportunity When Disease Is Limited in Extensive-Stage Small Cell Lung Cancer?

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Alexander V. Louie




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Issue Highlights

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1





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Not All Nails Need a Hammer

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): James J. Urbanic




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In Regard to Churilla et al

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Paul W. Sperduto




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Ablative Hypofractionated Radiation Therapy Enhances Non-Small Cell Lung Cancer Cell Killing via Preferential Stimulation of Necroptosis In Vitro and In Vivo

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Huan-Huan Wang, Zhi-Qiang Wu, Dong Qian, Nicholas G. Zaorsky, Ming-Han Qiu, Jing-Jing Cheng, Chao Jiang, Juan Wang, Xian-Liang Zeng, Chun-Lei Liu, Li-Jun Tian, Guo-Guang Ying, Mao-Bin Meng, Xi-Shan Hao, Zhi-Yong Yuan
PurposeTo investigate how necroptosis (ie, programmed necrosis) is involved in killing of non-small cell lung cancer (NSCLC) after ablative hypofractionated radiation therapy (HFRT).Methods and MaterialsDeoxyribonucleic acid damage, DNA repair, and the death form of NSCLC cells were assessed after radiation therapy. The overexpression and silencing of receptor-interacting protein kinases 3 (RIP3, a key protein involved activation of necroptosis)-stable NSCLC cell lines were successfully constructed. The form of cell death, the number and area of colonies, and the regulatory proteins of necroptosis were characterized after radiation therapy in vitro. Finally, NSCLC xenografts and patient specimens were used to examine involvement of necroptosis after ablative HFRT in vivo.ResultsRadiation therapy induced expected DNA damage and repair of NSCLC cell lines, but ablative HFRT at ≥10 Gy per fraction preferentially stimulated necroptosis in NSCLC cells and xenografts with high RIP3 expression, as characterized by induction and activation of RIP3 and mixed-lineage kinase domain-like protein and release of immune-activating chemokine high-mobility group box 1. In contrast, RNA interference of RIP3 attenuated ablative HFRT-induced necroptosis and activation of its regulatory proteins. Among central early-stage NSCLC patients receiving stereotactic body radiation therapy, high expression of RIP3 was associated with improved local control and progression-free survival (all P < .05).ConclusionsAblative HFRT at ≥10 Gy per fraction enhances killing of NSCLC with high RIP3 expression via preferential stimulation of necroptosis. RIP3 may serve as a useful biomarker to predict favorable response to stereotactic body radiation therapy.



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In Reply to Gultekin et al

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Avani D. Rao, Stephanie A. Terezakis




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In Reply to El Majjaoui et al

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): David Pasquier




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Determination of Intrafraction Prostate Motion During External Beam Radiation Therapy With a Transperineal 4-Dimensional Ultrasound Real-Time Tracking System

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Dwi Seno Kuncoro Sihono, Michael Ehmann, Sigrun Heitmann, Sandra von Swietochowski, Mario Grimm, Judit Boda-Heggemann, Frank Lohr, Frederik Wenz, Hansjörg Wertz
Purpose/ObjectiveTo determine intrafraction prostate motion during volumetric modulated arc therapy (VMAT) using transperineal ultrasound (US) real-time tracking.Methods and Materials770 US monitoring sessions in 38 prostate cancer patients' VMAT treatment series were retrospectively evaluated. Intrafraction motion assessment of the prostate was based on continuous position monitoring with a 4-dimensional US system along the 3 directions: left-right (LR), anterior-posterior (AP), and inferior-superior (SI). The overall mean values and standard deviations (SD) along with random and systematic errors were calculated.ResultsThe mean duration of each monitoring session was 254 s. The mean (μ), the systematic error (Σ), and the random error (σ) of intrafraction prostate displacement were μ = (0.01, −0.08, 0.15) mm, Σ = (0.30, 0.34, 0.23) mm, and σ = (0.59, 0.73, 0.64) mm in the LR, AP and SI directions, respectively. The percentage of treatments for which prostate displacement was ≤2 mm was 97.01%, 92.24%, and 95.77% in the LR, AP, and SI directions, respectively. At 60 s, a vector length of prostate displacement >2 mm was present in 0.67% of the data. The percentage increased to 2.42%, 6.14%, and 9.35% at 120 s, 180 s, and 240 s, respectively.ConclusionsThe magnitudes of intrafraction prostate motion along the SI and AP directions were comparable. On average, the smallest motion was in the LR direction and the largest in AP direction. Most of the prostate displacements were within a few millimeters. However, with increasing treatment time (eg, during hypofractionation), larger 3-dimensional prostate displacements up to 18.30 mm could be observed. Shortening treatment time can reduce the impact of intrafraction motion and potentially allows smaller safety margins.



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A Prospective 4π Radiation Therapy Clinical Study in Recurrent High-Grade Glioma Patients

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Victoria Y. Yu, Angelia Landers, Kaley Woods, Dan Nguyen, Minsong Cao, Dongsu Du, Robert K. Chin, Ke Sheng, Tania B. Kaprealian
PurposeTo evaluate the feasibility, safety, dosimetric benefits, delivery efficiency, and patient comfort in the clinical implementation of 4π radiation therapy.Methods and MaterialsEleven patients with recurrent high-grade glioma were recruited for the trial. 4π plans integrating beam orientation and fluence-map optimization were created using an in-house column-generation algorithm. The collision-free beam solution space throughout the 4π steradian was determined using a computer-aided-design model of the Varian TrueBeam system and a human subject. Twenty beams were optimized for each case and imported into Eclipse for intensity modulated radiation therapy planning. Beam orientations with neighboring couch kicks were merged for increased delivery efficiency, generating plans with an average of 16 beam orientations. Volumetric modulated arc therapy (VMAT) plans with 3-4 arcs were also generated for each case, and the plan achieving superior dosimetric quality was selected for treatment. Patient comfort was surveyed after every fraction. Multiple 2-dimensional X-ray images were obtained to measure intrafractional motion.ResultsOf 11 patients, 9 were treated with 4π. Mean and maximum organ at risk doses were equal or significantly lower (P < .05) with 4π than with VMAT. Particularly substantial dose reduction of 2.92 Gy in the average accumulated brainstem maximum dose enabled treatments that would otherwise not satisfy safe dose constraints with VMAT. One patient was not treated because neither plan met the dosimetric criteria. The other was treated with VMAT owing to comparable dosimetry resulting from a planning target volume located in a separate co-plane superior to organs at risk. Treatments were well tolerated, with an average patient comfort score of 8.6/10. Intrafractional motion was <1.5 mm for all delivered fractions, and the average delivery time was 34.1 minutes.ConclusionsThe feasibility, safety, dosimetric benefits, delivery efficiency, and patient comfort of 4π radiation therapy have been clinically demonstrated with a prospective clinical trial. The results elucidate the potential and challenges of wider clinical implementations.



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National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Daphne Haas-Kogan, Daniel Indelicato, Harald Paganetti, Natia Esiashvili, Anita Mahajan, Torunn Yock, Stella Flampouri, Shannon MacDonald, Maryam Fouladi, Kry Stephen, John Kalapurakal, Stephanie Terezakis, Hanne Kooy, David Grosshans, Mike Makrigiorgos, Kavita Mishra, Tina Young Poussaint, Kenneth Cohen, Thomas Fitzgerald, Vinai Gondi, Arthur Liu, Jeff Michalski, Dragan Mirkovic, Radhe Mohan, Stephanie Perkins, Kenneth Wong, Bhadrasain Vikram, Jeff Buchsbaum, Larry Kun
PurposeProton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury.Methods and MaterialsTwenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016.ResultsThe average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning.ConclusionsBrainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.



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Regional Nodal Control for Head and Neck Alveolar Rhabdomyosarcoma

Publication date: 1 May 2018
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 101, Issue 1
Author(s): Ethan B. Ludmir, Arnold C. Paulino, David R. Grosshans, Mary Frances McAleer, Susan L. McGovern, Winston W. Huh, M. Fatih Okcu, Leslie M. Harrell, Anita Mahajan
PurposeTo assess clinical outcomes and patterns of failure, particularly regional nodal control, for pediatric patients treated with proton beam therapy (PBT) for head and neck alveolar rhabdomyosarcoma (HN-ARMS).Materials and MethodsBetween 2006 and 2015, 14 patients with HN-ARMS were enrolled in a prospective registry protocol and treated with PBT at a single institution. Of the patients, 8 (57%) presented with localized disease and 6 (43%) with regional nodal metastases. All patients were treated with systemic therapy per accepted cooperative group regimens. All patients received PBT to the primary site and involved nodal disease with a median dose of 50.4 Gy (relative biological effectiveness). Elective nodal irradiation was not delivered.ResultsThe median follow-up period for surviving patients was 4.3 years. The 5-year overall survival and disease-free survival rates for the cohort (N = 14) were 45% and 25%, respectively. There were 10 relapses in the cohort: 7 regional nodal, 1 combination local and regional nodal, and 2 leptomeningeal. In 6 of 8 patients (75%) with no nodal disease at diagnosis, isolated regional nodal relapse developed. All nodal relapses occurred in first-echelon draining lymph node basins relative to the primary tumor site. Of 6 patients who presented with nodal metastases, 2 had regional nodal relapse; both of these nodal relapses occurred in the same nodal basin that was initially involved by disease but was not completely targeted as part of the primary treatment plan.ConclusionsHigh rates of regional nodal relapse are observed for HN-ARMS patients, including patients with no nodal disease at diagnosis. These data suggest that HN-ARMS patients may benefit from elective nodal irradiation to treat at-risk draining lymph node stations relative to the primary tumor site. We further recommend coverage of the entire nodal level for any sites of initial nodal disease at diagnosis, given the high risk of failure at these sites.



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