Incidental Findings in Reduction Mammoplasty Specimens in Patients with No Prior History of Breast Cancer. An Analysis of 783 Specimens

Abstract

Breast reduction surgery is a common procedure and the rate of incidental findings in the removed specimens varies between 0% and 4.6%. There are no guidelines about pathological evaluation of breast reduction surgery. We reviewed all pathology reports of patients undergoing breast reduction surgery in a single tertiary institution in Brazil from January 2008 to August 2014. Exclusion criteria were a personal history of breast cancer, unclear reason for mastectomy and incomplete data on the pathology report. We considered "relevant findings" flat epithelial atypia, atypical hyperplasia, carcinomas in situ and invasive carcinoma. Of 1672 specimens from breast reduction surgery, 783 met inclusion criteria. Median patient age was 40 (8–77), 91% underwent bilateral mastectomy and 57% of the specimens weighted less than 200 g. In 55% of cases, 4 or more paraffin blocks were sampled. There were 40 (5.1%) relevant findings and the most common was atypical lobular hyperplasia (16–2%). There were 3 invasive carcinomas (0.38%). In multivariate analysis, the only variables associated with a higher odds of relevant pathological findings were patient age ≥ 40 (OR 4.73 CI95% 1.98–11.3 p < 0.001) and sampling of ≥4 paraffin blocks from each specimen (OR 6.69 95% CI 2.25–19.9 p < 0.001). The incidence of pre-malignant and malignant lesions in specimens from breast reduction surgery is around 5%, but this risk is significantly higher for patients older than 40 years-old. Sampling at least 4 paraffin blocks from each specimen significantly increases detection rates.

http://ift.tt/2odtWfj

Disease Burden of Mild Asthma: Findings from a Cross-Sectional Real-World Survey

Abstract

Introduction

Most asthma patients have mild disease, although the burden of mild asthma is not well understood nor studied. Some evidence suggests that many patients with mild asthma experience suboptimal symptom control and exacerbations. This study characterizes the burden of illness and treatment patterns among patients with a confirmed diagnosis of mild asthma, defined as GINA Step 1 or Step 2, and residing in China, France, Germany, Italy, Japan, Spain, the United Kingdom, or the United States.

Methods

The Respiratory Disease-Specific Programme prospective cross-sectional survey was conducted with primary care and specialty physicians in each of the eight countries. Physician and patient surveys assessed demographic and clinical characteristics, frequency and timing of asthma symptoms, exacerbations, and rescue inhaler usage, the most recent FEV₁% predicted, and healthcare utilization. GINA Step was determined by prescribed treatment regimen. GINA Step 1 patients were prescribed as-needed reliever medication and Step 2 required treatment with a low-dose inhaled corticosteroid, leukotriene receptor antagonist, or theophylline. Treatment adherence was assessed with the Morisky Medication Adherence scale, disease control with the Asthma Control Test, and work and activity impairments with the Work Productivity and Activity Impairment scale.

Results

The sample included 1115 GINA Step 1 and 2 patients, with 53% classified as Step 2. Overall asthma control was suboptimal, with reports of nocturnal symptoms (40.6%), symptom worsening (10.5%), and rescue inhaler usage in the last 4 weeks (33.6%). 25% of patients were uncontrolled. The overall mean number of exacerbations in the last 12 months was 0.4, with a higher frequency of exacerbations in Step 2 patients who also experienced more exacerbations requiring treatment intensification, an emergency department visit, or hospitalization.

Conclusion

Mild asthma imposes a substantial burden on patients, establishing the need for comprehensive management plans and ongoing support for treatment adherence.

Funding

AstraZeneca.

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Disease Burden of Mild Asthma: Findings from a Cross-Sectional Real-World Survey

Abstract

Introduction

Most asthma patients have mild disease, although the burden of mild asthma is not well understood nor studied. Some evidence suggests that many patients with mild asthma experience suboptimal symptom control and exacerbations. This study characterizes the burden of illness and treatment patterns among patients with a confirmed diagnosis of mild asthma, defined as GINA Step 1 or Step 2, and residing in China, France, Germany, Italy, Japan, Spain, the United Kingdom, or the United States.

Methods

The Respiratory Disease-Specific Programme prospective cross-sectional survey was conducted with primary care and specialty physicians in each of the eight countries. Physician and patient surveys assessed demographic and clinical characteristics, frequency and timing of asthma symptoms, exacerbations, and rescue inhaler usage, the most recent FEV₁% predicted, and healthcare utilization. GINA Step was determined by prescribed treatment regimen. GINA Step 1 patients were prescribed as-needed reliever medication and Step 2 required treatment with a low-dose inhaled corticosteroid, leukotriene receptor antagonist, or theophylline. Treatment adherence was assessed with the Morisky Medication Adherence scale, disease control with the Asthma Control Test, and work and activity impairments with the Work Productivity and Activity Impairment scale.

Results

The sample included 1115 GINA Step 1 and 2 patients, with 53% classified as Step 2. Overall asthma control was suboptimal, with reports of nocturnal symptoms (40.6%), symptom worsening (10.5%), and rescue inhaler usage in the last 4 weeks (33.6%). 25% of patients were uncontrolled. The overall mean number of exacerbations in the last 12 months was 0.4, with a higher frequency of exacerbations in Step 2 patients who also experienced more exacerbations requiring treatment intensification, an emergency department visit, or hospitalization.

Conclusion

Mild asthma imposes a substantial burden on patients, establishing the need for comprehensive management plans and ongoing support for treatment adherence.

Funding

AstraZeneca.

http://ift.tt/2pfoOFf

Masthead

Publication date: February 2017
Source:Seminars in Oncology, Volume 44, Issue 1





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Editorial Board

Publication date: February 2017
Source:Seminars in Oncology, Volume 44, Issue 1





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Table of Contents

Publication date: February 2017
Source:Seminars in Oncology, Volume 44, Issue 1





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outside front cover

Publication date: February 2017
Source:Seminars in Oncology, Volume 44, Issue 1





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A Peutz–Jeghers syndrome family associated with sinonasal adenocarcinoma: 28 years follow up report

Abstract

Peutz–Jeghers syndrome (PJS) is a rare hereditary disorder characterized by hamartomatous polyps in both of the gastrointestinal tract and mucosal pigmentation. It could increase in risk of intestinal and extra-intestinal neoplasms. We here described three cases of sinonasal polyposis in a PJS family and two developed sinonasal type adenocarcinoma. Genetic study revealed a germline STK11/LKB1 mutation on codon 179 (c.C536G, p.P179R) of exon 4. LOH analysis of the LKB1 locus confirms this to be a deleterious mutation. Sinonasal polyposis with malignant transformation could be encountered in PJS patients. Regular follow-up was recommended for the risk of malignant changes in nasal polyps.

http://ift.tt/2okDYvO

Predicting posttraumatic hydrocephalus: derivation and validation of a risk scoring system based on clinical characteristics

Abstract

Posttraumatic hydrocephalus (PTH) is a disorder of disturbed cerebrospinal fluid (CSF) dynamics after traumatic brain injury (TBI). It can lead to brain metabolic impairment and dysfunction and has a high risk of clinical deterioration and worse outcomes. The incidence and risk factors for the development of PTH after decompressive craniectomy (DC) has been assessed in previous studies, but rare studies identify patients with higher risk for PTH among all TBI patients. This study aimed to develop and validate a risk scoring system to predict PTH after TBI. Demographics, injury severity, duration of coma, radiologic findings, and DC were evaluated to determine the independent predictors of PTH during hospitalization until 6 months following TBI through logistic regression analysis. A risk stratification system was created by assigning a number of points for each predictor and validated in an independent cohort. The model accuracy was assessed by the area under the receiver operating characteristic curve (AUC). Of 526 patients in the derivation cohort, 57 (10.84%) developed PTH during 6 months follow up. Age > 50 yrs (Odd ratio [OR] = 1.91, 95% confidence interval [CI] 1.09–3.75, 4 points), duration of coma ≥1 w (OR = 5.68, 95% CI 2.57–13.47, 9 points), Fisher grade III (OR = 2.19, 95% CI 1.24–4.36, 5 points) or IV (OR = 3.87, 95% CI 1.93–8.43, 7 points), bilateral DC (OR = 6.13, 95% CI 2.82–18.14, 9 points), and extra herniation after DC (OR = 2.36, 95% CI 1.46–4.92, 5 points) were independently associated with PTH. Rates of PTH for the low- (0–12 points), intermediate- (13–22 points) and high-risk (23–34 points) groups were 1.16%, 35.19% and 78.57% (p < 0.0001). The corresponding rates in the validation cohort, where 17/175 (9.71%) developed PTH, were 1.35%, 37.50% and 81.82% (p < 0.0001). The risk score model exhibited good-excellent discrimination in both cohorts, with AUC of 0.839 versus 0.894 (derivation versus validation) and good calibration (Hosmer-Lemshow p = 0.56 versus 0.68). This model will be useful to identify patients at high risk for PTH who may be candidates for preventive interventions, and to improve their outcomes.

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Predicting posttraumatic hydrocephalus: derivation and validation of a risk scoring system based on clinical characteristics

Abstract

Posttraumatic hydrocephalus (PTH) is a disorder of disturbed cerebrospinal fluid (CSF) dynamics after traumatic brain injury (TBI). It can lead to brain metabolic impairment and dysfunction and has a high risk of clinical deterioration and worse outcomes. The incidence and risk factors for the development of PTH after decompressive craniectomy (DC) has been assessed in previous studies, but rare studies identify patients with higher risk for PTH among all TBI patients. This study aimed to develop and validate a risk scoring system to predict PTH after TBI. Demographics, injury severity, duration of coma, radiologic findings, and DC were evaluated to determine the independent predictors of PTH during hospitalization until 6 months following TBI through logistic regression analysis. A risk stratification system was created by assigning a number of points for each predictor and validated in an independent cohort. The model accuracy was assessed by the area under the receiver operating characteristic curve (AUC). Of 526 patients in the derivation cohort, 57 (10.84%) developed PTH during 6 months follow up. Age > 50 yrs (Odd ratio [OR] = 1.91, 95% confidence interval [CI] 1.09–3.75, 4 points), duration of coma ≥1 w (OR = 5.68, 95% CI 2.57–13.47, 9 points), Fisher grade III (OR = 2.19, 95% CI 1.24–4.36, 5 points) or IV (OR = 3.87, 95% CI 1.93–8.43, 7 points), bilateral DC (OR = 6.13, 95% CI 2.82–18.14, 9 points), and extra herniation after DC (OR = 2.36, 95% CI 1.46–4.92, 5 points) were independently associated with PTH. Rates of PTH for the low- (0–12 points), intermediate- (13–22 points) and high-risk (23–34 points) groups were 1.16%, 35.19% and 78.57% (p < 0.0001). The corresponding rates in the validation cohort, where 17/175 (9.71%) developed PTH, were 1.35%, 37.50% and 81.82% (p < 0.0001). The risk score model exhibited good-excellent discrimination in both cohorts, with AUC of 0.839 versus 0.894 (derivation versus validation) and good calibration (Hosmer-Lemshow p = 0.56 versus 0.68). This model will be useful to identify patients at high risk for PTH who may be candidates for preventive interventions, and to improve their outcomes.

http://ift.tt/2odCQJZ

Inhibition of Voltage-Gated Na+ Channels by Bupivacaine Is Enhanced by the Adjuvants Buprenorphine, Ketamine, and Clonidine.

Background and Objectives: Regional anesthesia includes application of local anesthetics (LAs) into the vicinity of peripheral nerves. Prolongation or improvement of nerve blocks with LAs can be accomplished by coapplication with adjuvants, including buprenorphine, ketamine, and clonidine. While the mechanisms mediating prolonged or improved LA-induced effects by adjuvants are poorly understood, we hypothesized that they are likely to increase LA-induced block of voltage-gated Na+ channels. In this study, we investigated the inhibitory effects of the LA bupivacaine alone and in combination with the adjuvants on neuronal Na+ channels. Methods: Effects of bupivacaine, buprenorphine, ketamine, and clonidine on endogenous Na+ channels in ND7/23 neuroblastoma cells were investigated with whole-cell patch clamp. Results: Bupivacaine, buprenorphine, ketamine, and clonidine are concentration- and state-dependent inhibitors of Na+ currents in ND7/23 cells. Tonic block of resting channels revealed an order of potency of bupivacaine (half-maximal inhibitory concentration [IC50] 178 +/- 8 [mu]M) > buprenorphine (IC50 172 +/- 25) > clonidine (IC50 824 +/- 55 [mu]M) > ketamine (IC50 1377 +/- 92 [mu]M). Bupivacaine and buprenorphine, but not clonidine and ketamine, induced a strong use-dependent block at 10 Hz. Except for clonidine, all substances enhanced fast and slow inactivation. The combination of bupivacaine with one of the adjuvants resulted in a concentration-dependent potentiation bupivacaine-induced block. Conclusions: We demonstrate that buprenorphine, ketamine, and clonidine directly inhibit Na+ channels and that they potentiate the blocking efficacy of bupivacaine on Na+ channels. These data indicate that block of Na+ channels may account for the additive effects of adjuvants used for regional anesthesia. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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A New Step Toward Evidence of In Vivo Perineural Dexamethasone Safety: An Animal Study.

Background and Objectives: The aim of this study was to analyze histological nerve toxicity of perineural dexamethasone administration in combination with ropivacaine on mice. Efficacy of perineural dexamethasone in combination with regional anesthesia is clearly demonstrated. However, the safety of this procedure is still a matter of debate. Methods: A sciatic nerve block was performed on 90 mice. Five groups, each containing 18 mice assigned randomly, were used in these experiments: the sham group (isotonic saline solution), R group (perineural ropivacaine), D group (perineural dexamethasone), RDPN group (perineural ropivacaine and perineural dexamethasone), and the RDS group (perineural ropivacaine and systemic dexamethasone). Sensory and motor blocks were evaluated every 30 minutes for 14 hours. Fourteen and 28 days after this procedure, 9 mice in each group were killed for sciatic nerve histological assessment. Results: No statistical difference was observed between different groups for Wallerian degeneration (P = 0.28 at day 14 and P = 0.22 at day 28) and perineural inflammation (P = 0.9 at day 14). Motor and sensory block durations were tested for each group. A statistical difference was observed for motor block duration between the RDPN group (150 minutes [127-172 minutes]), the RDS group (120 minutes [90-120 minutes]), and the R group (60 minutes [60-90 minutes]). Sensory block duration was also statistically different: 660 minutes (660-720 minutes) in the RDPN group, 480 minutes (427-660 minutes) in RDS group, 330 minutes (240-410) in the R group. Conclusions: A combination of ropivacaine and perineural dexamethasone allows longer sensory block duration compared with ropivacaine alone or ropivacaine and systemic dexamethasone, without increased neural toxicity. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

http://ift.tt/2ocbJNw

Pro-angiogenic capacities of microvesicles produced by skin wound myofibroblasts

Abstract

Wound healing is a very highly organized process where numerous cell types are tightly regulated to restore injured tissue. Myofibroblasts are cells that produce new extracellular matrix and contract wound edges. We previously reported that the human myofibroblasts isolated from normal wound (WMyos) produced microvesicles (MVs) in the presence of the serum. In this study, MVs were further characterized using a proteomic strategy and potential functions of the MVs were determined. MV proteins isolated from six WMyo populations were separated using two-dimensional differential gel electrophoresis. Highly conserved spots were selected and analyzed using mass spectrometry resulting in the identification of 381 different human proteins. Using the DAVID database, clusters of proteins involved in cell motion, apoptosis and adhesion, but also in extracellular matrix production (21 proteins, enrichment score: 3.32) and in blood vessel development/angiogenesis (19 proteins, enrichment score: 2.66) were identified. Another analysis using the functional enrichment analysis tool FunRich was consistent with these results. While the action of the myofibroblasts on extracellular matrix formation is well known, their angiogenic potential is less studied. To further characterize the angiogenic activity of the MVs, they were added to cultured microvascular endothelial cells to evaluate their influence on cell growth and migration using scratch test and capillary-like structure formation in Matrigel^®. The addition of a MV-enriched preparation significantly increased endothelial cell growth, migration and capillary formation compared with controls. The release of microvesicles by the wound myofibroblasts brings new perspectives to the field of communication between cells during the normal healing process.

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Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment

Abstract

Uveal melanoma (UM) is characterized by a number of genetic aberrations that follow a certain chronology and are tightly linked to tumor recurrence and survival. Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells. We used a set of genetically-classified UM to study immune infiltration in the context of their genetic evolution. We show in two independent cohorts that lack of BAP1 expression is associated with an increased density of CD3⁺ T cells and CD8⁺ T cells. The presence of extra copies of chromosome 8q in disomy 3 tumors with a normal BAP1 expression is associated with an increased influx of macrophages (but not T cells). Therefore, we propose that the genetic evolution of UM is associated with changes in the inflammatory phenotype. Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.

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Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer

Abstract

In newly diagnosed metastatic hormone-naive prostate cancer (mPC), telomerase-based immunotherapy with the novel hTERT peptide vaccine UV1 can induce immune responses with potential clinical benefit. This phase I dose escalation study of UV1 evaluated safety, immune response, effects on prostate-specific antigen (PSA) levels, and preliminary clinical outcome. Twenty-two patients with newly diagnosed metastatic hormone-naïve PC (mPC) were enrolled; all had started androgen deprivation therapy and had no visceral metastases. Bone metastases were present in 17 (77%) patients and 16 (73%) patients had affected lymph nodes. Three dose levels of UV1 were given as intradermal injections combined with GM-CSF (Leukine^®). Twenty-one patients in the intention-to-treat population (95%) received conformal radiotherapy. Adverse events reported were predominantly grade 1, most frequently injection site pruritus (86.4%). Serious adverse events considered possibly related to UV1 and/or GM-CSF included anaphylactic reaction in two patients and thrombocytopenia in one patient. Immune responses against UV1 peptides were confirmed in 18/21 evaluable patients (85.7%), PSA declined to <0.5 ng/mL in 14 (64%) patients and in ten patients (45%) no evidence of persisting tumour was seen on MRI in the prostatic gland. At the end of the nine-month reporting period for the study, 17 patients had clinically stable disease. Treatment with UV1 and GM-CSF gave few adverse events and induced specific immune responses in a large proportion of patients unselected for HLA type. The intermediate dose of 0.3 mg UV1 resulted in the highest proportion of, and most rapid UV1-specific immune responses with an acceptable safety profile. These results warrant further clinical studies in mPC.

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Pro-angiogenic capacities of microvesicles produced by skin wound myofibroblasts

Abstract

Wound healing is a very highly organized process where numerous cell types are tightly regulated to restore injured tissue. Myofibroblasts are cells that produce new extracellular matrix and contract wound edges. We previously reported that the human myofibroblasts isolated from normal wound (WMyos) produced microvesicles (MVs) in the presence of the serum. In this study, MVs were further characterized using a proteomic strategy and potential functions of the MVs were determined. MV proteins isolated from six WMyo populations were separated using two-dimensional differential gel electrophoresis. Highly conserved spots were selected and analyzed using mass spectrometry resulting in the identification of 381 different human proteins. Using the DAVID database, clusters of proteins involved in cell motion, apoptosis and adhesion, but also in extracellular matrix production (21 proteins, enrichment score: 3.32) and in blood vessel development/angiogenesis (19 proteins, enrichment score: 2.66) were identified. Another analysis using the functional enrichment analysis tool FunRich was consistent with these results. While the action of the myofibroblasts on extracellular matrix formation is well known, their angiogenic potential is less studied. To further characterize the angiogenic activity of the MVs, they were added to cultured microvascular endothelial cells to evaluate their influence on cell growth and migration using scratch test and capillary-like structure formation in Matrigel^®. The addition of a MV-enriched preparation significantly increased endothelial cell growth, migration and capillary formation compared with controls. The release of microvesicles by the wound myofibroblasts brings new perspectives to the field of communication between cells during the normal healing process.

http://ift.tt/2nqZvDM

Interactions between dietary acrylamide intake and genes for ovarian cancer risk

Abstract

Some epidemiological studies observed a positive association between dietary acrylamide intake and ovarian cancer risk but the causality needs to be substantiated. By analyzing gene-acrylamide interactions for ovarian cancer risk for the first time, we aimed to contribute to this. The prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55–69 years. At baseline in 1986, a random subcohort of 2589 women was sampled from the total cohort for a case cohort analysis approach. Dietary acrylamide intake of subcohort members and ovarian cancer cases (n = 252, based on 20.3 years of follow-up) was assessed with a food frequency questionnaire. We selected single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism and in genes involved in the possible mechanisms of acrylamide-induced carcinogenesis (effects on sex steroid systems, oxidative stress and DNA damage). Genotyping was done on DNA from toenails through Agena's MassARRAY iPLEX platform. Multiplicative interaction between acrylamide intake and SNPs was assessed with Cox proportional hazards analysis. Among the results for 57 SNPs and 2 gene deletions, there were no statistically significant interactions between acrylamide and gene variants after adjustment for multiple testing. However, there were several nominally statistically significant interactions between acrylamide intake and SNPs in the HSD3B1/B2 gene cluster: (rs4659175 (p interaction = 0.04), rs10923823 (p interaction = 0.06) and its proxy rs7546652 (p interaction = 0.05), rs1047303 (p interaction = 0.005), and rs6428830 (p interaction = 0.05). Although in need of confirmation, results of this study suggest that acrylamide may cause ovarian cancer through effects on sex hormones.

http://ift.tt/2nWf0zK

Interactions between dietary acrylamide intake and genes for ovarian cancer risk

Abstract

Some epidemiological studies observed a positive association between dietary acrylamide intake and ovarian cancer risk but the causality needs to be substantiated. By analyzing gene-acrylamide interactions for ovarian cancer risk for the first time, we aimed to contribute to this. The prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55–69 years. At baseline in 1986, a random subcohort of 2589 women was sampled from the total cohort for a case cohort analysis approach. Dietary acrylamide intake of subcohort members and ovarian cancer cases (n = 252, based on 20.3 years of follow-up) was assessed with a food frequency questionnaire. We selected single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism and in genes involved in the possible mechanisms of acrylamide-induced carcinogenesis (effects on sex steroid systems, oxidative stress and DNA damage). Genotyping was done on DNA from toenails through Agena's MassARRAY iPLEX platform. Multiplicative interaction between acrylamide intake and SNPs was assessed with Cox proportional hazards analysis. Among the results for 57 SNPs and 2 gene deletions, there were no statistically significant interactions between acrylamide and gene variants after adjustment for multiple testing. However, there were several nominally statistically significant interactions between acrylamide intake and SNPs in the HSD3B1/B2 gene cluster: (rs4659175 (p interaction = 0.04), rs10923823 (p interaction = 0.06) and its proxy rs7546652 (p interaction = 0.05), rs1047303 (p interaction = 0.005), and rs6428830 (p interaction = 0.05). Although in need of confirmation, results of this study suggest that acrylamide may cause ovarian cancer through effects on sex hormones.

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Incidental Findings in Reduction Mammoplasty Specimens in Patients with No Prior History of Breast Cancer. An Analysis of 783 Specimens

Abstract

Breast reduction surgery is a common procedure and the rate of incidental findings in the removed specimens varies between 0% and 4.6%. There are no guidelines about pathological evaluation of breast reduction surgery. We reviewed all pathology reports of patients undergoing breast reduction surgery in a single tertiary institution in Brazil from January 2008 to August 2014. Exclusion criteria were a personal history of breast cancer, unclear reason for mastectomy and incomplete data on the pathology report. We considered "relevant findings" flat epithelial atypia, atypical hyperplasia, carcinomas in situ and invasive carcinoma. Of 1672 specimens from breast reduction surgery, 783 met inclusion criteria. Median patient age was 40 (8–77), 91% underwent bilateral mastectomy and 57% of the specimens weighted less than 200 g. In 55% of cases, 4 or more paraffin blocks were sampled. There were 40 (5.1%) relevant findings and the most common was atypical lobular hyperplasia (16–2%). There were 3 invasive carcinomas (0.38%). In multivariate analysis, the only variables associated with a higher odds of relevant pathological findings were patient age ≥ 40 (OR 4.73 CI95% 1.98–11.3 p < 0.001) and sampling of ≥4 paraffin blocks from each specimen (OR 6.69 95% CI 2.25–19.9 p < 0.001). The incidence of pre-malignant and malignant lesions in specimens from breast reduction surgery is around 5%, but this risk is significantly higher for patients older than 40 years-old. Sampling at least 4 paraffin blocks from each specimen significantly increases detection rates.

http://ift.tt/2odtWfj

Incidental Findings in Reduction Mammoplasty Specimens in Patients with No Prior History of Breast Cancer. An Analysis of 783 Specimens

Abstract

Breast reduction surgery is a common procedure and the rate of incidental findings in the removed specimens varies between 0% and 4.6%. There are no guidelines about pathological evaluation of breast reduction surgery. We reviewed all pathology reports of patients undergoing breast reduction surgery in a single tertiary institution in Brazil from January 2008 to August 2014. Exclusion criteria were a personal history of breast cancer, unclear reason for mastectomy and incomplete data on the pathology report. We considered "relevant findings" flat epithelial atypia, atypical hyperplasia, carcinomas in situ and invasive carcinoma. Of 1672 specimens from breast reduction surgery, 783 met inclusion criteria. Median patient age was 40 (8–77), 91% underwent bilateral mastectomy and 57% of the specimens weighted less than 200 g. In 55% of cases, 4 or more paraffin blocks were sampled. There were 40 (5.1%) relevant findings and the most common was atypical lobular hyperplasia (16–2%). There were 3 invasive carcinomas (0.38%). In multivariate analysis, the only variables associated with a higher odds of relevant pathological findings were patient age ≥ 40 (OR 4.73 CI95% 1.98–11.3 p < 0.001) and sampling of ≥4 paraffin blocks from each specimen (OR 6.69 95% CI 2.25–19.9 p < 0.001). The incidence of pre-malignant and malignant lesions in specimens from breast reduction surgery is around 5%, but this risk is significantly higher for patients older than 40 years-old. Sampling at least 4 paraffin blocks from each specimen significantly increases detection rates.

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Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors

Summary

Background Tanibirumab is a fully human monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of tanibirumab in patients with solid tumors refractory to standard chemotherapy. Primary endpoints were evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Methods We designed our study to escalate tanibirumab at 9 different dose levels with a 3 + 3 method and tanibirumab (1–28 mg/kg) was administered intravenously on D1, 8, 15 in 28-day courses. Dose limiting toxicities (DLTs) were only assessed during the first cycle of treatment and response evaluation was performed every 2 cycles. The effects of tanibirumab on several angiogenic factors were analyzed. Results From October 2011 to September 2013, a total of 26 patients with refractory solid tumors were enrolled. The median age was 58 years (range, 27–75) and 20 patients were male. The most common tumor type was colorectal cancer (N = 19) and seven patients had a history of previous bevacizumab treatment. As hemangioma continued to occur, the final dose level, 28 mg/kg, was not performed. DLTs were not found, and the MTD was confirmed to be 24 mg/kg. Hemangioma was observed in 16 patients (61.5%), but all were grade 1–2 and disappeared after discontinuation of the study drug. Among the 18 patients in the efficacy set, no objective response was observed, but 11 patients showed stable disease. PKs were characterized by dose-dependent linear exposure and the mean trough concentrations exceeded biologically relevant target levels at 12 mg/kg and above. Serum VEGF, soluble VEGFR-2, and PlGF increased at the 4 mg/kg dose level and above. Conclusions Treatment with tanibirumab showed a tolerable toxicity profile and modest clinical efficacy in patients with refractory solid tumors. A phase II trial of tanibirumab is ongoing now.

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Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors

Summary

Background Tanibirumab is a fully human monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of tanibirumab in patients with solid tumors refractory to standard chemotherapy. Primary endpoints were evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Methods We designed our study to escalate tanibirumab at 9 different dose levels with a 3 + 3 method and tanibirumab (1–28 mg/kg) was administered intravenously on D1, 8, 15 in 28-day courses. Dose limiting toxicities (DLTs) were only assessed during the first cycle of treatment and response evaluation was performed every 2 cycles. The effects of tanibirumab on several angiogenic factors were analyzed. Results From October 2011 to September 2013, a total of 26 patients with refractory solid tumors were enrolled. The median age was 58 years (range, 27–75) and 20 patients were male. The most common tumor type was colorectal cancer (N = 19) and seven patients had a history of previous bevacizumab treatment. As hemangioma continued to occur, the final dose level, 28 mg/kg, was not performed. DLTs were not found, and the MTD was confirmed to be 24 mg/kg. Hemangioma was observed in 16 patients (61.5%), but all were grade 1–2 and disappeared after discontinuation of the study drug. Among the 18 patients in the efficacy set, no objective response was observed, but 11 patients showed stable disease. PKs were characterized by dose-dependent linear exposure and the mean trough concentrations exceeded biologically relevant target levels at 12 mg/kg and above. Serum VEGF, soluble VEGFR-2, and PlGF increased at the 4 mg/kg dose level and above. Conclusions Treatment with tanibirumab showed a tolerable toxicity profile and modest clinical efficacy in patients with refractory solid tumors. A phase II trial of tanibirumab is ongoing now.

http://ift.tt/2npSQK9

An association study between CHEK2 gene mutations and susceptibility to breast cancer

Abstract

CHEK2 gene is known as a tumor suppressor gene in breast cancer (BC), which plays a role in DNA repair. The germ line mutations in CEHK2 have been associated with different types of cancer. The present study was aimed at studying the association between CHEK2 mutations and BC. Peripheral blood was collected from patients into a test tube containing EDTA, and DNA was extracted from blood samples. Then, we analyzed mutations including 1100delc, IVS2+1>A, del5395bp, and I157T within CHEK2 gene in patients with BC and 100 normal healthy controls according to PCR-RFLP, allelic specific PCR, and multiplex-PCR. Although IVS2+1G>A mutation within CHEK2 gene was found in two BC patients, other defined mutants were not detected. For the first time, we identified CHEK2 IVS2+1G>A mutation, one out of four different CHEK2 alterations in two Iranian BC patients (2%). Also, our results showed that CHEK2 1100elC, del5395bp, and I157T mutations are not associated with genetic susceptibility for BC among Iranian population.

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The predictive value of pre-recruitment achievement on resident performance in anesthesiology

Selecting candidates for residency positions is challenging and there is little research on the correlation between commonly used selection criteria and subsequent performance in anesthesiology. This study examined the association between the selection measures and post-recruitment performance in residency.

http://ift.tt/2pfuK1a

Clinical experiences of ultrasound-guided lateral thoracolumbar Interfascial plane (TLIP) block

An ultrasound-guided thoracolumbar interfascial plane (TLIP) block injects a local anesthetic into the fascial plane between the multifidus and longissimus muscles at approximately the level of the third lumbar vertebra (L3), and can block the ventral rami of the thoracolumbar nerves (L2, 3) [1]. Therefore, the TLIP block provides good perioperative pain relief during lumbar vertebra surgery, as reported by some studies on the TLIP block [2,3]. However, as the injection site is near the incision site of the lumber vertebra surgery, the TLIP block may carry a risk of infection.

http://ift.tt/2ode7Wh

Postoperative analgesic efficacy of single-shot and continuous transversus abdominis plane block after laparoscopic cholecystectomy: A randomized controlled clinical trial

To compare the analgesic efficacy of ultrasound-guided single-shot and continuous transversus abdominis plane (TAP) block to that of IV-PCA in patients undergoing laparoscopic cholecystectomy.

http://ift.tt/2pf7mAH

Influence of the perioperative administration of magnesium sulfate on the total dose of anesthetics during general anesthesia. A systematic review and meta-analysis

Magnesium sulfate displays numerous characteristics that make it a useful drug in anesthesiology (N-methyl-d-aspartate receptor antagonist, vasodilator, antiarrhythmic, inhibitor of catecholamine release and of acetylcholine in the terminal motor plate). The perioperative use of this drug as an adjuvant capable of decreasing the required dose of anesthetics, has been proposed.

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Reassessment of the clinical significance of portal-superior mesenteric vein invasion in borderline resectable pancreatic cancer

Publication date: Available online 8 April 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Sojun Hoshimoto, Shoichi Hishinuma, Hirofumi Shirakawa, Moriaki Tomikawa, Iwao Ozawa, Saho Wakamatsu, Sayuri Hoshi, Nobuo Hoshi, Kaoru Hirabayashi, Yoshiro Ogata
ObjectiveThe principal objective of this study is to clarify the prognostic significance of borderline resectable pancreatic cancer (BRPC). The second objective is to evaluate the prognostic impact of the depth of pathological venous invasion.MethodsThe study included 122 pancreatic cancer patients who underwent curative surgery. All computed tomography scans of the patients were retrospectively interpreted and classified according to the NCCN guidelines, version 1.2016, as resectable (-) or borderline resectable (+) in each arterial (BR-A) and venous (BR-PV) involvement.ResultsThe overall survival (OS) rate was significantly higher in BR-A(-) patients (n=94) than in BR-A(+) patients (n=28) (P=0.001), whereas there was no difference between BR-PV(-) (n=101) and BR-PV(+) patients (n=21) (P=0.257). In a multivariate analysis, the independent predictors of OS included BR-A(+) (P=0.002), lymph node metastasis (P=0.008), pathological venous invasion (P=0.003), and adjuvant chemotherapy (P=0.001). Of 39 patients who underwent venous resection, no significant difference was observed between BR-PV(-) (n=20) and BR-PV(+) patients (n=19) in resection rate, lymph node metastasis, the presence of extrapancreatic nerve invasion, recurrence rate, frequency of initial recurrence at a liver or local site, and OS. Pathological venous invasion was significantly deeper in BR-PV(+) patients. However, the depth of invasion was not associated with OS.ConclusionThe definition of venous involvement in the current guidelines predicted the depth of pathological venous invasion but not OS in BRPC patients. Further prospective, randomized studies are needed to establish treatment strategies for BRPC patients with isolated venous involvement.



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Pressurized IntraPeritoneal Aerosol Chemotherapy – Practical Aspects

Publication date: Available online 8 April 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Martin Hübner, Fabian Grass, Hugo Teixeira-Farinha, Basile Pache, Patrice Mathevet, Nicolas Demartines
IntroductionPressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) has been introduced as novel treatment for peritoneal carcinomatosis. Only proper patient selection, stringent safety protocol and careful surgery allow for a secure procedure. We hereby report the essentials for safe implementation.MethodsAll consecutive procedures within 20 months after PIPAC implementation were analyzed with regards to practical and surgical aspects. Special emphasis was laid on modifications of technique and safety measures during the implementation process with systematic use of a dedicated checklist. Further, surgical difficulty was documented by use of a visual analogue scale (VAS).Results127 PIPAC procedures were performed in 58 patients from January 2015 until October 2016. 81% of patients had at least one previous laparotomy. Median operation time was 91 min (87-103) for the first 20 cases, 93 min (IQR 88-107) for PIPAC21-50, and 103 min (IQR 91-121) for the following 77 procedures. Primary and secondary non-access occurred in 3 patients (2%), all of them having prior hyperthermic intraperitoneal chemotherapy (HIPEC). Using open Hasson technique, one single bowel lesion occurred, which was the only intraoperative complication. One 5mm and another 10/12mm trocar were used in 88% of procedures while additional trocars were needed in 12%. No leak of cytostatics was observed and no procedure needed to be stopped. VAS for overall difficulty of the procedure was 3±2.4, and 3±2.9 and 3±2.5, respectively, for abdominal access and intraoperative staging.ConclusionsWith standardized surgical approach and dedicated safety checklist, PIPAC can be safely introduced in clinical routine with minimal learning curve.



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Surgical treatment for periacetabular metastatic lesions

Publication date: Available online 8 April 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Tatiana Charles, Lieveke Ameye, Michael Gebhart
IntroductionPeriacetabular bone metastasis present with severe pain and functional loss leading to a poor quality of life. Surgical treatment remains challenging.Material and methodsWe reviewed all cases operated at our institution. We analyzed pain scores and functional status as well as complications and their risk factors.ResultsThirty-five patients underwent curettage and cemented reconstruction. Mean surgical time was 168 minutes. Mean surgical blood losses were 3 150ml. Major complications were encountered in 23% and minor complications in 29% of cases. We found a significant pain relief (p < 0.0001) and improvement in functional status in the postoperative period (p < 0.0001). A Harrington grade 4 lesion was correlated with a higher complication rate (p-value= 0.002).ConclusionsIn this series we were able to show that surgical management is an effective option in the treatment of metastatic bone disease to the pelvis. However, this treatment is very complex and associated with very high complication rates. Therefore, adequate patient selection and preoperative management is advocated.



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Changes in arm tissue composition with slowly progressive weight-lifting among women with breast cancer-related lymphedema

Abstract

Background

Studies in breast cancer-related lymphedema (BRCL) have exclusively examined total arm volume, but not the specific tissue composition that contributes to total volume. We evaluated baseline differences in arm tissue composition [fat mass, lean mass, bone mineral content (BMC), and bone mineral density (BMD)] between the affected and unaffected arms in women with BRCL. We compared changes in arm tissue composition and self-reported lymphedema symptoms after 1 year of weight-lifting versus control.

Methods

We utilized data from physical activity and lymphedema trial that included 141 women with BRCL. Arm tissue composition was quantified using dual-energy X-ray absorptiometry. The severity of lymphedema was quantified using self-report survey. Weight-lifting was performed at community fitness facilities.

Results

At baseline, the affected arm had more fat (∆ = 89.7 g; P < 0.001) and lean mass (∆ = 149.1 g; P < 0.001), but less BMC (∆ = −3.2 g; P < 0.001) and less BMD (∆ = −5.5 mg/cm²; P = 0.04) than the unaffected arm. After 12 months of weight-lifting, composition of the affected arm was improved: lean mass (71.2 g; P = 0.01) and BMD (14.0 mg/cm²; P = 0.02) increased, arm fat percentage decreased (−1.5%; P = 0.003). Composition of the unaffected arm was only improved in lean mass (65.2 g; P = 0·04). Increases in lean mass were associated with less severe BCRL symptoms.

Conclusions

Among women with BRCL, slowly progressive weight-lifting could improve arm tissue composition. Changes in arm tissue composition predict changes in symptom burden. Investigating the combined effects of exercise and weight loss on arm tissue composition and BCRL symptoms may provide additional insight into the benefits of lifestyle modification on lymphedema biology.

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Primary cranial sarcomatoid carcinoma

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Primary cranial sarcomatoid carcinoma

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Is Regression after Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer Different in Sentinel and Non-sentinel Nodes?

Abstract

Tumor draining sentinel lymph nodes (SLNs) are the sites of selective changes as compared to non-SLNs. They show features of tumor-reactive lymphadenopathy, including increased total number of functional blood vessels, but a relative immunosuppressed status has also been described in them. We explored the hypothesis of a selective regression or non-regression in SLNs versus non-SLNs in 142 patients with 110 estrogen receptor-positive and 32 estrogen receptor-negative tumors undergoing both SLN biopsy and axillary lymph node dissection after neoadjuvant therapy by assessing the tumoral (metastatic) and regression statuses of SLNs and non-SLNs separately. Of the 89 cases with signs of nodal regression, 22 cases (25%) were in favor of a selective non-regression in SLNs, 18 cases (20%) were supportive of a selective and more pronounced regression in the SLNs and the remaining showed equal degrees of regression or non-regression in SLNs and non-SLNs. The results indicate that there is no obvious difference in the degree of regressive histological changes shown by SLNs and NSLNs. Therefore, this phenomenon may not be a major contributor to the higher false negative rate of SLN biopsy after neoadjuvant treatment.

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Neuroendocrine Tumors of the Breast

Abstract

A small but increasingly recognized and studied subset of breast carcinomas are characterized by neuroendocrine (NE) differentiation. As with nearly all forms of breast neoplasia, NE tumors are characterized by considerable heterogeneity in microscopic appearance and clinical aggressiveness. About half of NE breast carcinomas recapitulate the histological spectrum typical of their counterparts in other organ systems, varying from "carcinoid-like" to small cell carcinoma, with most representing intermediate grade tumors. Despite NE morphology, these tumors have a high frequency of estrogen receptor expression. Clinical outcomes of women with NE breast carcinomas are reliably grade and stage dependent. Tumors associated with "solid papillary" differentiation comprise the remaining cases of NE breast neoplasia. Solid papillary carcinoma is an intrinsically low grade/favorable prognosis class of breast neoplasia that usually presents in post-menopausal age groups. About half of solid papillary carcinoma present as a distinctive pattern of ductal carcinoma in situ that may be difficult to recognize owing to its close resemblance to florid proliferative lesions. Invasive solid papillary carcinomas are characterized by a variety of histological patterns and often show mucinous differentiation. Future studies are necessary to better define the histogenesis, optimal classification, and improved directed therapies for NE breast neoplasia.

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Interactions between dietary acrylamide intake and genes for ovarian cancer risk

Abstract

Some epidemiological studies observed a positive association between dietary acrylamide intake and ovarian cancer risk but the causality needs to be substantiated. By analyzing gene-acrylamide interactions for ovarian cancer risk for the first time, we aimed to contribute to this. The prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55–69 years. At baseline in 1986, a random subcohort of 2589 women was sampled from the total cohort for a case cohort analysis approach. Dietary acrylamide intake of subcohort members and ovarian cancer cases (n = 252, based on 20.3 years of follow-up) was assessed with a food frequency questionnaire. We selected single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism and in genes involved in the possible mechanisms of acrylamide-induced carcinogenesis (effects on sex steroid systems, oxidative stress and DNA damage). Genotyping was done on DNA from toenails through Agena's MassARRAY iPLEX platform. Multiplicative interaction between acrylamide intake and SNPs was assessed with Cox proportional hazards analysis. Among the results for 57 SNPs and 2 gene deletions, there were no statistically significant interactions between acrylamide and gene variants after adjustment for multiple testing. However, there were several nominally statistically significant interactions between acrylamide intake and SNPs in the HSD3B1/B2 gene cluster: (rs4659175 (p interaction = 0.04), rs10923823 (p interaction = 0.06) and its proxy rs7546652 (p interaction = 0.05), rs1047303 (p interaction = 0.005), and rs6428830 (p interaction = 0.05). Although in need of confirmation, results of this study suggest that acrylamide may cause ovarian cancer through effects on sex hormones.

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Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment

Abstract

Uveal melanoma (UM) is characterized by a number of genetic aberrations that follow a certain chronology and are tightly linked to tumor recurrence and survival. Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells. We used a set of genetically-classified UM to study immune infiltration in the context of their genetic evolution. We show in two independent cohorts that lack of BAP1 expression is associated with an increased density of CD3⁺ T cells and CD8⁺ T cells. The presence of extra copies of chromosome 8q in disomy 3 tumors with a normal BAP1 expression is associated with an increased influx of macrophages (but not T cells). Therefore, we propose that the genetic evolution of UM is associated with changes in the inflammatory phenotype. Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.

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Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer

Abstract

In newly diagnosed metastatic hormone-naive prostate cancer (mPC), telomerase-based immunotherapy with the novel hTERT peptide vaccine UV1 can induce immune responses with potential clinical benefit. This phase I dose escalation study of UV1 evaluated safety, immune response, effects on prostate-specific antigen (PSA) levels, and preliminary clinical outcome. Twenty-two patients with newly diagnosed metastatic hormone-naïve PC (mPC) were enrolled; all had started androgen deprivation therapy and had no visceral metastases. Bone metastases were present in 17 (77%) patients and 16 (73%) patients had affected lymph nodes. Three dose levels of UV1 were given as intradermal injections combined with GM-CSF (Leukine^®). Twenty-one patients in the intention-to-treat population (95%) received conformal radiotherapy. Adverse events reported were predominantly grade 1, most frequently injection site pruritus (86.4%). Serious adverse events considered possibly related to UV1 and/or GM-CSF included anaphylactic reaction in two patients and thrombocytopenia in one patient. Immune responses against UV1 peptides were confirmed in 18/21 evaluable patients (85.7%), PSA declined to <0.5 ng/mL in 14 (64%) patients and in ten patients (45%) no evidence of persisting tumour was seen on MRI in the prostatic gland. At the end of the nine-month reporting period for the study, 17 patients had clinically stable disease. Treatment with UV1 and GM-CSF gave few adverse events and induced specific immune responses in a large proportion of patients unselected for HLA type. The intermediate dose of 0.3 mg UV1 resulted in the highest proportion of, and most rapid UV1-specific immune responses with an acceptable safety profile. These results warrant further clinical studies in mPC.

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Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment

Abstract

Uveal melanoma (UM) is characterized by a number of genetic aberrations that follow a certain chronology and are tightly linked to tumor recurrence and survival. Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells. We used a set of genetically-classified UM to study immune infiltration in the context of their genetic evolution. We show in two independent cohorts that lack of BAP1 expression is associated with an increased density of CD3⁺ T cells and CD8⁺ T cells. The presence of extra copies of chromosome 8q in disomy 3 tumors with a normal BAP1 expression is associated with an increased influx of macrophages (but not T cells). Therefore, we propose that the genetic evolution of UM is associated with changes in the inflammatory phenotype. Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.

http://ift.tt/2pen8vJ

Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer

Abstract

In newly diagnosed metastatic hormone-naive prostate cancer (mPC), telomerase-based immunotherapy with the novel hTERT peptide vaccine UV1 can induce immune responses with potential clinical benefit. This phase I dose escalation study of UV1 evaluated safety, immune response, effects on prostate-specific antigen (PSA) levels, and preliminary clinical outcome. Twenty-two patients with newly diagnosed metastatic hormone-naïve PC (mPC) were enrolled; all had started androgen deprivation therapy and had no visceral metastases. Bone metastases were present in 17 (77%) patients and 16 (73%) patients had affected lymph nodes. Three dose levels of UV1 were given as intradermal injections combined with GM-CSF (Leukine^®). Twenty-one patients in the intention-to-treat population (95%) received conformal radiotherapy. Adverse events reported were predominantly grade 1, most frequently injection site pruritus (86.4%). Serious adverse events considered possibly related to UV1 and/or GM-CSF included anaphylactic reaction in two patients and thrombocytopenia in one patient. Immune responses against UV1 peptides were confirmed in 18/21 evaluable patients (85.7%), PSA declined to <0.5 ng/mL in 14 (64%) patients and in ten patients (45%) no evidence of persisting tumour was seen on MRI in the prostatic gland. At the end of the nine-month reporting period for the study, 17 patients had clinically stable disease. Treatment with UV1 and GM-CSF gave few adverse events and induced specific immune responses in a large proportion of patients unselected for HLA type. The intermediate dose of 0.3 mg UV1 resulted in the highest proportion of, and most rapid UV1-specific immune responses with an acceptable safety profile. These results warrant further clinical studies in mPC.

http://ift.tt/2nridel

Comparison between hypersensitivity reactions to cycles of modified FOLFOX6 and XELOX therapies in patients with colorectal cancer

Abstract

Purpose

Although hypersensitivity reactions (HSRs) to oxaliplatin (L-OHP) therapy are well-documented, few reports have compared different therapies in terms of HSR occurrence. In this study, we compared the frequency and pattern of HSRs to modified FOLFOX6 (mFOLFOX6; 5-fluorouracil, levofolinate calcium and L-OHP infusions) and XELOX (capecitabine and L-OHP) therapies, and sought to identify risk factors associated with HSRs.

Methods

Patients who had received mFOLFOX6 or XELOX chemotherapeutic regimens for unresectable colon or rectal cancer or as adjuvant chemotherapy following colon cancer surgery between April 2012 and August 2015 were included. Potential correlation between treatment modalities (regimen, dosage and route of administration of L-OHP, and injection timing for dexamethasone administration) and HSRs was assessed.

Results

Among the 240 patients included in the study, 136 had received mFOLFOX6 therapy and 104 had received XELOX therapy. Although the frequency of HSRs did not differ between the two groups, incidence of HSRs in the first cycle was higher in the XELOX therapy group. Treatment method or cumulative dosage was not identified as a risk factor for HSR; however, the incidence of ≥grade-2 HSR was higher in cases where the cumulative L-OHP dosage was ≥600 mg/m² and in patients in whom dexamethasone was not co-infused with L-OHP.

Conclusion

Although HSR rates were comparable among patients treated with mFOLFOX6 and XELOX, HSRs tended to occur more frequently during the first cycle of XELOX therapy as compared to that with mFOLFOX6 therapy. Our findings warrant careful assessment of ≥grade-2 HSRs in patients who are prescribed cumulative L-OHP dosages of ≥600 mg/m².

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Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment

Abstract

Uveal melanoma (UM) is characterized by a number of genetic aberrations that follow a certain chronology and are tightly linked to tumor recurrence and survival. Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells. We used a set of genetically-classified UM to study immune infiltration in the context of their genetic evolution. We show in two independent cohorts that lack of BAP1 expression is associated with an increased density of CD3⁺ T cells and CD8⁺ T cells. The presence of extra copies of chromosome 8q in disomy 3 tumors with a normal BAP1 expression is associated with an increased influx of macrophages (but not T cells). Therefore, we propose that the genetic evolution of UM is associated with changes in the inflammatory phenotype. Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.

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Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer

Abstract

In newly diagnosed metastatic hormone-naive prostate cancer (mPC), telomerase-based immunotherapy with the novel hTERT peptide vaccine UV1 can induce immune responses with potential clinical benefit. This phase I dose escalation study of UV1 evaluated safety, immune response, effects on prostate-specific antigen (PSA) levels, and preliminary clinical outcome. Twenty-two patients with newly diagnosed metastatic hormone-naïve PC (mPC) were enrolled; all had started androgen deprivation therapy and had no visceral metastases. Bone metastases were present in 17 (77%) patients and 16 (73%) patients had affected lymph nodes. Three dose levels of UV1 were given as intradermal injections combined with GM-CSF (Leukine^®). Twenty-one patients in the intention-to-treat population (95%) received conformal radiotherapy. Adverse events reported were predominantly grade 1, most frequently injection site pruritus (86.4%). Serious adverse events considered possibly related to UV1 and/or GM-CSF included anaphylactic reaction in two patients and thrombocytopenia in one patient. Immune responses against UV1 peptides were confirmed in 18/21 evaluable patients (85.7%), PSA declined to <0.5 ng/mL in 14 (64%) patients and in ten patients (45%) no evidence of persisting tumour was seen on MRI in the prostatic gland. At the end of the nine-month reporting period for the study, 17 patients had clinically stable disease. Treatment with UV1 and GM-CSF gave few adverse events and induced specific immune responses in a large proportion of patients unselected for HLA type. The intermediate dose of 0.3 mg UV1 resulted in the highest proportion of, and most rapid UV1-specific immune responses with an acceptable safety profile. These results warrant further clinical studies in mPC.

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Trial-level analysis of progression-free survival and response rate as end points of trials of first-line chemotherapy in advanced ovarian cancer

Abstract

Progression-free survival (PFS) has been reported as surrogate end point of overall survival (OS) in trials of advanced ovarian cancer (AOC). However, there is not a trial-level evaluation of surrogacy. The aim of this study is to perform an analysis of randomized trials enrolling patients with AOC receiving a first-line systemic chemotherapy, in order to evaluate the results of PFS, the other intermediate end points and their relationship with OS. A literature search of phase 3 randomized trials was performed by a predefined protocol. For each trial, the differences between arms of the results of OS and of other end points were calculated. These differences were compared by Spearman's rho coefficient to find out the potential correlation between every end point and OS. For the end points with the higher relationships with OS, the proportion of variability explained (R ²) was calculated by regression analysis. Thirty-eight studies have been included. PFS appears to be the end point more closely related to OS (R ² = 0.506; p < 0.001), and this correlation is higher among studies published before 2003. ORR is correlated with OS only in the trials published after 2003 (R ² = 0.344; p 0.027; 14 trials). In conclusion, in more recent trials ORR shows a level of correlation with OS similar to that of PFS. Though PFS should no longer be considered a surrogate end points of OS in trials of patients receiving a first-line chemotherapy for AOC, a prospective evaluation of new response-related end points is strongly recommended.

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Feasibility of concurrent chemoradiotherapy with high-dose cisplatin after induction TPF chemotherapy in head and neck cancer: a critical review of the literature and the experience of the European Institute of Oncology

Abstract

Many concerns are related to the idea that the acute toxicity of induction chemotherapy (IC) performed with TPF (docetaxel, cisplatin, 5-fluorouracil) could reduce the ability to deliver the subsequent standard concurrent chemoradiotherapy (CRT) in head and neck cancer patients. We performed a critical review of the literature on the toxicity profile of the standard CRT administered after the IC with TPF. A total of 13 papers (including 950 patients) were selected. Results showed that most patients were treated with an adequate radiation total dose although a significant proportion of them (from 15 to 30%) completed the planned treatment with a delay of more than 5 days. A minority of patients were able to be treated with three cycles of concurrent cisplatin, but only few papers reported how many of patients reached the cumulative total dose of almost 200 mg/m² cisplatin. The rate of deaths due to treatment-related toxicity varied from 0 to 9% (median and mean 2%). Two prospective trials stopped patient enrollment due to acute treatment-related toxicity and because a low number of patients were able to undergo the planned full schedule of cisplatin during the CRT, respectively. Retrospective analysis of 45 patients treated at our institute showed that this schedule was feasible with manageable side effects. In conclusion, the literature data did not provide homogeneous information on the feasibility of the standard CRT after induction TPF. A more uniform data collection of treatment-related toxicity will be helpful in better selecting the patients who might adequately tolerate this multimodality strategy.

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Neoadjuvant treatment in pancreatic cancer: Evidence-based medicine? A systematic review and meta-analysis

Abstract

Neoadjuvant treatment in non-metastatic pancreatic cancer (PaC) has the theoretical advantages of downstaging the tumor, sterilizing any present systemic undetectable disease, selecting patients for surgery and administering therapy to each patient. The aim of this systematic review is to analyze the state of the art on neoadjuvant protocols for non-metastatic PaC. A literature search over the last 10 years was conducted, and papers had to be focused on resectable, borderline resectable (BLR) or locally advanced (LA) histo- or cytologically proven PaC; to be prospective studies or prospectively collected databases; to report percentage of protocol achievement and survival data at least in an intention-to-treat (ITT) analysis. Twelve studies were eligible for systematic review. Studies included a total of 624 patients: 248 resectable, 268 BLR, 71 LA and 37 non-specified. All studies were included for meta-analysis. ITT overall survival (OS) was 16.7 months (95% CI 15.16–18.26 months); for resected patients OS was 22.78 months (95% CI 20.42–25.16), and for eventually non-resected patients it was 9.89 months (95% CI 8.84–10.96). Neoadjuvant approaches for resectable, BLR and LA PaC are spreading. Outcomes tend to be better outside an RCT context, but strong evidences are lacking. Actually such treatments should be performed only in a randomized clinical trial setting.

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Trial-level analysis of progression-free survival and response rate as end points of trials of first-line chemotherapy in advanced ovarian cancer

Abstract

Progression-free survival (PFS) has been reported as surrogate end point of overall survival (OS) in trials of advanced ovarian cancer (AOC). However, there is not a trial-level evaluation of surrogacy. The aim of this study is to perform an analysis of randomized trials enrolling patients with AOC receiving a first-line systemic chemotherapy, in order to evaluate the results of PFS, the other intermediate end points and their relationship with OS. A literature search of phase 3 randomized trials was performed by a predefined protocol. For each trial, the differences between arms of the results of OS and of other end points were calculated. These differences were compared by Spearman's rho coefficient to find out the potential correlation between every end point and OS. For the end points with the higher relationships with OS, the proportion of variability explained (R ²) was calculated by regression analysis. Thirty-eight studies have been included. PFS appears to be the end point more closely related to OS (R ² = 0.506; p < 0.001), and this correlation is higher among studies published before 2003. ORR is correlated with OS only in the trials published after 2003 (R ² = 0.344; p 0.027; 14 trials). In conclusion, in more recent trials ORR shows a level of correlation with OS similar to that of PFS. Though PFS should no longer be considered a surrogate end points of OS in trials of patients receiving a first-line chemotherapy for AOC, a prospective evaluation of new response-related end points is strongly recommended.

http://ift.tt/2oTEpLt

Feasibility of concurrent chemoradiotherapy with high-dose cisplatin after induction TPF chemotherapy in head and neck cancer: a critical review of the literature and the experience of the European Institute of Oncology

Abstract

Many concerns are related to the idea that the acute toxicity of induction chemotherapy (IC) performed with TPF (docetaxel, cisplatin, 5-fluorouracil) could reduce the ability to deliver the subsequent standard concurrent chemoradiotherapy (CRT) in head and neck cancer patients. We performed a critical review of the literature on the toxicity profile of the standard CRT administered after the IC with TPF. A total of 13 papers (including 950 patients) were selected. Results showed that most patients were treated with an adequate radiation total dose although a significant proportion of them (from 15 to 30%) completed the planned treatment with a delay of more than 5 days. A minority of patients were able to be treated with three cycles of concurrent cisplatin, but only few papers reported how many of patients reached the cumulative total dose of almost 200 mg/m² cisplatin. The rate of deaths due to treatment-related toxicity varied from 0 to 9% (median and mean 2%). Two prospective trials stopped patient enrollment due to acute treatment-related toxicity and because a low number of patients were able to undergo the planned full schedule of cisplatin during the CRT, respectively. Retrospective analysis of 45 patients treated at our institute showed that this schedule was feasible with manageable side effects. In conclusion, the literature data did not provide homogeneous information on the feasibility of the standard CRT after induction TPF. A more uniform data collection of treatment-related toxicity will be helpful in better selecting the patients who might adequately tolerate this multimodality strategy.

http://ift.tt/2ojyLnO

Neoadjuvant treatment in pancreatic cancer: Evidence-based medicine? A systematic review and meta-analysis

Abstract

Neoadjuvant treatment in non-metastatic pancreatic cancer (PaC) has the theoretical advantages of downstaging the tumor, sterilizing any present systemic undetectable disease, selecting patients for surgery and administering therapy to each patient. The aim of this systematic review is to analyze the state of the art on neoadjuvant protocols for non-metastatic PaC. A literature search over the last 10 years was conducted, and papers had to be focused on resectable, borderline resectable (BLR) or locally advanced (LA) histo- or cytologically proven PaC; to be prospective studies or prospectively collected databases; to report percentage of protocol achievement and survival data at least in an intention-to-treat (ITT) analysis. Twelve studies were eligible for systematic review. Studies included a total of 624 patients: 248 resectable, 268 BLR, 71 LA and 37 non-specified. All studies were included for meta-analysis. ITT overall survival (OS) was 16.7 months (95% CI 15.16–18.26 months); for resected patients OS was 22.78 months (95% CI 20.42–25.16), and for eventually non-resected patients it was 9.89 months (95% CI 8.84–10.96). Neoadjuvant approaches for resectable, BLR and LA PaC are spreading. Outcomes tend to be better outside an RCT context, but strong evidences are lacking. Actually such treatments should be performed only in a randomized clinical trial setting.

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Tackling endocrine resistance in ER-positive HER2-negative advanced breast cancer: a tale of imprecision medicine

Publication date: Available online 7 April 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Alexios Matikas, Theodoros Foukakis, Jonas Bergh
The selection of patients with advanced breast cancer as appropriate for endocrine manipulation according to hormone receptor status is a successful strategy. Unfortunately, the emergence of resistance is inevitable and subsequent treatment is not well defined. Numerous mechanisms have been implicated in the development of resistance; central among them is the activation of compensatory signaling pathways. Despite the rationale that supports combining agents targeting these pathways with hormonal therapies in an attempt to delay or even reverse endocrine resistance, most clinical trials have failed to demonstrate improved outcomes. Although the inhibition of the PI3K/mTOR pathway and of CDK 4/6 function has led to meaningful prolongations of progression free survival, no overall survival gains have been reported yet. Considering the associated toxicity and costs, genomic-driven trials are eagerly needed in order to refine management strategies and achieve a truly personalized approach for this patient subgroup.



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Tackling endocrine resistance in ER-positive HER2-negative advanced breast cancer: a tale of imprecision medicine

Publication date: Available online 7 April 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Alexios Matikas, Theodoros Foukakis, Jonas Bergh
The selection of patients with advanced breast cancer as appropriate for endocrine manipulation according to hormone receptor status is a successful strategy. Unfortunately, the emergence of resistance is inevitable and subsequent treatment is not well defined. Numerous mechanisms have been implicated in the development of resistance; central among them is the activation of compensatory signaling pathways. Despite the rationale that supports combining agents targeting these pathways with hormonal therapies in an attempt to delay or even reverse endocrine resistance, most clinical trials have failed to demonstrate improved outcomes. Although the inhibition of the PI3K/mTOR pathway and of CDK 4/6 function has led to meaningful prolongations of progression free survival, no overall survival gains have been reported yet. Considering the associated toxicity and costs, genomic-driven trials are eagerly needed in order to refine management strategies and achieve a truly personalized approach for this patient subgroup.



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Current Management of Peritoneal Carcinomatosis From Colorectal Cancer: the Role of Cytoreductive Surgery and Hyperthermic Peritoneal Chemoperfusion

Abstract

Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a disease with a poor prognosis, often thought to be a terminal illness with no hope except for palliative treatment. New therapeutic modalities combining cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown favorable outcomes and may provide a significant survival benefit in a selected group of patients. The main rational for CRS is to remove all visible tumor burden to allow for the chemotherapeutic agent (HIPEC) to eradicate any microscopic residual disease. The Amsterdam statement formulated at the 9th International Congress on Peritoneal Surface Malignancies supports the use of CRS with HIPEC as a standard of care for selected patients with small-to-moderate volume PC from CRC. Selecting appropriate patients who would benefit from CRS/HIPEC is paramount to derive the maximum oncological outcomes while minimizing the risks of postoperative complications and mortality. In this paper, we will review the role for CRS/HIPEC in the management of PC from CRC.

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A Survey of the Knowledge of African-American Women About Prostate Cancer Screening

Abstract

Prostate cancer is the second most common cancer diagnosed in men. Its incident and mortality rates are generally higher in populations of African descent. The scientific community recommends that men should be informed of the benefits, risks, and limitations of screening in order to make an informed decision regarding participation in prostate cancer screening. Women are known to act as the healthcare gatekeeper for the family. As such, African-American (AA) women could facilitate the informed decision-making process by providing prostate cancer and screening information to AA men. However, little is known about AA women's knowledge regarding prostate cancer and screening. This report describes the findings of a non-experimental cross-sectional study conducted using a convenience sample of 200 AA women. Data was collected using the knowledge subscale of the Eastland prostate cancer survey. Data was analyzed using JMP 13 statistical software developed by Statistical Analysis Systems (SAS) Institute. The overall mean knowledge score was 6.59 (47.1%). Knowledge was significantly associated with personal or family history of cancer (p = .02), family history of prostate cancer (p = .002), and the age of the respondents (p = .004) with those of older age (51 years and above) scoring higher on the knowledge scale. The results indicated that the AA women had a low knowledge of prostate cancer and screening. The findings indicate the need to develop and implement prostate cancer educational programs that include AA women.

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Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment

Abstract

Uveal melanoma (UM) is characterized by a number of genetic aberrations that follow a certain chronology and are tightly linked to tumor recurrence and survival. Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells. We used a set of genetically-classified UM to study immune infiltration in the context of their genetic evolution. We show in two independent cohorts that lack of BAP1 expression is associated with an increased density of CD3⁺ T cells and CD8⁺ T cells. The presence of extra copies of chromosome 8q in disomy 3 tumors with a normal BAP1 expression is associated with an increased influx of macrophages (but not T cells). Therefore, we propose that the genetic evolution of UM is associated with changes in the inflammatory phenotype. Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.

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Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer

Abstract

In newly diagnosed metastatic hormone-naive prostate cancer (mPC), telomerase-based immunotherapy with the novel hTERT peptide vaccine UV1 can induce immune responses with potential clinical benefit. This phase I dose escalation study of UV1 evaluated safety, immune response, effects on prostate-specific antigen (PSA) levels, and preliminary clinical outcome. Twenty-two patients with newly diagnosed metastatic hormone-naïve PC (mPC) were enrolled; all had started androgen deprivation therapy and had no visceral metastases. Bone metastases were present in 17 (77%) patients and 16 (73%) patients had affected lymph nodes. Three dose levels of UV1 were given as intradermal injections combined with GM-CSF (Leukine^®). Twenty-one patients in the intention-to-treat population (95%) received conformal radiotherapy. Adverse events reported were predominantly grade 1, most frequently injection site pruritus (86.4%). Serious adverse events considered possibly related to UV1 and/or GM-CSF included anaphylactic reaction in two patients and thrombocytopenia in one patient. Immune responses against UV1 peptides were confirmed in 18/21 evaluable patients (85.7%), PSA declined to <0.5 ng/mL in 14 (64%) patients and in ten patients (45%) no evidence of persisting tumour was seen on MRI in the prostatic gland. At the end of the nine-month reporting period for the study, 17 patients had clinically stable disease. Treatment with UV1 and GM-CSF gave few adverse events and induced specific immune responses in a large proportion of patients unselected for HLA type. The intermediate dose of 0.3 mg UV1 resulted in the highest proportion of, and most rapid UV1-specific immune responses with an acceptable safety profile. These results warrant further clinical studies in mPC.

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Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment

Abstract

Uveal melanoma (UM) is characterized by a number of genetic aberrations that follow a certain chronology and are tightly linked to tumor recurrence and survival. Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells. We used a set of genetically-classified UM to study immune infiltration in the context of their genetic evolution. We show in two independent cohorts that lack of BAP1 expression is associated with an increased density of CD3⁺ T cells and CD8⁺ T cells. The presence of extra copies of chromosome 8q in disomy 3 tumors with a normal BAP1 expression is associated with an increased influx of macrophages (but not T cells). Therefore, we propose that the genetic evolution of UM is associated with changes in the inflammatory phenotype. Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.

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Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer

Abstract

In newly diagnosed metastatic hormone-naive prostate cancer (mPC), telomerase-based immunotherapy with the novel hTERT peptide vaccine UV1 can induce immune responses with potential clinical benefit. This phase I dose escalation study of UV1 evaluated safety, immune response, effects on prostate-specific antigen (PSA) levels, and preliminary clinical outcome. Twenty-two patients with newly diagnosed metastatic hormone-naïve PC (mPC) were enrolled; all had started androgen deprivation therapy and had no visceral metastases. Bone metastases were present in 17 (77%) patients and 16 (73%) patients had affected lymph nodes. Three dose levels of UV1 were given as intradermal injections combined with GM-CSF (Leukine^®). Twenty-one patients in the intention-to-treat population (95%) received conformal radiotherapy. Adverse events reported were predominantly grade 1, most frequently injection site pruritus (86.4%). Serious adverse events considered possibly related to UV1 and/or GM-CSF included anaphylactic reaction in two patients and thrombocytopenia in one patient. Immune responses against UV1 peptides were confirmed in 18/21 evaluable patients (85.7%), PSA declined to <0.5 ng/mL in 14 (64%) patients and in ten patients (45%) no evidence of persisting tumour was seen on MRI in the prostatic gland. At the end of the nine-month reporting period for the study, 17 patients had clinically stable disease. Treatment with UV1 and GM-CSF gave few adverse events and induced specific immune responses in a large proportion of patients unselected for HLA type. The intermediate dose of 0.3 mg UV1 resulted in the highest proportion of, and most rapid UV1-specific immune responses with an acceptable safety profile. These results warrant further clinical studies in mPC.

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The Rising Incidence of Younger Patients With Colorectal Cancer: Questions About Screening, Biology, and Treatment

Opinion statement

Colorectal cancer (CRC) is the third leading cancer diagnosed globally and an important cause of cancer-related mortality. Of interest, while we have witnessed a declining incidence trend over the past few decades in the older population, incidence rates for adolescents and young adults have been increasing steadily. Several factors may well explain this apparent epidemic in the young, namely a lack of routine screening and emerging lifestyle issues such as obesity, lack of exercise, and dietary factors. It is known that both environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility is associated with the most striking increases in risk, and must always be considered in a young patient with CRC, the majority of CRCs are in fact sporadic rather than familial. Early-onset CRC is a truly heterogeneous disease, with mounting evidence to suggest that this patient population has a distinctive molecular profile, very different to late-onset CRC cases. Currently, both younger and older patients with CRC are treated in essentially the same manner, but with a better understanding of the molecular mechanisms underlying CRC in the young, we will have the opportunity to specifically tailor screening and clinical management strategies in this unique patient population in an effort to improve outcomes. The aim of this review is to outline our current knowledge of the distinguishing features of early-onset CRC, the ongoing research efforts, and the evolving evidence in this field.

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Optimal Radiation Therapy for Small Cell Lung Cancer

Opinion statement

Radiation therapy plays an important role in the management of both limited stage and extensive stage small cell lung cancer. For limited stage disease, there has been a trend toward reduced size of thoracic radiation fields, which has the potential to reduce toxicity. FDG-PET staging helps make this possible by more accurately identifying areas of nodal and metastatic involvement. Trials have demonstrated similar outcomes using a range of radiation fractionation schedules, allowing flexibility in individualizing treatment. Using advanced radiation therapy techniques such as intensity-modulated radiation therapy, it may be possible to deliver fewer, higher dose fractions and achieve similar results to the hyperfractionated regimen. For extensive stage disease, consolidative thoracic radiation therapy after chemotherapy was recently shown to improve overall survival in certain patient subsets. Prophylactic cranial irradiation continues to play an important role in management of all stages of small cell lung cancer. Debate continues about the neurocognitive effects of this treatment, and whether MRI surveillance is an acceptable alternative. Strategies such as hippocampal avoidance may reduce the cognitive effects of prophylactic cranial irradiation in the future. Finally, in the last few years stereotactic ablative radiation therapy followed by chemotherapy has emerged as a promising treatment for stage I small cell lung cancer. This radiation treatment is usually given over 1–5 fractions and appears to provide a good rate of local control with a low rate of serious toxicity.

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Osteogenic Sarcoma: Systemic Chemotherapy Options for Localized Disease

Opinion statement

Treatment for osteosarcoma, the most common malignant tumor of bone in children and adolescents, has not changed in decades. Treatment is multimodal, employing neoadjuvant chemotherapy followed by aggressive and complete surgical resection to achieve negative margins and a prolonged course of adjuvant chemotherapy. The primary tumor is usually successfully managed via surgery, but micrometastases are likely present in most patients at diagnosis. Death is the result of tumor recurrence in the lungs or more rarely in other bones despite aggressive treatment regimens and is likely attributable to innate resistance to chemotherapy. Better therapies are desperately needed. The three most active agents—high-dose methotrexate, doxorubicin, and cisplatin—commonly referred to as "MAP," form the backbone of therapy. After 2 cycles of MAP, surgical resection is performed of all sites of disease if possible. Histologic response following neoadjuvant chemotherapy is prognostic in non-metastatic osteosarcoma, but augmentation of adjuvant therapy for poor responders with additional agents (ifosfamide, etoposide) has not improved outcome. Inclusion of immunotherapy into treatment regimens is promising. Specifically, liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), a macrophage and monocyte activator, improved 10-year overall survival for patients with localized disease, with a similar pattern of response in patients with metastatic disease. L-MTP-PE (mifamurtide) is approved and in widespread use in Europe and elsewhere but has not been approved for use by the Federal Drug Administration in the USA. Identifying novel targeted therapies to improve outcomes for patients with osteosarcoma remains an area of active research.

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Image-Guided Thermal Ablative Therapies in the Treatment of Sarcoma

Opinion Statement

Percutaneous thermal ablation, including microwave ablation (MWA), radiofrequency ablation (RFA), and cryoablation, is a well-established focal treatment option for primary and metastatic malignancies. While published literature specific to ablation of sarcomas is relatively lacking compared with non-sarcomatous malignancies, what is available is promising. In situations where a focal treatment option is desired, strong consideration should be given to percutaneous thermal ablation, in addition to surgery and radiation therapy. A significant advantage of percutaneous thermal ablation over surgery and radiation includes the repeatability of ablation, as there is no absolute limit on the number of times an ablation can be performed. Compared with surgery, ablation offers the potential of decreased recovery time, a less invasive procedure, and is often performed in patients deemed not medically fit for surgery.

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A Neuro-oncologist’s Perspective on Management of Brain Metastases in Patients with EGFR Mutant Non-small Cell Lung Cancer

Opinion statement

Management of non-small cell lung cancer (NSCLC) with brain metastasis (BrM) has been revolutionized by identification of molecular subsets that have targetable oncogenes. Historically, survival for NSCLC with symptomatic BrM was weeks to months. Now, many patients are surviving years with limited data to guide treatment decisions. Tumors with activating mutations in epidermal growth factor receptor (EGFRact+) have a higher incidence of BrM, but a longer overall survival. The high response rate of both systemic and BrM EGFRact+ NSCLC to tyrosine kinase inhibitors (TKIs) has led to the rapid incorporation of new therapies but is outpacing evidence-based decisions for BrM in NSCLC. While whole brain radiation therapy (WBRT) was the foundation of management of BrM, extended survival raises concerns for the subacute and late effects radiotherapy. We favor the use of TKIs and delaying the use of WBRT when able. At inevitable disease progression, we consider alternative dosing schedules to increase CNS penetration (such as pulse dosing of erlotinib) or advance to next generation TKI if available. We utilize local control options of surgery or stereotactic radiosurgery (SRS) for symptomatic accessible lesions based on size and edema. At progression despite available TKIs, we use pemetrexed-based platinum doublet chemotherapy or immunotherapy if the tumor has high expression of PDL-1. We reserve the use of WBRT for patients with more than 10 BrM and progression despite TKI and conventional chemotherapy, if performance status is appropriate.

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Curcumin inhibits prostate cancer by targeting PGK1 in the FOXD3/miR-143 axis

Abstract

Purpose

Curcumin is a potent antitumor agent. The objective of this study was to explore the interaction between curcumin and PGK1, an oncogene in the FOXD3/miR-143 axis, in prostate cancer therapy.

Methods

MiRNA microarray analysis was used to identify miRNAs upregulated by curcumin treatment. MiR-143 was dramatically upregulated by curcumin. Cells were treated with antimiR-143 in combination to curcumin, followed by examining cell viability and migration. Bioinformatics analysis was used to investigate target genes of miR-143. The interaction between miR-143 and PGK1 was evaluated with dual-luciferase assay. Since FOXD3 is important in the regulation of miR-143, we explored whether curcumin regulated FOXD3 expression. FOXD3 was also ectopically overexpressed to investigate its effects on curcumin's regulation of miR-143.

Results

Curcumin treatment significantly upregulated miR-143 and decreased prostate cancer cell proliferation and migration. Those effects were attenuated by anti-miR-143 transfection. Both miR-143 overexpression and curcumin treatment inhibited PGK1 expression and ectopic expression of PGK1 antagonized curcumin's antitumor effects. FOXD3 was upregulated by miR-143. Ectopic expression of FOXD3 synergized with curcumin in upregulating miR-143 expression.

Conclusion

Curcumin inhibits prostate cancer by upregulating miR-143. PGK1 is downregulated by miR-143, and FOXD3 upregulation is essential for the antitumor effect of curcumin.

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The impact of a solitary kidney on tolerability to gemcitabine plus cisplatin chemotherapy in urothelial carcinoma patients: a retrospective study

Abstract

Purpose

There is little information on tolerability to cisplatin-based chemotherapies in patients with a solitary kidney after nephroureterectomy. We evaluated the impact of having a solitary kidney on tolerability to gemcitabine plus cisplatin (GC) chemotherapy in urothelial carcinoma patients.

Methods

We retrospectively reviewed medical records of patients treated between August 2007 and November 2015. Eligible patients had received GC as first-line chemotherapy, including as neoadjuvant and adjuvant treatment. Patients who commenced GC chemotherapy after nephroureterectomy comprised the solitary kidney (SK) group; the remaining patients (i.e., those with both kidneys) comprised the BK group. Incidences of hematologic toxicities and renal insufficiency were examined and compared between two groups.

Results

There were 16 patients in the SK group and 31 in the BK group. The incidence of hematologic toxicity (grade 3/4) was not significantly different between the two groups (neutropenia: 68.8 vs. 74.2%, respectively (P = 0.959); thrombocytopenia: 31.2 vs. 51.6%, respectively (P = 0.307); and anemia: 12.5 vs. 38.7%, respectively (P = 0.094)). Multivariate analysis revealed no statistically significant association between having a SK and severe hematologic toxicities. Moreover, no significant differences were observed in the incidence of acute kidney injury. The mean differences in serum creatinine and estimated glomerular filtration rate between baseline and each post-chemotherapy cycle were similar when comparing the SK and BK groups.

Conclusions

There is no evidence that tolerability to GC chemotherapy is inferior in patients with a solitary kidney. Therefore, there may be no need to avoid administering CDDP-based chemotherapy to such patients.

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Low plasma concentration of gefitinib in patients with EGFR exon 21 L858R point mutations shortens progression-free survival

Abstract

Purpose

The relationship between the pharmacokinetics and effects of gefitinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is unknown. In this study, we examined the correlation between gefitinib plasma concentration and progression-free survival (PFS) in patients with two common types of EGFR mutations: a deletion in exon 19 and point mutations in exon 21 L858R.

Methods

The retrospective analysis examined 40 patients who were administered 250 mg of gefitinib daily. All patients were diagnosed with and treated for advanced non-small cell lung carcinoma with sensitive EGFR mutations between January 2011 and November 2013 at Akita University Hospital, Akita, Japan. The 40 patients were divided into four groups by trough plasma concentration (high or low) and mutation type (exon 19 deletions or exon 21 L858R point mutations). PFS, response rate, and toxic effects were analyzed in all four groups.

Results

After excluding 5 patients, the remaining 35 were successfully analyzed. For the patients with exon 19 deletions, there was no significant difference in PFS between the high and low plasma concentration groups (median survival: 12.0 vs. 17.0 months, P = 0.9548). In contrast, the PFS was significantly shorter for patients with exon 21 point mutations and low vs. high concentrations of gefitinib (median survival: 8.0 vs. 16.0 months, P < 0.05).

Conclusions

The results suggest that low gefitinib plasma concentrations in patients with exon 21 L858R point mutations may be associated with shorter PFS in NSCLC patients.

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WBP2 modulates G1/S transition in ER+ breast cancer cells and is a direct target of miR-206

Abstract

Purpose

The mechanisms underlying the oncogenic properties of WW domain binding protein 2 (WBP2) in breast cancer have not been fully understood. In this study, we explored the role of WBP2 in cell cycle regulation in ER+ breast cancer cells and how it is regulated in the cancer cells.

Methods

The association between WBP2 expression and prognosis in ER+ breast cancer was assessed by data mining in Breast Cancer Gene-Expression Miner v4.0. Cell cycle was assessed by PI staining and flow cytometry. EdU staining was applied to visualize cells in S phase. The binding between miR-206 and WBP2 were verified by dual luciferase assay. CCK-8 assay and flow cytometric analysis were applied to assess the functional role of WBP2 and miR-206 in the cancer cells.

Results

High WBP2 expression correlates with higher risk of any events (AE) and metastatic relapse (MR) and also indicates shorter AE-free survival and MR-free survival in ER+ breast cancer patients. In both MCF-7 and BT474 cells, WBP can influence the expression of G1/S-related cell cycle proteins, including p21, CDK4, and cyclin D1. In addition, WBP2 overexpression resulted in facilitated G1/S transition, while WBP2 knockdown impaired the transition. The 3′UTR of WBP2 has a conserved miR-206 binding site. Functionally, miR-206 knockdown decreased tamoxifen sensitivity in tamoxifen-sensitive (Tam^S) MCF-7 cells, while miR-206 overexpression and WBP2 knockdown enhanced the sensitivity in tamoxifen-resistant (Tam^R) MCF-7 cells.

Conclusion

Based on these findings, we infer that the miR-206/WBP2 axis can modulate tamoxifen sensitivity via regulating G1/S progression in ER+ breast cancer.

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Comparison between hypersensitivity reactions to cycles of modified FOLFOX6 and XELOX therapies in patients with colorectal cancer

Abstract

Purpose

Although hypersensitivity reactions (HSRs) to oxaliplatin (L-OHP) therapy are well-documented, few reports have compared different therapies in terms of HSR occurrence. In this study, we compared the frequency and pattern of HSRs to modified FOLFOX6 (mFOLFOX6; 5-fluorouracil, levofolinate calcium and L-OHP infusions) and XELOX (capecitabine and L-OHP) therapies, and sought to identify risk factors associated with HSRs.

Methods

Patients who had received mFOLFOX6 or XELOX chemotherapeutic regimens for unresectable colon or rectal cancer or as adjuvant chemotherapy following colon cancer surgery between April 2012 and August 2015 were included. Potential correlation between treatment modalities (regimen, dosage and route of administration of L-OHP, and injection timing for dexamethasone administration) and HSRs was assessed.

Results

Among the 240 patients included in the study, 136 had received mFOLFOX6 therapy and 104 had received XELOX therapy. Although the frequency of HSRs did not differ between the two groups, incidence of HSRs in the first cycle was higher in the XELOX therapy group. Treatment method or cumulative dosage was not identified as a risk factor for HSR; however, the incidence of ≥grade-2 HSR was higher in cases where the cumulative L-OHP dosage was ≥600 mg/m² and in patients in whom dexamethasone was not co-infused with L-OHP.

Conclusion

Although HSR rates were comparable among patients treated with mFOLFOX6 and XELOX, HSRs tended to occur more frequently during the first cycle of XELOX therapy as compared to that with mFOLFOX6 therapy. Our findings warrant careful assessment of ≥grade-2 HSRs in patients who are prescribed cumulative L-OHP dosages of ≥600 mg/m².

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