Publication date: Available online 12 April 2017
Source:Practical Radiation Oncology
Author(s): Erin S. Murphy, Kevin Rogacki, Andrew Godley, Peng Qi, Chandana Reddy, Manmeet Ahluwalia, David Peereboom, Glen Stevens, Jennifer S. Yu, John H. Suh, Sam T. Chao
BackgroundPulsed reduced dose rate (PRDR) is a re-irradiation technique that potentially overcomes volume and dose limitations in the setting of previous radiotherapy for recurrent central nervous system tumors. Intensity modulated radiation therapy (IMRT) has not yet been reported as a PRDR delivery technique. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for CNS re-irradiation.Material/MethodsA total of 24 patients with recurrent brain tumors received PRDR re-irradiation between 8/2012 and 12/2014. Twenty-two patients were planned with IMRT. Linear accelerators delivered an effective dose rate of 0.0667Gy/min. Data collected included number of prior interventions, diagnosis, tumor grade, radiotherapy dose and fractionation, normal tissue dose, radiotherapy planning parameters, time to progression, overall survival and adverse events.ResultsThe median time to PRDR from completion of initial radiotherapy was 47.8months (R: 11–389.1months). The median PRDR dose was 54Gy (R: 38–60Gy). The mean planning target volume was 369.1 +/− 177.9cm3. The median PFS and 6month PFS after PRDR treatment was 3.1months and 31%, respectively. The median OS and 6month OS after PRDR treatment was 8.7months and 71%, respectively. 50% of patients had ≥4 chemotherapy regimens prior to PRDR. Toxicity was similar to initial treatment including no cases of radiation necrosis.ConclusionIMRT PRDR re-irradiation is a feasible and appropriate treatment strategy for large volume recurrent CNS tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated. Prospective studies are necessary to determine the optimal timing of PRDR re-irradiation, the role of concurrent systemic agents, and the ideal patient population who would receive the maximal benefit from this treatment approach.SummaryIntensity modulated radiation therapy (IMRT) has not yet been reported as a pulsed reduced dose rate (PRDR) delivery technique for recurrent brain tumors and may allow for safe and comprehensive re-irradiation for large volume tumors. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for recurrent central nervous system tumors. We conclude that IMRT PRDR re-irradiation is a feasible and appropriate treatment strategy for large volume recurrent brain tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τετάρτη 12 Απριλίου 2017
Intensity Modulated Radiation Therapy with Pulsed Reduced Dose Rate as a Re-irradiation Strategy for Recurrent Central Nervous System Tumors: An Institutional Series and Literature Review
IDH1 R132C mutation is detected in clear cell hepatocellular carcinoma by pyrosequencing
Abstract
Background
Isocitrate dehydrogenase 1 (IDH1) mutation is common in low-grade glioma (approximately 80%) and acute myeloid leukemia (approximately 10%). Other than brain tumor or hematologic malignancies, intrahepatic cholangiocarcinoma (iCC) is a well-known solid tumor with IDH1 mutation (6.8–20%). Histologically, poor differentiation and clear cell change are associated with IDH1 mutation in iCC. Since hepatocellular carcinoma (HCC) shares histologic features with iCC, some specific subtypes of HCC might show a higher IDH1 mutation rate than reported before (0.5–1.5%).
Methods
Forty-six cases of iCC and 48 cases of HCC (including 20 cases of clear cell type and 13 cases of pseudoglandular pattern) were tested for IDH1 mutation by pyrosequencing.
Results
Three cases in iCC (6.5%) and five cases in HCC (10.4%) had IDH1 mutation, all of which were Arg132Cys. IDH1 mutant HCCs were all clear cell type. Although the IDH1 mutation rate between iCC and HCC demonstrated no significant difference, clear cell HCC revealed statistically increased mutation rate compared to that of HCC without clear cell change (P = 0.009). Presence of IDH1 mutation was related with poor survival in clear cell HCC patients (P = 0.004).
Conclusions
Clear cell HCC showed higher frequency of IDH1 mutation rate than other variants of HCC. This result consolidates the assumption that morphological features of tumors reflect molecular alterations.
http://ift.tt/2oBw4y2
Orchitis reveals an extragonadal primary mediastinal thymic seminoma: a coincidence or not?
Abstract
Background
Mediastinal thymic seminomas are rare male germ cell tumors with extragonadal origin that appear predominately with a cystic appearance.
Case presentation
A 22-year-old male was referred to our department for further investigation of a mediastinal mass discovered incidentally during routine chest X-ray. The patient has denied any symptoms including dyspnea, chest pain, cough, fever, dysphagia, hemoptysis, weight loss, and weakness. His past medical history was remarkable for orchitis, for which he had undergone a bilateral testicular biopsy, without the latter however, indicating the presence of a germ cell tumor or a premalignant lesion. Contrast-enhanced chest computed tomography revealed a lobulated and well-marginated cystic lesion in the anterior mediastinum. Differential diagnosis included mostly a multilocular thymic cyst, a lymphoma, a seminoma, or a soft tissue tumor. Resection of the mass revealed a primary thymic seminoma.
Conclusions
A surgical approach for the management of these tumors might be reasonable considering that an extensive sampling is mandatory to gain an appropriate biopsy preoperatively in order to securely confirm or refute the presence of a mediastinal extragonadal tumor. Orchitis might be a sign of a general disorder of the germ cells which might transform in time.
http://ift.tt/2opVY64
Lower limb function and quality of life after ILP for soft-tissue sarcoma
Abstract
Background
Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) in combination with complete tumor resection is an effective treatment option for non-resectable soft-tissue sarcoma of the extremities, with limb salvage rates greater than 80%. The aim of this study was to assess quality of life (QoL) after TM-ILP, also with regard to long-term survival.
Methods
We retrospectively examined 27 patients who had primarily non-resectable soft-tissue sarcoma of the leg and who had undergone TM-ILP and complete tumor resection (with limb-sparing intent) during their follow-up examinations using the Quality of Life Questionnaire (QLQ-C30) and the German Short Musculoskeletal Function Assessment (SMFA-D). The results from the QLQ-C30 were compared to the reference values for the general population, to the "all cancer patients" reference values (both reference values published by the European Organization for Research and Treatment of Cancer (EORTC)), and to the reference values of a historical amputation group from the literature. The results of the SMFA were compared with those from a reference group of healthy individuals.
Results
Surprisingly, we found that the global health status/QoL in the TM-ILP group was not significantly different from the general population or from patients with amputation, but it was higher than that of patients with cancer in general. Concerning the SMFA, we did find functional impairments in patients after TM-ILP compared to the reference group. With regard to long-term survival, we found no time-dependent deterioration in QoL for longer time intervals after treatment.
Conclusions
These results support the use of TM-ILP in limb-sparing multimodal therapy settings from a quality-of-life perspective, but they also encourage further research on this matter.
http://ift.tt/2oBAMfp
Debulking surgery for venous hemangioma arising from the epicardium: report of a case
Abstract
Background
Cardiac hemangiomas are rare benign vascular tumors that can occur in any cardiac layer: endocardium, myocardium, or epicardium. Histologically, cardiac hemangiomas may be classified as capillary, cavernous, or arteriovenous; venous hemangiomas are extremely rare.
Case presentation
A 46-year-old man reported experiencing precordial discomfort. Computed tomography revealed a massive tumor adjacent to the right ventricle. The right coronary artery was found to be located at the center of the tumor. Cardiovascular angiography showed that the artery was completely encased by the tumor without any obstruction and that the right ventricular lumen was compressed by the tumor. Surgical debulking of the tumor was performed under cardiopulmonary bypass, and the frozen section led to a diagnosis of benign hemangioma. The tumor was debulked as much as possible until the right coronary artery appeared. For decompression of the heart, the pericardium was left open to the thoracic cavity and unsutured. Histopathologic examination revealed a diagnosis of epicardial venous hemangioma.
Conclusions
Cardiac hemangioma should be included in the differential diagnosis of mediastinal tumor in reference to the location and flow of the coronary artery. Surgical resection, or at least tumor debulking, is required to confirm the diagnosis and prevent further complications and has a favorable clinical outcome.
http://ift.tt/2oqqzAo
Orchitis reveals an extragonadal primary mediastinal thymic seminoma: a coincidence or not?
Abstract
Background
Mediastinal thymic seminomas are rare male germ cell tumors with extragonadal origin that appear predominately with a cystic appearance.
Case presentation
A 22-year-old male was referred to our department for further investigation of a mediastinal mass discovered incidentally during routine chest X-ray. The patient has denied any symptoms including dyspnea, chest pain, cough, fever, dysphagia, hemoptysis, weight loss, and weakness. His past medical history was remarkable for orchitis, for which he had undergone a bilateral testicular biopsy, without the latter however, indicating the presence of a germ cell tumor or a premalignant lesion. Contrast-enhanced chest computed tomography revealed a lobulated and well-marginated cystic lesion in the anterior mediastinum. Differential diagnosis included mostly a multilocular thymic cyst, a lymphoma, a seminoma, or a soft tissue tumor. Resection of the mass revealed a primary thymic seminoma.
Conclusions
A surgical approach for the management of these tumors might be reasonable considering that an extensive sampling is mandatory to gain an appropriate biopsy preoperatively in order to securely confirm or refute the presence of a mediastinal extragonadal tumor. Orchitis might be a sign of a general disorder of the germ cells which might transform in time.
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Lower limb function and quality of life after ILP for soft-tissue sarcoma
Abstract
Background
Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) in combination with complete tumor resection is an effective treatment option for non-resectable soft-tissue sarcoma of the extremities, with limb salvage rates greater than 80%. The aim of this study was to assess quality of life (QoL) after TM-ILP, also with regard to long-term survival.
Methods
We retrospectively examined 27 patients who had primarily non-resectable soft-tissue sarcoma of the leg and who had undergone TM-ILP and complete tumor resection (with limb-sparing intent) during their follow-up examinations using the Quality of Life Questionnaire (QLQ-C30) and the German Short Musculoskeletal Function Assessment (SMFA-D). The results from the QLQ-C30 were compared to the reference values for the general population, to the "all cancer patients" reference values (both reference values published by the European Organization for Research and Treatment of Cancer (EORTC)), and to the reference values of a historical amputation group from the literature. The results of the SMFA were compared with those from a reference group of healthy individuals.
Results
Surprisingly, we found that the global health status/QoL in the TM-ILP group was not significantly different from the general population or from patients with amputation, but it was higher than that of patients with cancer in general. Concerning the SMFA, we did find functional impairments in patients after TM-ILP compared to the reference group. With regard to long-term survival, we found no time-dependent deterioration in QoL for longer time intervals after treatment.
Conclusions
These results support the use of TM-ILP in limb-sparing multimodal therapy settings from a quality-of-life perspective, but they also encourage further research on this matter.
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IDH1 R132C mutation is detected in clear cell hepatocellular carcinoma by pyrosequencing
Abstract
Background
Isocitrate dehydrogenase 1 (IDH1) mutation is common in low-grade glioma (approximately 80%) and acute myeloid leukemia (approximately 10%). Other than brain tumor or hematologic malignancies, intrahepatic cholangiocarcinoma (iCC) is a well-known solid tumor with IDH1 mutation (6.8–20%). Histologically, poor differentiation and clear cell change are associated with IDH1 mutation in iCC. Since hepatocellular carcinoma (HCC) shares histologic features with iCC, some specific subtypes of HCC might show a higher IDH1 mutation rate than reported before (0.5–1.5%).
Methods
Forty-six cases of iCC and 48 cases of HCC (including 20 cases of clear cell type and 13 cases of pseudoglandular pattern) were tested for IDH1 mutation by pyrosequencing.
Results
Three cases in iCC (6.5%) and five cases in HCC (10.4%) had IDH1 mutation, all of which were Arg132Cys. IDH1 mutant HCCs were all clear cell type. Although the IDH1 mutation rate between iCC and HCC demonstrated no significant difference, clear cell HCC revealed statistically increased mutation rate compared to that of HCC without clear cell change (P = 0.009). Presence of IDH1 mutation was related with poor survival in clear cell HCC patients (P = 0.004).
Conclusions
Clear cell HCC showed higher frequency of IDH1 mutation rate than other variants of HCC. This result consolidates the assumption that morphological features of tumors reflect molecular alterations.
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Debulking surgery for venous hemangioma arising from the epicardium: report of a case
Abstract
Background
Cardiac hemangiomas are rare benign vascular tumors that can occur in any cardiac layer: endocardium, myocardium, or epicardium. Histologically, cardiac hemangiomas may be classified as capillary, cavernous, or arteriovenous; venous hemangiomas are extremely rare.
Case presentation
A 46-year-old man reported experiencing precordial discomfort. Computed tomography revealed a massive tumor adjacent to the right ventricle. The right coronary artery was found to be located at the center of the tumor. Cardiovascular angiography showed that the artery was completely encased by the tumor without any obstruction and that the right ventricular lumen was compressed by the tumor. Surgical debulking of the tumor was performed under cardiopulmonary bypass, and the frozen section led to a diagnosis of benign hemangioma. The tumor was debulked as much as possible until the right coronary artery appeared. For decompression of the heart, the pericardium was left open to the thoracic cavity and unsutured. Histopathologic examination revealed a diagnosis of epicardial venous hemangioma.
Conclusions
Cardiac hemangioma should be included in the differential diagnosis of mediastinal tumor in reference to the location and flow of the coronary artery. Surgical resection, or at least tumor debulking, is required to confirm the diagnosis and prevent further complications and has a favorable clinical outcome.
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Prophylactic atropine administration attenuates the negative haemodynamic effects of induction of anaesthesia with propofol and high-dose remifentanil: A randomised controlled trial.
http://ift.tt/2nFsqnD
Effects of different fresh gas flows with or without a heat and moisture exchanger on inhaled gas humidity in adults undergoing general anaesthesia: A systematic review and meta-analysis of randomised controlled trials.
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The Role of Early Molecular Response in the Management of Chronic Phase CML
Abstract
Purpose of Review
Although tyrosine kinase inhibitors (TKIs) spectacularly improve the disease burden and the overall survival of chronic myeloid leukemia patients, early identification of a subset of poor TKI responders has been recognized as a critical goal to prevent disease progression in these patients. We herein review the past and recent evidence on the impact of early response.
Recent Findings
In the recent years, the achievement of an early molecular response (EMR, defined as 3-month BCR-ABL1 transcript <10% IS) has emerged as a useful tool to identify poor-risk patients. Although several groups have reported the importance of such milestone, clinical intervention based on it remains controversial partly due to its low specificity to predict progression, which may be partially improved by using the rate of decline in BCR-ABL1 transcript level (halving time or velocity of ratio reduction).
Summary
Standardization of halving time or velocity of ratio reduction will likely help establishing more stringent recommendation and modify current clinical practices.
http://ift.tt/2p8TYSq
The Role of Early Molecular Response in the Management of Chronic Phase CML
Abstract
Purpose of Review
Although tyrosine kinase inhibitors (TKIs) spectacularly improve the disease burden and the overall survival of chronic myeloid leukemia patients, early identification of a subset of poor TKI responders has been recognized as a critical goal to prevent disease progression in these patients. We herein review the past and recent evidence on the impact of early response.
Recent Findings
In the recent years, the achievement of an early molecular response (EMR, defined as 3-month BCR-ABL1 transcript <10% IS) has emerged as a useful tool to identify poor-risk patients. Although several groups have reported the importance of such milestone, clinical intervention based on it remains controversial partly due to its low specificity to predict progression, which may be partially improved by using the rate of decline in BCR-ABL1 transcript level (halving time or velocity of ratio reduction).
Summary
Standardization of halving time or velocity of ratio reduction will likely help establishing more stringent recommendation and modify current clinical practices.
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The senile functional evolution of the larynx after supracricoid reconstructive surgery.
| Related Articles |
The senile functional evolution of the larynx after supracricoid reconstructive surgery.
Eur Arch Otorhinolaryngol. 2016 Dec;273(12):4359-4368
Authors: Serra A, Maiolino L, Di Mauro P, Licciardello L, Cocuzza S
Abstract
Supracricoid partial laryngectomy is a relevant organ-preserving surgical technique used for the treatment of early or locally advanced laryngeal tumors with an oncologic outcome comparable with that of total laryngectomy. This reconstructive surgery is certainly technically feasible also in the elderly, but the problem is postoperatively as the patient may lack the will and strength to be successfully rehabilitated. The goal was to evaluate functional outcomes, in a maximum follow-up period of ten years from the end of the postoperative follow-up, in a cohort of elderly patients to look at the senile evolution of the laryngeal post surgical function comparing the amount of resection and grade of possible impairment of swallowing and phonatory parameters. A group of 33 patients were selected for a retrospective study aimed at evaluating the long-term evolution of laryngeal functionality after surgery, with the baseline at 5 years from the end of follow-up. All the patients had three-monthly visits for a period up to ten years, during which the objective and subjective swallowing and phonatory parameters were recorded, analyzed and, at the end of the study, compared with baseline. The results suggest that long-term post surgical functional problems may develop also in the neolarynx where the effects of the reconstructive surgery, on speech and swallowing, are largely stabilized. The presence of arytenoid resection had significantly impacted on the occurrence of aspiration even if the overall number of dysphagic patients was not statistically significant compared to baseline.
PMID: 27363403 [PubMed - indexed for MEDLINE]
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Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel HDAC/PI3K dual inhibitor
Abstract
Histone deacetylase (HDAC)/phosphatidylinositol 3-kinase (PI3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and exhibiting synergistic effects. Therefore, development of an HDAC/PI3K dual inhibitor is reasonably attractive. Romidepsin (FK228, depsipeptide) is a potent HDAC inhibitor. We have previously reported that depsipeptide and its analogs have an additional activity as PI3K inhibitors and are defined as HDAC/PI3K dual inhibitors. Subsequently, we identified FK-A11 as the most potent analog and reported its biochemical, biological, and structural properties as an HDAC/PI3K dual inhibitor. In this study, we demonstrated in vitro and in vivo efficacy of FK-A11 in HT1080 fibrosarcoma and PC3 prostate cancer cell xenograft mouse models. FK-A11 showed in vivo antitumor activity by both intravenous and intraperitoneal administration in a dose-dependent manner. In both xenograft models, FK-A11 showed superior antitumor effects compared to other depsipeptide analogs in accordance with in vitro anti-cell proliferation effects and the potency of HDAC/PI3K dual inhibition. In addition, we showed evidence of HDAC/PI3K dual inhibition accompanying antitumor efficacy in xenograft tumor tissues by immunohistochemistry. We also detailed pharmacokinetic characterization of FK-A11 in mice. These findings will be essential for guiding further preclinical and clinical studies.
This article is protected by copyright. All rights reserved.
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Anti-tumor effect of FAK inhibitor PF562271 against human osteosarcoma in vitro and in vivo
Abstract
Focal adhesion kinase (FAK) overexpression is related to the invasive and metastatic property in different kind of cancers. Target therapy by inhibiting FAK has achieved promising effect in some cancer treatment, but its effect in human osteosarcoma has not yet well studied. In present study, we analyzed the anti-tumor efficacy of PF562271, a FAK inhibitor, against osteosarcoma in vitro and vivo. p-FAK (Y397) was highly expressed in primary human osteosarcoma tumor samples and was associated with osteosarcoma prognosis and lung metastasis. PF562271 greatly suppressed the proliferation, colony formation in human osteosarcoma cell lines. In addition, treatment of osteosarcoma cell lines with PF562271 induced apoptosis and down-regulated the activity of AKT/mTOR pathway. Furthermore, PF562271 impaired tube formation ability of endothelial cells in vitro. Finally, oral administration of PF562271 in mice dramatically reduced tumor volume, weight and angiogenesis of osteosarcoma xenografts in vivo. These results indicate that FAK inhibitor PF562271 can potentially be effectively used for the treatment of osteosarcoma.
This article is protected by copyright. All rights reserved.
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Role of hepatic resection in patients with intermediate-stage hepatocellular carcinoma: a multicenter study from Japan
Summary
Transarterial chemoembolization (TACE) is recommended for patients with intermediate-stage (Barcelona Clinic Liver Cancer (BCLC) criteria B, BCLC-B) hepatocellular carcinoma (HCC). However, patients with BCLC-B HCC can differ in background factors related to hepatic function as well as tumor size and number. In the present study, we clarified the role of hepatic resection in patients with BCLC-B HCC. A total of 489 BCLC-B HCC patients with Child-Pugh class A disease initially treated with hepatic resection or TACE were included. In patients after propensity score matching (n=264), hepatic resection (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.35–0.91) was independently associated with survival in the multivariate analysis. We then divided patients into 2 groups based on the results of statistical analysis. There were 170 patients treated with resection and 319 with TACE. Child-Pugh score and number of tumors (cut-off, 3 tumors) were independently associated with type of HCC treatment in the multivariate analysis. We then divided patients in Group A (Child-Pugh score of 5 and ≤3 tumors; n=186) and Group B (Child-Pugh score of 6 or ≥4 tumors; n=303). In Group A, cumulative survival was significantly higher in the hepatic resection group than in the TACE group (p=0.014). In Cox proportional hazards models, hepatic resection (HR, 0.38; 95% CI, 0.23–0.64) was independently associated with survival in Group A patients. In Group B, treatment status was not associated with overall survival. Hepatic resection should be considered in patients with a Child-Pugh score of 5 and ≤3 tumors, despite having BCLC-B HCC.
This article is protected by copyright. All rights reserved.
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Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel HDAC/PI3K dual inhibitor
Abstract
Histone deacetylase (HDAC)/phosphatidylinositol 3-kinase (PI3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and exhibiting synergistic effects. Therefore, development of an HDAC/PI3K dual inhibitor is reasonably attractive. Romidepsin (FK228, depsipeptide) is a potent HDAC inhibitor. We have previously reported that depsipeptide and its analogs have an additional activity as PI3K inhibitors and are defined as HDAC/PI3K dual inhibitors. Subsequently, we identified FK-A11 as the most potent analog and reported its biochemical, biological, and structural properties as an HDAC/PI3K dual inhibitor. In this study, we demonstrated in vitro and in vivo efficacy of FK-A11 in HT1080 fibrosarcoma and PC3 prostate cancer cell xenograft mouse models. FK-A11 showed in vivo antitumor activity by both intravenous and intraperitoneal administration in a dose-dependent manner. In both xenograft models, FK-A11 showed superior antitumor effects compared to other depsipeptide analogs in accordance with in vitro anti-cell proliferation effects and the potency of HDAC/PI3K dual inhibition. In addition, we showed evidence of HDAC/PI3K dual inhibition accompanying antitumor efficacy in xenograft tumor tissues by immunohistochemistry. We also detailed pharmacokinetic characterization of FK-A11 in mice. These findings will be essential for guiding further preclinical and clinical studies.
This article is protected by copyright. All rights reserved.
http://ift.tt/2oBBMA6
Anti-tumor effect of FAK inhibitor PF562271 against human osteosarcoma in vitro and in vivo
Abstract
Focal adhesion kinase (FAK) overexpression is related to the invasive and metastatic property in different kind of cancers. Target therapy by inhibiting FAK has achieved promising effect in some cancer treatment, but its effect in human osteosarcoma has not yet well studied. In present study, we analyzed the anti-tumor efficacy of PF562271, a FAK inhibitor, against osteosarcoma in vitro and vivo. p-FAK (Y397) was highly expressed in primary human osteosarcoma tumor samples and was associated with osteosarcoma prognosis and lung metastasis. PF562271 greatly suppressed the proliferation, colony formation in human osteosarcoma cell lines. In addition, treatment of osteosarcoma cell lines with PF562271 induced apoptosis and down-regulated the activity of AKT/mTOR pathway. Furthermore, PF562271 impaired tube formation ability of endothelial cells in vitro. Finally, oral administration of PF562271 in mice dramatically reduced tumor volume, weight and angiogenesis of osteosarcoma xenografts in vivo. These results indicate that FAK inhibitor PF562271 can potentially be effectively used for the treatment of osteosarcoma.
This article is protected by copyright. All rights reserved.
http://ift.tt/2pvYLd8
Role of hepatic resection in patients with intermediate-stage hepatocellular carcinoma: a multicenter study from Japan
Summary
Transarterial chemoembolization (TACE) is recommended for patients with intermediate-stage (Barcelona Clinic Liver Cancer (BCLC) criteria B, BCLC-B) hepatocellular carcinoma (HCC). However, patients with BCLC-B HCC can differ in background factors related to hepatic function as well as tumor size and number. In the present study, we clarified the role of hepatic resection in patients with BCLC-B HCC. A total of 489 BCLC-B HCC patients with Child-Pugh class A disease initially treated with hepatic resection or TACE were included. In patients after propensity score matching (n=264), hepatic resection (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.35–0.91) was independently associated with survival in the multivariate analysis. We then divided patients into 2 groups based on the results of statistical analysis. There were 170 patients treated with resection and 319 with TACE. Child-Pugh score and number of tumors (cut-off, 3 tumors) were independently associated with type of HCC treatment in the multivariate analysis. We then divided patients in Group A (Child-Pugh score of 5 and ≤3 tumors; n=186) and Group B (Child-Pugh score of 6 or ≥4 tumors; n=303). In Group A, cumulative survival was significantly higher in the hepatic resection group than in the TACE group (p=0.014). In Cox proportional hazards models, hepatic resection (HR, 0.38; 95% CI, 0.23–0.64) was independently associated with survival in Group A patients. In Group B, treatment status was not associated with overall survival. Hepatic resection should be considered in patients with a Child-Pugh score of 5 and ≤3 tumors, despite having BCLC-B HCC.
This article is protected by copyright. All rights reserved.
http://ift.tt/2oBLsKP
Multidirectional inhibition of cortico-hippocampal neurodegeneration by kolaviron treatment in rats
Abstract
Earliest signs of neurodegenerative cascades in the course of Alzheimer's disease (AD) are seen within the prefrontal cortex (PFC) and hippocampus, with pathological evidences in both cortical structures correlating with manifestation of behavioural and cognitive deficits. Despite the enormous problems associated with AD's clinical manifestations in sufferers, therapeutic advances for the disorder are still very limited. Therefore, this study examined cortico-hippocampal microstructures in models of AD, and evaluated the possible beneficial roles of kolaviron (Kv)-a biflavonoid complex in rats. Nine groups of rats were orally exposed to sodium azide (NaN3) or aluminium chloride (AlCl3) solely or in different combinations with Kv. Sequel to sacrifice and transcardial perfusion (using buffered saline then 4% paraformaldehyde), PFC and hippocampal tissues were harvested and processed for: spectrophotometric assays of oxidative stress and neuronal bioenergetics parameters, histological demonstration of cytoarchitecture and immunohistochemical evaluation of astrocytes and neuronal cytoskeleton. Results showed alterations in mitochondrial functions, which led to compromised neuronal antioxidant system, dysfunctional neural bioenergetics, hypertrophic astrogliosis, cytoskeletal dysregulation and neuronal death within the PFC and hippocampus. These degenerative events were associated with NaN3 and AlCl3 toxicity in rats. Furthermore, Kv inhibited cortico-hippocampal degeneration through multiple mechanisms that primarily involved halting of biochemical cascades that activate proteases which destroy molecules expedient for cell survival, and others that mediate a program of cell suicide in neuronal apoptosis. In conclusion, Kv showed important neuroprotective roles within cortico-hippocampal cells through multiple mechanisms, and particularly has prominent prophylactic activity than regenerative potentials.
http://ift.tt/2oBjxuy
Multidirectional inhibition of cortico-hippocampal neurodegeneration by kolaviron treatment in rats
Abstract
Earliest signs of neurodegenerative cascades in the course of Alzheimer's disease (AD) are seen within the prefrontal cortex (PFC) and hippocampus, with pathological evidences in both cortical structures correlating with manifestation of behavioural and cognitive deficits. Despite the enormous problems associated with AD's clinical manifestations in sufferers, therapeutic advances for the disorder are still very limited. Therefore, this study examined cortico-hippocampal microstructures in models of AD, and evaluated the possible beneficial roles of kolaviron (Kv)-a biflavonoid complex in rats. Nine groups of rats were orally exposed to sodium azide (NaN3) or aluminium chloride (AlCl3) solely or in different combinations with Kv. Sequel to sacrifice and transcardial perfusion (using buffered saline then 4% paraformaldehyde), PFC and hippocampal tissues were harvested and processed for: spectrophotometric assays of oxidative stress and neuronal bioenergetics parameters, histological demonstration of cytoarchitecture and immunohistochemical evaluation of astrocytes and neuronal cytoskeleton. Results showed alterations in mitochondrial functions, which led to compromised neuronal antioxidant system, dysfunctional neural bioenergetics, hypertrophic astrogliosis, cytoskeletal dysregulation and neuronal death within the PFC and hippocampus. These degenerative events were associated with NaN3 and AlCl3 toxicity in rats. Furthermore, Kv inhibited cortico-hippocampal degeneration through multiple mechanisms that primarily involved halting of biochemical cascades that activate proteases which destroy molecules expedient for cell survival, and others that mediate a program of cell suicide in neuronal apoptosis. In conclusion, Kv showed important neuroprotective roles within cortico-hippocampal cells through multiple mechanisms, and particularly has prominent prophylactic activity than regenerative potentials.
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Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer
Abstract
In this study, we investigated the clinical relevance of CD274 (PD-L1) protein expression by tumor cells and tumor-infiltrating immune cells in colorectal cancer (CRC). To this end, 186 microsatellite instability-high (MSI-H) and 153 microsatellite stable (MSS) CRCs were subjected to immunohistochemistry (IHC) analysis for the expression of CD274 and mismatch repair proteins. CD274 expression was evaluated in tumor cells at the center (TC) and periphery (TP), and immune cells at the center (IC) and periphery (IP) of CRC. IHC slides stained for CD3 and CD8 were scanned using an Aperio ScanScope for precise calculation of tumor-infiltrating T cell density. Additionally, samples were screened for the B-Raf (BRAF)-V600E mutation using a Cobas 4800 System and IHC. In total, CD274TC, CD274TP, CD274IC, and CD274IP were observed in 43 (23.1%), 47 (25.3%), 107 (57.5%), and 102 (54.8%) of the MSI-H CRCs examined, and in three (2.0%), four (2.6%), 47 (30.7%), and 56 (36.6%) of the 153 MSS CRCs tested. Meanwhile, intratumoral heterogeneity of CD274 expression in tumor cells and immune cells was detected in 24 (12.9%) and 47 (25.3%) MSI-H CRCs, respectively. Notably, in both MSI-H and MSS CRC, CD274IC and CD274IP were independently associated with improved prognosis (P < 0.05), while BRAF mutation was associated with CD274TP, poor differentiation, sporadic type, and hMLH1(−)/hMSH2(+)/hMSH6(+)/PMS2(−) in MSI-H CRC (P < 0.006). In conclusion, CD274 expression in tumor-infiltrating immune cells was an independent factor for improved prognosis in CRC patients. A deeper understanding of CD274 status may yield improved responses to future CRC immunotherapies.
http://ift.tt/2nFxPv1
Coexpressed modular gene expression reveals inverse correlation between immune responsive transcription and aggressiveness in gastric tumours
Abstract
The existing large number of gene expression profiles of tumour samples offers a great advantage for the integrative functional genomic exploration of molecular dysregulation in cancers. The clusters of genes (modules) derived from a gastric cancer (GC) coexpression network were explored to understand their clinical and functional significance. Among the modules derived from the GC mRNA expression network, six modules were relatively highly expressed in diffuse type gastric tumours. Elevated expression of genes related to extracellular matrix (ECM), angiogenesis, collagen and intracellular cytoskeletal components and immune response were identified in these modules. ECM-related modules exhibited an inverse correlation with modules representing the expression of immune response genes. A reduced expression of immune response genes was identified as the key factor associated with the aggressive features of diffuse gastric tumours, which is indicative of tumour progression involving the escape from immune surveillance in diffuse tumours. A part of the identified aggressive factors was common between intestinal and diffuse type tumours. The coexpressed modules and their expression patterns delineate the fine transition involved in cancer progression in the later stages of tumours. The identified modules could serve as surrogate gene-sets, indicating the molecular staging of GC aggressiveness with underlying biological interaction.
http://ift.tt/2p9owAs
The Importance of Nutrition in a Conceptual Framework of Frailty Syndrome
Abstract
Purpose
The present review intends to present different concepts of frailty syndrome in aging and construct a conceptual framework from these concepts, and highlight the importance of nutrition in this framework.
Recent Findings
Frailty is an important pre-disability syndrome, with a multifactorial origin, and as such, needs to be monitored and treated. Nutritional aspects, such as the anabolic resistance to proteins, the inflammatory and oxidative status, and nutritional risk, are strong determinants of frailty and are suggested, therefore, to be part of the framework.
Summary
Most publications on frailty have focused mainly on the biological aspects of this condition, and nutrition is not directly mentioned in the current definitions of frailty. We, herein, propose a conceptual framework to include environmental, demographic, and socioeconomic aspects when defining frailty; the core framework was complemented with second- and third-level variables, to include and highlight nutritional aspects.
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The Importance of Nutrition in a Conceptual Framework of Frailty Syndrome
Abstract
Purpose
The present review intends to present different concepts of frailty syndrome in aging and construct a conceptual framework from these concepts, and highlight the importance of nutrition in this framework.
Recent Findings
Frailty is an important pre-disability syndrome, with a multifactorial origin, and as such, needs to be monitored and treated. Nutritional aspects, such as the anabolic resistance to proteins, the inflammatory and oxidative status, and nutritional risk, are strong determinants of frailty and are suggested, therefore, to be part of the framework.
Summary
Most publications on frailty have focused mainly on the biological aspects of this condition, and nutrition is not directly mentioned in the current definitions of frailty. We, herein, propose a conceptual framework to include environmental, demographic, and socioeconomic aspects when defining frailty; the core framework was complemented with second- and third-level variables, to include and highlight nutritional aspects.
http://ift.tt/2p8kGdV
CIC-DUX4 induces small round cell sarcomas distinct from Ewing sarcoma
CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Hoever, recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Few ancillary markers have been used in the differential diagnosis of CDS, and additional CDS-specific biomarkers are needed for more definitive classification. Here we report the generation of an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human CIC-DUX4 cDNA. Recipient mice transplanted with eMC expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small-round to short-spindle cells. Gene expression profiles of CDS and eMC revealed upregulation of CIC-DUX4 downstream genes such as PEA3 family genes, Ccnd2, Crh and Zic1. Immunohistochemical analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2 effectively inhibited CDS tumor growth in vitro. The CDK4/6 inhibitor palbociclib and the soft tissue sarcoma drug trabectedin also blocked the growth of mouse CDS. In summary, our mouse model provides important biological information about CDS and provides a useful platform to explore biomarkers and therapeutic agents for CDS.
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CIC-DUX4 induces small round cell sarcomas distinct from Ewing sarcoma
CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Hoever, recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Few ancillary markers have been used in the differential diagnosis of CDS, and additional CDS-specific biomarkers are needed for more definitive classification. Here we report the generation of an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human CIC-DUX4 cDNA. Recipient mice transplanted with eMC expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small-round to short-spindle cells. Gene expression profiles of CDS and eMC revealed upregulation of CIC-DUX4 downstream genes such as PEA3 family genes, Ccnd2, Crh and Zic1. Immunohistochemical analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2 effectively inhibited CDS tumor growth in vitro. The CDK4/6 inhibitor palbociclib and the soft tissue sarcoma drug trabectedin also blocked the growth of mouse CDS. In summary, our mouse model provides important biological information about CDS and provides a useful platform to explore biomarkers and therapeutic agents for CDS.
http://ift.tt/2paB36G
Molecular Pathways: Metabolic control of histone methylation and gene expression in cancer
Epigenetic alterations contribute to tumor development, progression, and therapeutic response. Many epigenetic enzymes use metabolic intermediates as cofactors to modify chromatin structure. Emerging evidence suggests that fluctuation in metabolite levels may regulate activities of these chromatin-modifying enzymes. Here we summarize recent progress in understanding the crosstalk between metabolism and epigenetic control of gene expression in cancer. We focus on how metabolic changes, due to diet, genetic mutations, or tumor microenvironment, regulate histone methylation status and consequently affect gene expression profiles to promote tumorigenesis. Importantly, we also suggest some potential therapeutic approaches to target the oncogenic role of metabolic alterations and epigenetic modifications in cancer.
http://ift.tt/2pvR8mX
Molecular Pathways: Metabolic control of histone methylation and gene expression in cancer
Epigenetic alterations contribute to tumor development, progression, and therapeutic response. Many epigenetic enzymes use metabolic intermediates as cofactors to modify chromatin structure. Emerging evidence suggests that fluctuation in metabolite levels may regulate activities of these chromatin-modifying enzymes. Here we summarize recent progress in understanding the crosstalk between metabolism and epigenetic control of gene expression in cancer. We focus on how metabolic changes, due to diet, genetic mutations, or tumor microenvironment, regulate histone methylation status and consequently affect gene expression profiles to promote tumorigenesis. Importantly, we also suggest some potential therapeutic approaches to target the oncogenic role of metabolic alterations and epigenetic modifications in cancer.
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The 21-Gene Recurrence Score Assay for Node-Positive, Early-Stage Breast Cancer and Impact of RxPONDER Trial on Chemotherapy Decision-Making: Have Clinicians Already Decided?
Background: The 21-gene recurrence score (RS) assay is retrospectively validated for assessing prognosis and benefit from chemotherapy in hormone receptor–positive, early-stage breast cancer (EBC) with low RS. We hypothesized that oncologists have already incorporated the RS assay for decision-making in higher-risk, node-positive disease, despite the lack of prospective data and contrary to NCCN Guideline recommendations. This study provides the first analysis of trends and differences in RS use and therapeutic implications in a population-based data set of patients with node-positive EBC. It also assesses the impact of the RxPONDER trial on clinicians' chemotherapy recommendations. Methods: Node-positive EBC cases diagnosed during 2010 through 2012 and included in the National Cancer Data Base were used. Multivariate logistic regression was used to estimate test use and impact on chemotherapy recommendations. Results: The RS assay was ordered for 16.5% of the 80,405 identified patients. Of all variables, the RS assay had the strongest association with chemotherapy recommendation, with adjusted odds ratios (AORs) of 19 for scores >30. Odds of chemotherapy recommendation were significantly lower for the group who received the test (AOR, 0.21; 95% CI, 0.20–0.22). When divided based on the cutoff point of 25 adopted by the RxPONDER trial, those with an RS of 18 to 25 had significantly lower odds of chemotherapy recommendation compared with those with an RS of 26 to 30 (AOR, 0.32; 95% CI, 0.26–0.40). Test use was lower for blacks, community centers, uninsured/governmentally insured patients, higher tumor grade, larger tumor size, and more nodes involved. Chemotherapy recommendation was higher for patients of younger age, with private insurance, and with higher tumor grade, size, and number of nodes involved. Black patients had significantly higher RS (AOR, 1.37; 95% CI, 1.25–1.79). Conclusions: The RS assay influences clinicians' chemotherapy recommendation in node-positive EBC. Clinicians are using the inclusion criteria of the RxPONDER trial before its final release. Black patients have higher RS, likely representing worse biology. Significant differences exist in test use and clinical implications based on race, insurance, and facility.
http://ift.tt/2pvHnoF
Regional Radiation Therapy Impacts Outcome for Node-Positive Cutaneous Melanoma
Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board–approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30–60 Gy) in 27 fractions (range, 5–30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13–180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05–0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24–92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.
http://ift.tt/2pvsH92
Implementation of Systemic Hedgehog Inhibitors in Daily Practice as Neoadjuvant Therapy
The most common cancer in both men and women is basal cell carcinoma (BCC). Although most primary and recurrent BCCs have high cure rates with standard therapies, advanced BCCs present a greater treatment challenge, especially in cosmetically and functionally sensitive areas. In patients unable to undergo surgery or radiation therapy, hedgehog inhibitors can be used neoadjuvantly to reduce tumor size, decreasing the extent and complexity of any subsequent surgery and providing either a cure or palliation. The goal of this review is to summarize the pharmacology, efficacy, and safety of systemic hedgehog inhibitors, as well as their role in daily practice as neoadjuvant therapy. Relevant English-language literature was identified and evaluated based on results from database searches of PubMed. Terms searched included, but were not limited to, "vismodegib," "Erivedge," "sonidegib," "DE225," "BCC," and "neoadjuvant treatment." Additional literature was identified from the reference lists of previously identified articles. The authors' personal experience in treating advanced BCC using hedgehog inhibitors has been incorporated into the recommendations made herein.
http://ift.tt/2pvsFhq
Therapeutic Response of Metastatic Colorectal Cancer Harboring a KRAS Missense Mutation After Combination Chemotherapy With the EGFR Inhibitor Panitumumab
Over the past decade, subset analyses of retrospective and prospective clinical studies have determined that KRAS-mutated metastatic colorectal cancers do not respond effectively to inhibition of epidermal growth factor receptor (EGFR) with the EGFR-targeting monoclonal antibodies cetuximab or panitumumab. Within the past few years, the scope of tested variants in the KRAS oncogene has expanded significantly, and testing of all RAS family genes has become more widely available in clinical laboratories. Expert consensus guidelines have recommended not using EGFR inhibitors in patients with KRAS-mutated tumors. However, with increasing identification of low-prevalence variants, it is conceivable that some RAS mutations do not provide equivalent resistance to EGFR inhibition compared with the most prevalent mutations at codons 12, 13, and 61. This report describes a case of a patient with metastatic colon cancer harboring the p.A59T variant of KRAS, with objective radiographic response (36% decrease per RECIST 1.1) and carcinoembryonic antigen biomarker response to panitumumab therapy given with FOLFIRI chemotherapy. We propose that A59T represents one potential exception to the guidelines that KRAS mutant tumors fail to respond to therapy with EGFR inhibitors, altering the paradigm of using this generalized approach.
http://ift.tt/2oBaxWb
NCCN Guidelines Insights: Breast Cancer, Version 1.2017
These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor–positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.
http://ift.tt/2oBobZv
Paving the Way for Dose Banding of Chemotherapy: An Analytical Approach
Background: In an interdepartmental cooperation, we investigated the feasibility and benefits of implementing dose banding of chemotherapy at our medical center. Based on this concept, chemotherapy doses are clustered into bands of similar dosage levels, thereby allowing the preproduction of frequently used standard doses of drugs, with sufficient physicochemical stability. Although established practice in the United Kingdom, there is little published evidence of its introduction elsewhere. Methods: We performed an analysis of local prescribing practice (22,310 chemotherapies) and identified gemcitabine, 5-fluorouracil, and carboplatin, among various others, as cytotoxic drugs suitable for dose banding. Results: First, we determined the physicochemical stability of the selected chemotherapy drugs during 12-weeks' storage by performing pH analysis and visual examination for color change or particles. No relevant changes were identified. Gemcitabine was selected for quantitative high-performance liquid chromatography analysis and we were able to show that ≥95% remained after 12 weeks' storage, in accordance with international guidelines. To simulate a worst case scenario, we performed microbiological stability testing of simulated cytotoxic compounding by replacing the cytotoxic drug with liquid media. Samples were incubated over defined storage time points (3, 6, and 12 weeks) and evaluated using the direct inoculation method. For the container integrity test, we deposited the samples into highly contaminated broth for 1 hour. Microbiological stability was demonstrated in both tests for the full storage period. Conclusions: Our data show that 12-weeks' storage of selected cytotoxic products is feasible from a microbiological perspective. Sterility of prepared products was maintained under extreme storage conditions. Gemcitabine content was in accordance with international guidelines after 12-weeks' storage. These results support the introduction of dose-banded gemcitabine products with the predicted advantages of optimized pharmacy workflow and reduced patient waiting times. We highlight the need for further research and consensus on the performance of purity analyses in dose-banded drug products.
http://ift.tt/2oB1gxo
Infusion-Compatible Antibiotic Formulations for Rapid Administration to Improve Outcomes in Cancer Outpatients With Severe Sepsis and Septic Shock: The Sepsis STAT Pack
Background: Patients with cancer are at high risk for severe sepsis and septic shock (SS/SSh), and a delay in receiving effective antibiotics is strongly associated with mortality. Delays are due to logistics of clinic flow and drug delivery. In an era of increasing antimicrobial resistance, combination therapy may be superior to monotherapy for patients with SS/SSh. Patients and Methods: At the Seattle Cancer Care Alliance, we implemented the Sepsis STAT Pack (SSP) program to simplify timely and effective provision of empiric antibiotics and other resuscitative care to outpatients with cancer with suspected SS/SSh before hospitalization. Over a 49-month period from January 1, 2008, through January 31, 2012, a total of 162 outpatients with cancer received the intervention. A retrospective cohort study was conducted to determine outcomes, including mortality and adverse events associated with the use of a novel care bundle designed for compatibility of broad-spectrum antibiotics and other supportive care administered concurrently via rapid infusion at fixed doses. Results: Of 162 sequential patients with cancer and suspected SS/SSh who received the SSP, 71 (44%) were diagnosed with SS/SSh. Median age was 53 years and 65% were men; 141 (87%) had hematologic malignancies, 77 (48%) were transplant recipients, and 80 (49%) were neutropenic. Median time to completion of antibiotics was 111 minutes (interquartile range, 60–178 minutes). A total of 71 patients (44%) had bacteremia and 17% of 93 isolates were multidrug-resistant. Possibly related nephrotoxicity occurred in 7 patients, and 30-day mortality occured in 6 of 160 patients (4%), including 3 of 71 (4%) with SS/SSh. Risk of developing SSh or death within 30 days increased 18% (95% CI, 4%–34%) for each hour delay to completion of antibiotics (P=.01). Conclusions: Rapidly administered combination antibiotics and supportive care delivered emergently to ambulatory patients with cancer with suspected SS/SSh was well-tolerated and associated with excellent short-term survival.
http://ift.tt/2pvJb0T
Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology
This selection from the NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.
http://ift.tt/2oBdSVf
Trends in the Incidence and Outcomes of Hospitalized Cancer Patients With Clostridium difficile Infection: A Nationwide Analysis
Background: Patients with cancer have several risk factors for Clostridium difficile infection (CDI), but the impact of CDI on outcomes in this population needs elucidation. We analyzed the incidence of CDI and its impact on outcomes in patients with cancer using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis codes were used to identify patients with cancer and CDI events. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study CDI incidence and CDI-associated outcomes. Analyses were performed using SAS version 9.4. Results: During the 10-year study period, 20.1 million discharges had a cancer diagnosis. CDI developed in 1.09% of patients with cancer versus 0.77% of patients without cancer (adjusted odds ratio [aOR], 1.28; 95% CI, 1.28–1.29; P<.001). The incidence of CDI in patients with cancer increased during the 10-year study period (64.7 per 10,000 discharges in 2001–2002 to 109.1 in 2009–2010; P<.001). In multivariable analysis, compared with patients with cancer without CDI, patients with cancer and CDI had a longer mean LOS (5.67 days; 95% CI, 5.39–5.94) and higher rates of in-hospital mortality (aOR, 1.18; 95% CI, 1.16–1.20) and discharge to a care facility (aOR, 1.74; 95% CI, 1.72–1.75; all P<.001). Conclusions: In this national database, CDI incidence increased significantly in patients with cancer over the study period and was associated with prolonged hospitalization, increased mortality, and discharge to a care facility. Despite increased attention, CDI remained a serious infection and merits appropriate prevention and management.
http://ift.tt/2pvM7Lb
The 21-Gene Recurrence Score Assay for Node-Positive, Early-Stage Breast Cancer and Impact of RxPONDER Trial on Chemotherapy Decision-Making: Have Clinicians Already Decided?
Background: The 21-gene recurrence score (RS) assay is retrospectively validated for assessing prognosis and benefit from chemotherapy in hormone receptor–positive, early-stage breast cancer (EBC) with low RS. We hypothesized that oncologists have already incorporated the RS assay for decision-making in higher-risk, node-positive disease, despite the lack of prospective data and contrary to NCCN Guideline recommendations. This study provides the first analysis of trends and differences in RS use and therapeutic implications in a population-based data set of patients with node-positive EBC. It also assesses the impact of the RxPONDER trial on clinicians' chemotherapy recommendations. Methods: Node-positive EBC cases diagnosed during 2010 through 2012 and included in the National Cancer Data Base were used. Multivariate logistic regression was used to estimate test use and impact on chemotherapy recommendations. Results: The RS assay was ordered for 16.5% of the 80,405 identified patients. Of all variables, the RS assay had the strongest association with chemotherapy recommendation, with adjusted odds ratios (AORs) of 19 for scores >30. Odds of chemotherapy recommendation were significantly lower for the group who received the test (AOR, 0.21; 95% CI, 0.20–0.22). When divided based on the cutoff point of 25 adopted by the RxPONDER trial, those with an RS of 18 to 25 had significantly lower odds of chemotherapy recommendation compared with those with an RS of 26 to 30 (AOR, 0.32; 95% CI, 0.26–0.40). Test use was lower for blacks, community centers, uninsured/governmentally insured patients, higher tumor grade, larger tumor size, and more nodes involved. Chemotherapy recommendation was higher for patients of younger age, with private insurance, and with higher tumor grade, size, and number of nodes involved. Black patients had significantly higher RS (AOR, 1.37; 95% CI, 1.25–1.79). Conclusions: The RS assay influences clinicians' chemotherapy recommendation in node-positive EBC. Clinicians are using the inclusion criteria of the RxPONDER trial before its final release. Black patients have higher RS, likely representing worse biology. Significant differences exist in test use and clinical implications based on race, insurance, and facility.
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Regional Radiation Therapy Impacts Outcome for Node-Positive Cutaneous Melanoma
Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board–approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30–60 Gy) in 27 fractions (range, 5–30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13–180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05–0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24–92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.
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Implementation of Systemic Hedgehog Inhibitors in Daily Practice as Neoadjuvant Therapy
The most common cancer in both men and women is basal cell carcinoma (BCC). Although most primary and recurrent BCCs have high cure rates with standard therapies, advanced BCCs present a greater treatment challenge, especially in cosmetically and functionally sensitive areas. In patients unable to undergo surgery or radiation therapy, hedgehog inhibitors can be used neoadjuvantly to reduce tumor size, decreasing the extent and complexity of any subsequent surgery and providing either a cure or palliation. The goal of this review is to summarize the pharmacology, efficacy, and safety of systemic hedgehog inhibitors, as well as their role in daily practice as neoadjuvant therapy. Relevant English-language literature was identified and evaluated based on results from database searches of PubMed. Terms searched included, but were not limited to, "vismodegib," "Erivedge," "sonidegib," "DE225," "BCC," and "neoadjuvant treatment." Additional literature was identified from the reference lists of previously identified articles. The authors' personal experience in treating advanced BCC using hedgehog inhibitors has been incorporated into the recommendations made herein.
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Therapeutic Response of Metastatic Colorectal Cancer Harboring a KRAS Missense Mutation After Combination Chemotherapy With the EGFR Inhibitor Panitumumab
Over the past decade, subset analyses of retrospective and prospective clinical studies have determined that KRAS-mutated metastatic colorectal cancers do not respond effectively to inhibition of epidermal growth factor receptor (EGFR) with the EGFR-targeting monoclonal antibodies cetuximab or panitumumab. Within the past few years, the scope of tested variants in the KRAS oncogene has expanded significantly, and testing of all RAS family genes has become more widely available in clinical laboratories. Expert consensus guidelines have recommended not using EGFR inhibitors in patients with KRAS-mutated tumors. However, with increasing identification of low-prevalence variants, it is conceivable that some RAS mutations do not provide equivalent resistance to EGFR inhibition compared with the most prevalent mutations at codons 12, 13, and 61. This report describes a case of a patient with metastatic colon cancer harboring the p.A59T variant of KRAS, with objective radiographic response (36% decrease per RECIST 1.1) and carcinoembryonic antigen biomarker response to panitumumab therapy given with FOLFIRI chemotherapy. We propose that A59T represents one potential exception to the guidelines that KRAS mutant tumors fail to respond to therapy with EGFR inhibitors, altering the paradigm of using this generalized approach.
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NCCN Guidelines Insights: Breast Cancer, Version 1.2017
These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor–positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.
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Paving the Way for Dose Banding of Chemotherapy: An Analytical Approach
Background: In an interdepartmental cooperation, we investigated the feasibility and benefits of implementing dose banding of chemotherapy at our medical center. Based on this concept, chemotherapy doses are clustered into bands of similar dosage levels, thereby allowing the preproduction of frequently used standard doses of drugs, with sufficient physicochemical stability. Although established practice in the United Kingdom, there is little published evidence of its introduction elsewhere. Methods: We performed an analysis of local prescribing practice (22,310 chemotherapies) and identified gemcitabine, 5-fluorouracil, and carboplatin, among various others, as cytotoxic drugs suitable for dose banding. Results: First, we determined the physicochemical stability of the selected chemotherapy drugs during 12-weeks' storage by performing pH analysis and visual examination for color change or particles. No relevant changes were identified. Gemcitabine was selected for quantitative high-performance liquid chromatography analysis and we were able to show that ≥95% remained after 12 weeks' storage, in accordance with international guidelines. To simulate a worst case scenario, we performed microbiological stability testing of simulated cytotoxic compounding by replacing the cytotoxic drug with liquid media. Samples were incubated over defined storage time points (3, 6, and 12 weeks) and evaluated using the direct inoculation method. For the container integrity test, we deposited the samples into highly contaminated broth for 1 hour. Microbiological stability was demonstrated in both tests for the full storage period. Conclusions: Our data show that 12-weeks' storage of selected cytotoxic products is feasible from a microbiological perspective. Sterility of prepared products was maintained under extreme storage conditions. Gemcitabine content was in accordance with international guidelines after 12-weeks' storage. These results support the introduction of dose-banded gemcitabine products with the predicted advantages of optimized pharmacy workflow and reduced patient waiting times. We highlight the need for further research and consensus on the performance of purity analyses in dose-banded drug products.
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Infusion-Compatible Antibiotic Formulations for Rapid Administration to Improve Outcomes in Cancer Outpatients With Severe Sepsis and Septic Shock: The Sepsis STAT Pack
Background: Patients with cancer are at high risk for severe sepsis and septic shock (SS/SSh), and a delay in receiving effective antibiotics is strongly associated with mortality. Delays are due to logistics of clinic flow and drug delivery. In an era of increasing antimicrobial resistance, combination therapy may be superior to monotherapy for patients with SS/SSh. Patients and Methods: At the Seattle Cancer Care Alliance, we implemented the Sepsis STAT Pack (SSP) program to simplify timely and effective provision of empiric antibiotics and other resuscitative care to outpatients with cancer with suspected SS/SSh before hospitalization. Over a 49-month period from January 1, 2008, through January 31, 2012, a total of 162 outpatients with cancer received the intervention. A retrospective cohort study was conducted to determine outcomes, including mortality and adverse events associated with the use of a novel care bundle designed for compatibility of broad-spectrum antibiotics and other supportive care administered concurrently via rapid infusion at fixed doses. Results: Of 162 sequential patients with cancer and suspected SS/SSh who received the SSP, 71 (44%) were diagnosed with SS/SSh. Median age was 53 years and 65% were men; 141 (87%) had hematologic malignancies, 77 (48%) were transplant recipients, and 80 (49%) were neutropenic. Median time to completion of antibiotics was 111 minutes (interquartile range, 60–178 minutes). A total of 71 patients (44%) had bacteremia and 17% of 93 isolates were multidrug-resistant. Possibly related nephrotoxicity occurred in 7 patients, and 30-day mortality occured in 6 of 160 patients (4%), including 3 of 71 (4%) with SS/SSh. Risk of developing SSh or death within 30 days increased 18% (95% CI, 4%–34%) for each hour delay to completion of antibiotics (P=.01). Conclusions: Rapidly administered combination antibiotics and supportive care delivered emergently to ambulatory patients with cancer with suspected SS/SSh was well-tolerated and associated with excellent short-term survival.
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Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology
This selection from the NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.
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Trends in the Incidence and Outcomes of Hospitalized Cancer Patients With Clostridium difficile Infection: A Nationwide Analysis
Background: Patients with cancer have several risk factors for Clostridium difficile infection (CDI), but the impact of CDI on outcomes in this population needs elucidation. We analyzed the incidence of CDI and its impact on outcomes in patients with cancer using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis codes were used to identify patients with cancer and CDI events. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study CDI incidence and CDI-associated outcomes. Analyses were performed using SAS version 9.4. Results: During the 10-year study period, 20.1 million discharges had a cancer diagnosis. CDI developed in 1.09% of patients with cancer versus 0.77% of patients without cancer (adjusted odds ratio [aOR], 1.28; 95% CI, 1.28–1.29; P<.001). The incidence of CDI in patients with cancer increased during the 10-year study period (64.7 per 10,000 discharges in 2001–2002 to 109.1 in 2009–2010; P<.001). In multivariable analysis, compared with patients with cancer without CDI, patients with cancer and CDI had a longer mean LOS (5.67 days; 95% CI, 5.39–5.94) and higher rates of in-hospital mortality (aOR, 1.18; 95% CI, 1.16–1.20) and discharge to a care facility (aOR, 1.74; 95% CI, 1.72–1.75; all P<.001). Conclusions: In this national database, CDI incidence increased significantly in patients with cancer over the study period and was associated with prolonged hospitalization, increased mortality, and discharge to a care facility. Despite increased attention, CDI remained a serious infection and merits appropriate prevention and management.
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Treatment Patterns and Early Outcomes of ALK -Positive Non-Small Cell Lung Cancer Patients Receiving Ceritinib: A Chart Review Study
Abstract
Introduction
This study aimed to provide the first real-world description of the characteristics, treatments, dosing patterns, and early outcomes of patients with ALK-positive non-small cell lung cancer (NSCLC) who received ceritinib in US clinical practice.
Methods
US oncologists provided data from medical charts of adult patients diagnosed with locally advanced or metastatic ALK-positive NSCLC who received ceritinib following crizotinib. Patient characteristics, treatment patterns, ceritinib dosing, early outcomes, and occurrence of gastrointestinal adverse events (AEs) by dose and instructions on food intake were assessed, and Kaplan–Meier analysis was used to describe clinician-defined progression-free survival (PFS) on ceritinib.
Results
Medical charts of 58 ALK-positive NSCLC patients treated with ceritinib were reviewed (median age 63 years; 41% male; 21% with prior chemotherapy experience). At ceritinib initiation, 44 patients had multiple distant metastases, most commonly in the liver (60%), bone (53%), and brain (38%). Initial ceritinib dose varied: 71% received 750 mg, 19% 600 mg, and 10% 450 mg. Although median follow-up after ceritinib initiation was short (3.8 months), most patients achieved either a complete or partial response (69%) on ceritinib, regardless of metastatic sites present at initiation or initial dose. Median PFS on ceritinib was 12.9 months. 17% of patients had a gastrointestinal AE reported during follow-up. The majority of events occurred in patients instructed to fast; no patients instructed to take a lower dose of ceritinib with food reported gastrointestinal AEs.
Conclusion
These early findings of ceritinib use in clinical practice suggest that ceritinib is effective at treating crizotinib-experienced ALK-positive NSCLC patients, regardless of metastatic sites or initial dose, and dosing ceritinib with food may lead to fewer gastrointestinal AEs. Future studies with larger sample size and longer follow-up are warranted, including an ongoing randomized trial to assess the gastrointestinal tolerability of ceritinib 450 and 600 mg with low-fat meals.
Funding
Novartis Pharmaceutical Corporation.
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Outcome Measures of Adjustable Transobturator Male System with Pre-attached Scrotal Port for Male Stress Urinary Incontinence After Radical Prostatectomy: A Prospective Study
Abstract
Introduction
The objective of this study was to report outcome measures with third-generation pre-attached scrotal port adjustable transobturator male system (ATOMS) for male stress urinary incontinence (SUI) after radical prostatectomy.
Methods
A prospective open study was conducted on consecutive patients. Evaluation included cough test, urethroscopy, filling and voiding cystometry, 24-h pad count and pad test, patient-reported outcomes (ICIQ-SF, IIQ-7, PGI, GRA, and VAS), complications according to the Clavien–Dindo system, operative results, number of adjustments, and filling of the system.
Results
Thirty-four patients with median pad test 510 (170–1225) ml were operated on. Preoperative SUI was mild (5.9%), moderate (17.6%), and severe (76.5%). At median 18.5 (12–26) months follow-up distribution of SUI was none (85.3%), mild (8.8%), and moderate (5.9%). Median intraoperative filling was 14 (8–17) ml, number of adjustments 1 (0–5), and total filling 17.5 (11–33.5) ml. At 3 months, median ICIQ-SF (p = 0.0001) and IIQ-7 (p < 0.0001) decreased. At 12 months, 24-h pad count and pad test decreased (both p < 0.0001), residual volume slightly increased (p = 0.018), PGI-I was 1 (1–3), GRA 6 (3–6), and 97% were satisfied with treatment. Continence (p = 0.016) and satisfaction (p = 0.09) were worse in irradiated patients. Median operative time was 67 (35–120) min, hospital stay 1 (1–3) days, and VAS for pain on postoperative day 1 was 0 (0–2). Complications presented in 14.7% (8.8% grade I and 5.9% grade III).
Conclusion
Treatment of severe male SUI after radical prostatectomy with pre-attached scrotal port ATOMS is safe and very effective in the short term. A positive cough test before implant and intraoperative overfilling of the system may optimize patient selection and results.
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Treatment Patterns and Early Outcomes of ALK -Positive Non-Small Cell Lung Cancer Patients Receiving Ceritinib: A Chart Review Study
Abstract
Introduction
This study aimed to provide the first real-world description of the characteristics, treatments, dosing patterns, and early outcomes of patients with ALK-positive non-small cell lung cancer (NSCLC) who received ceritinib in US clinical practice.
Methods
US oncologists provided data from medical charts of adult patients diagnosed with locally advanced or metastatic ALK-positive NSCLC who received ceritinib following crizotinib. Patient characteristics, treatment patterns, ceritinib dosing, early outcomes, and occurrence of gastrointestinal adverse events (AEs) by dose and instructions on food intake were assessed, and Kaplan–Meier analysis was used to describe clinician-defined progression-free survival (PFS) on ceritinib.
Results
Medical charts of 58 ALK-positive NSCLC patients treated with ceritinib were reviewed (median age 63 years; 41% male; 21% with prior chemotherapy experience). At ceritinib initiation, 44 patients had multiple distant metastases, most commonly in the liver (60%), bone (53%), and brain (38%). Initial ceritinib dose varied: 71% received 750 mg, 19% 600 mg, and 10% 450 mg. Although median follow-up after ceritinib initiation was short (3.8 months), most patients achieved either a complete or partial response (69%) on ceritinib, regardless of metastatic sites present at initiation or initial dose. Median PFS on ceritinib was 12.9 months. 17% of patients had a gastrointestinal AE reported during follow-up. The majority of events occurred in patients instructed to fast; no patients instructed to take a lower dose of ceritinib with food reported gastrointestinal AEs.
Conclusion
These early findings of ceritinib use in clinical practice suggest that ceritinib is effective at treating crizotinib-experienced ALK-positive NSCLC patients, regardless of metastatic sites or initial dose, and dosing ceritinib with food may lead to fewer gastrointestinal AEs. Future studies with larger sample size and longer follow-up are warranted, including an ongoing randomized trial to assess the gastrointestinal tolerability of ceritinib 450 and 600 mg with low-fat meals.
Funding
Novartis Pharmaceutical Corporation.
http://ift.tt/2nGnf6O
Outcome Measures of Adjustable Transobturator Male System with Pre-attached Scrotal Port for Male Stress Urinary Incontinence After Radical Prostatectomy: A Prospective Study
Abstract
Introduction
The objective of this study was to report outcome measures with third-generation pre-attached scrotal port adjustable transobturator male system (ATOMS) for male stress urinary incontinence (SUI) after radical prostatectomy.
Methods
A prospective open study was conducted on consecutive patients. Evaluation included cough test, urethroscopy, filling and voiding cystometry, 24-h pad count and pad test, patient-reported outcomes (ICIQ-SF, IIQ-7, PGI, GRA, and VAS), complications according to the Clavien–Dindo system, operative results, number of adjustments, and filling of the system.
Results
Thirty-four patients with median pad test 510 (170–1225) ml were operated on. Preoperative SUI was mild (5.9%), moderate (17.6%), and severe (76.5%). At median 18.5 (12–26) months follow-up distribution of SUI was none (85.3%), mild (8.8%), and moderate (5.9%). Median intraoperative filling was 14 (8–17) ml, number of adjustments 1 (0–5), and total filling 17.5 (11–33.5) ml. At 3 months, median ICIQ-SF (p = 0.0001) and IIQ-7 (p < 0.0001) decreased. At 12 months, 24-h pad count and pad test decreased (both p < 0.0001), residual volume slightly increased (p = 0.018), PGI-I was 1 (1–3), GRA 6 (3–6), and 97% were satisfied with treatment. Continence (p = 0.016) and satisfaction (p = 0.09) were worse in irradiated patients. Median operative time was 67 (35–120) min, hospital stay 1 (1–3) days, and VAS for pain on postoperative day 1 was 0 (0–2). Complications presented in 14.7% (8.8% grade I and 5.9% grade III).
Conclusion
Treatment of severe male SUI after radical prostatectomy with pre-attached scrotal port ATOMS is safe and very effective in the short term. A positive cough test before implant and intraoperative overfilling of the system may optimize patient selection and results.
http://ift.tt/2pvt3fR
Long-term neuropsychological follow-up of young children with medulloblastoma treated with sequential high-dose chemotherapy and irradiation sparing approach
Abstract
High-dose chemotherapy (HDC) strategies were developed in brain tumor protocols for young children to prevent neuropsychological (NP) impairments associated with radiotherapy. However, comprehensive NP evaluations of these children treated with such strategies remain limited. We examined the long-term neurocognitive outcomes of young children (<6 years) with medulloblastoma, treated similarly, with a HDC strategy "according to" the chemotherapy regimen of the protocol CCG 99703. This retrospective study included young children less than 6 years of age at diagnosis of medulloblastoma treated from 1998 to 2011 at 7 North American institutions. Twenty-four patients who had at least one NP assessment post-treatment are the focus of the current study. Of 24 patients in this review, 15 (63%) were male and the mean age at diagnosis was 29.4 months (SD = 13.5). Posterior fossa syndrome (PFs) was reported in five patients (21%). Nine (37.5%) received radiotherapy (5 focal, 4 craniospinal). On average, children were assessed 3.5 years (SD = 1.8) post-diagnosis, and full-scale intellectual quotient (FSIQ) scores ranged from 56 to 119 ( \({\bar{\text{X}}}\) = 92; SD = 16.8). The majority of children (74%) had low-average to average NP functioning. Very young children treated with radiotherapy, who needed hearing support or with PFs had worse neurocognitive outcomes. Clinically significant deficits (<10th percentile) in at least one area of NP functioning were found in 25% of the children. NP data obtained from this sample of survivors of medulloblastoma in early childhood, all treated with sequential HDC and 1/3 with radiotherapy, describe NP functioning within average normal limits overall. However, almost 25% of children had significant deficits in specific domains.
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MGMT promoter methylation status in Merkel cell carcinoma: in vitro versus invivo
Abstract
Purpose
Expression of O6-methylguanine-DNA methyltransferase (MGMT) in Merkel cell carcinoma (MCC) is very variable; thus, we tested whether this may be due to differential methylation of the MGMT gene promoter.
Methods
Quantitative analysis of MGMT mRNA and protein expression, as well as MGMT promoter methylation status, was performed in a series of tissue samples of MCC tumors, representing both primary and metastatic lesions, as well as in six MCC cell lines.
Results
These analyses revealed a very heterogeneous MGMT mRNA and protein expression in MCC both in vivo and in vitro. However, neither the MGMT mRNA nor protein expression correlated with the sensitivity of MCC cell lines toward the alkylating agent dacarbazine in vitro. Notably, increased methylation at the promoter of the MGMT gene was observed in 2/6 (33%) of the MCC cell lines; however, MGMT promoter methylation was absent in all MCC tissue samples. According to our results, albeit aberrant methylation of MGMT gene promoter can be observed in in vitro propagated MCC cell lines, it seems to be absent or very rare in MCC lesions in situ.
Conclusion
Thus, the evaluation of this marker has no or only little significance for predicting response to therapy or for improving efficacy of demethylating agents in the treatment of MCC. Microenvironmental factors may play a role in explaining the different results between MCC cell lines and MCC samples.
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Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives
Abstract
Purpose
Everolimus has been shown to be effective for advanced pancreatic neuroendocrine tumours (pNETs), but its positioning in the therapeutic algorithm for pNETs is matter of debate.
Methods
With the aim to shed light on this point, we performed an up-to-date critical review taking into account the results of both retrospective and prospective published studies, and the recommendations of international guidelines. In addition, we performed an extensive search on the Clinical Trial Registries databases worldwide, to gather information on the ongoing clinical trials related to this specific topic.
Results
We identified eight retrospective published studies, two prospective published studies, and five registered clinical trials. Moreover, we analyzed the content of four widespread international guidelines.
Conclusions
Our critical review confirms the lack of high-quality data to recommend everolimus as the first line therapy for pNETs. The ongoing clinical trials reported in this review will hopefully help clinicians, in the near future, to better evaluate the role of everolimus as the first line therapy for pNETs. However, at the moment, there is already enough evidence to recommend everolimus as the first line therapy for patients with symptomatic malignant unresectable insulin-secreting pNETs, to control the endocrine syndrome regardless of tumour growth.
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MGMT promoter methylation status in Merkel cell carcinoma: in vitro versus invivo
Abstract
Purpose
Expression of O6-methylguanine-DNA methyltransferase (MGMT) in Merkel cell carcinoma (MCC) is very variable; thus, we tested whether this may be due to differential methylation of the MGMT gene promoter.
Methods
Quantitative analysis of MGMT mRNA and protein expression, as well as MGMT promoter methylation status, was performed in a series of tissue samples of MCC tumors, representing both primary and metastatic lesions, as well as in six MCC cell lines.
Results
These analyses revealed a very heterogeneous MGMT mRNA and protein expression in MCC both in vivo and in vitro. However, neither the MGMT mRNA nor protein expression correlated with the sensitivity of MCC cell lines toward the alkylating agent dacarbazine in vitro. Notably, increased methylation at the promoter of the MGMT gene was observed in 2/6 (33%) of the MCC cell lines; however, MGMT promoter methylation was absent in all MCC tissue samples. According to our results, albeit aberrant methylation of MGMT gene promoter can be observed in in vitro propagated MCC cell lines, it seems to be absent or very rare in MCC lesions in situ.
Conclusion
Thus, the evaluation of this marker has no or only little significance for predicting response to therapy or for improving efficacy of demethylating agents in the treatment of MCC. Microenvironmental factors may play a role in explaining the different results between MCC cell lines and MCC samples.
http://ift.tt/2p7dxuo
Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives
Abstract
Purpose
Everolimus has been shown to be effective for advanced pancreatic neuroendocrine tumours (pNETs), but its positioning in the therapeutic algorithm for pNETs is matter of debate.
Methods
With the aim to shed light on this point, we performed an up-to-date critical review taking into account the results of both retrospective and prospective published studies, and the recommendations of international guidelines. In addition, we performed an extensive search on the Clinical Trial Registries databases worldwide, to gather information on the ongoing clinical trials related to this specific topic.
Results
We identified eight retrospective published studies, two prospective published studies, and five registered clinical trials. Moreover, we analyzed the content of four widespread international guidelines.
Conclusions
Our critical review confirms the lack of high-quality data to recommend everolimus as the first line therapy for pNETs. The ongoing clinical trials reported in this review will hopefully help clinicians, in the near future, to better evaluate the role of everolimus as the first line therapy for pNETs. However, at the moment, there is already enough evidence to recommend everolimus as the first line therapy for patients with symptomatic malignant unresectable insulin-secreting pNETs, to control the endocrine syndrome regardless of tumour growth.
http://ift.tt/2pv3nQQ
Prognostic implication of CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite unstable and stable colorectal cancer
Abstract
In this study, we investigated the clinical relevance of CD274 (PD-L1) protein expression by tumor cells and tumor-infiltrating immune cells in colorectal cancer (CRC). To this end, 186 microsatellite instability-high (MSI-H) and 153 microsatellite stable (MSS) CRCs were subjected to immunohistochemistry (IHC) analysis for the expression of CD274 and mismatch repair proteins. CD274 expression was evaluated in tumor cells at the center (TC) and periphery (TP), and immune cells at the center (IC) and periphery (IP) of CRC. IHC slides stained for CD3 and CD8 were scanned using an Aperio ScanScope for precise calculation of tumor-infiltrating T cell density. Additionally, samples were screened for the B-Raf (BRAF)-V600E mutation using a Cobas 4800 System and IHC. In total, CD274TC, CD274TP, CD274IC, and CD274IP were observed in 43 (23.1%), 47 (25.3%), 107 (57.5%), and 102 (54.8%) of the MSI-H CRCs examined, and in three (2.0%), four (2.6%), 47 (30.7%), and 56 (36.6%) of the 153 MSS CRCs tested. Meanwhile, intratumoral heterogeneity of CD274 expression in tumor cells and immune cells was detected in 24 (12.9%) and 47 (25.3%) MSI-H CRCs, respectively. Notably, in both MSI-H and MSS CRC, CD274IC and CD274IP were independently associated with improved prognosis (P < 0.05), while BRAF mutation was associated with CD274TP, poor differentiation, sporadic type, and hMLH1(−)/hMSH2(+)/hMSH6(+)/PMS2(−) in MSI-H CRC (P < 0.006). In conclusion, CD274 expression in tumor-infiltrating immune cells was an independent factor for improved prognosis in CRC patients. A deeper understanding of CD274 status may yield improved responses to future CRC immunotherapies.
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Coexpressed modular gene expression reveals inverse correlation between immune responsive transcription and aggressiveness in gastric tumours
Abstract
The existing large number of gene expression profiles of tumour samples offers a great advantage for the integrative functional genomic exploration of molecular dysregulation in cancers. The clusters of genes (modules) derived from a gastric cancer (GC) coexpression network were explored to understand their clinical and functional significance. Among the modules derived from the GC mRNA expression network, six modules were relatively highly expressed in diffuse type gastric tumours. Elevated expression of genes related to extracellular matrix (ECM), angiogenesis, collagen and intracellular cytoskeletal components and immune response were identified in these modules. ECM-related modules exhibited an inverse correlation with modules representing the expression of immune response genes. A reduced expression of immune response genes was identified as the key factor associated with the aggressive features of diffuse gastric tumours, which is indicative of tumour progression involving the escape from immune surveillance in diffuse tumours. A part of the identified aggressive factors was common between intestinal and diffuse type tumours. The coexpressed modules and their expression patterns delineate the fine transition involved in cancer progression in the later stages of tumours. The identified modules could serve as surrogate gene-sets, indicating the molecular staging of GC aggressiveness with underlying biological interaction.
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