Calcium - Induced Differentiation of Human Colon Adenomas In Colonoid Culture: Calcium alone versus calcium with additional trace elements

Previous murine studies have demonstrated that dietary Aquamin®, a calcium-rich, multi-mineral natural product, suppressed colon polyp formation and transition to invasive tumors more effectively than calcium alone when provided over the lifespan of the animals. In the present study, we compared calcium alone to Aquamin® for modulation of growth and differentiation in human colon adenomas in colonoid culture. Colonoids established from normal colonic tissue were examined in parallel. Both calcium alone at 1.5 mM and Aquamin® (provided at 1.5 mM calcium) fostered differentiation in the adenoma colonoid cultures as compared to control (calcium at 0.15 mM). When Aquamin® was provided at an amount delivering 0.15 mM calcium, adenoma differentiation also occurred, but was not as complete. Characteristic of colonoids undergoing differentiation was a reduction in the number of small, highly-proliferative buds and their replacement by fewer but larger buds with smoother surface. Proliferation marker (Ki67) expression was reduced and markers of differentiation (CK20 and Occludin) were increased along with E-cadherin translocalization to the cell surface. Additional proteins associated with differentiation / growth control (including histone-1 family members, certain keratins, NF-2 [merlin], olfactomedin-4 and metallothionines) were altered as assessed by proteomics. Immunohistological expression of NF-2 was higher with Aquamin® as compared to calcium at either concentration. These findings support the conclusions that i) calcium (1.5 mM) has the capacity to modulate growth and differentiation in large human colon adenomas and ii) Aquamin® delivering 0.15 mM calcium has effects on proliferation and differentiation not observed when calcium is used alone at this concentration.

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Ultraviolet radiation inhibits mammary carcinogenesis in an ER negative murine model by a mechanism independent of vitamin D3

Three decades ago the Garlands postulated that vitamin D3 produced in the skin by ultraviolet radiation (UVR)-induced conversion of 7-dehydrocholesterol to pre-D3 has anti-cancer effects, thus triggering more than 9500 publications on D3 and cancer. Here we report that UVR treatment of transgenic mice of the well-established C3(1)/SV40 Tag mammary cancer model significantly inhibits both autochthonous carcinogenesis and allograft tumor growth, but in contrast neither dietary nor topical D3 influences mammary carcinogenesis in this specific mouse model. Furthermore, UVR's inhibitory effects occur irrespective of whether or not the treatment increases circulating D3 in the mice. The inhibitory effect of UVR on autochthonous tumors occurs at or before the stage of ductal carcinoma in situ. Our studies indicate clearly that UVR can exert D3-independent anti-cancer effects in C3(1)/SV40 Tag mice. Therefore, supplemental D3 may not mimic all possible beneficial effects of UVR, and uncovering non-D3-mediated mechanisms of UVR tumor inhibition may lead to novel strategies for cancer prevention.

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Spatial variation of the native colon microbiota in healthy adults

The microbiome has been implicated in the development of colorectal cancer and inflammatory bowel diseases. The specific traits of these diseases vary along the axis of the digestive tract. Further, variation in the structure of the gut microbiota has been associated with both diseases. We profiled the microbiota of the healthy proximal and distal mucosa and lumen to better understand how bacterial populations vary along the colon. We used a two-colonoscope approach to sample proximal and distal mucosal and luminal contents from the colons of 20 healthy subjects that had not undergone any bowel preparation procedure. The biopsies and home-collected stool were subjected to 16S rRNA gene sequencing and Random Forest classification models were built using taxa abundance and location to identify microbiota specific to each site. The right mucosa and lumen had the most similar community structures of the five sites we considered from each subject. The distal mucosa had higher relative abundance of Finegoldia, Murdochiella, Peptoniphilus, Porphyromonas, and Anaerococcus. The proximal mucosa had more of the genera Enterobacteriaceae, Bacteroides, and Pseudomonas. The classification model performed well when classifying mucosal samples into proximal or distal sides (AUC=0.808). Separating proximal and distal luminal samples proved more challenging (AUC=0.599) and specific microbiota that differentiated the two were hard to identify. By sampling the unprepped colon, we identified distinct bacterial populations native to the proximal and distal sides. Further investigation of these bacteria may elucidate if and how these groups contribute to different disease processes on their respective sides of the colon.

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Disruption of NSD1 in head and neck cancer promotes favorable chemotherapeutic responses linked to hypomethylation

Human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC) represents a distinct classification of cancer with poor expected outcomes. Of the 11 genes recurrently mutated in HNSCC, we identify a singular and substantial survival advantage for mutations in the gene encoding Nuclear Set Domain Containing Protein 1 (NSD1), a histone methyltransferase altered in approximately 10% of patients. This effect, a 55% decrease in risk of death in NSD1-mutated versus non-mutated patients, can be validated in an independent cohort. NSD1 alterations are strongly associated with widespread genome hypomethylation in the same tumors, to a degree not observed for any other mutated gene. To address whether NSD1 plays a causal role in these associations, we use CRISPR-Cas9 to disrupt NSD1 in HNSCC cell lines and find that this leads to substantial CpG hypomethylation and sensitivity to cisplatin, a standard chemotherapy in head and neck cancer, with a 40 - 50% decrease in IC50. Such results are reinforced by a survey of 1,001 cancer cell lines, in which loss-of-function NSD1 mutations have an average 23% decrease in cisplatin IC50 compared to cell lines with wild type NSD1. This study identifies a favorable subtype of head and neck cancer linked to NSD1 mutation, hypomethylation and cisplatin sensitivity.

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Disruption of NSD1 in head and neck cancer promotes favorable chemotherapeutic responses linked to hypomethylation

Human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC) represents a distinct classification of cancer with poor expected outcomes. Of the 11 genes recurrently mutated in HNSCC, we identify a singular and substantial survival advantage for mutations in the gene encoding Nuclear Set Domain Containing Protein 1 (NSD1), a histone methyltransferase altered in approximately 10% of patients. This effect, a 55% decrease in risk of death in NSD1-mutated versus non-mutated patients, can be validated in an independent cohort. NSD1 alterations are strongly associated with widespread genome hypomethylation in the same tumors, to a degree not observed for any other mutated gene. To address whether NSD1 plays a causal role in these associations, we use CRISPR-Cas9 to disrupt NSD1 in HNSCC cell lines and find that this leads to substantial CpG hypomethylation and sensitivity to cisplatin, a standard chemotherapy in head and neck cancer, with a 40 - 50% decrease in IC50. Such results are reinforced by a survey of 1,001 cancer cell lines, in which loss-of-function NSD1 mutations have an average 23% decrease in cisplatin IC50 compared to cell lines with wild type NSD1. This study identifies a favorable subtype of head and neck cancer linked to NSD1 mutation, hypomethylation and cisplatin sensitivity.

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Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma

Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison to cluster II PCPGs that are related to kinase signaling and often present as benign tumors. Results: We found that cluster I PCPGs develop dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft. Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations.

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Discovery of a glucocorticoid receptor (GR) activity signature using selective GR antagonism in ER-negative breast cancer

Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer (BC) is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive BC behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary BCs. The resulting subset of GR targeted genes was analyzed in two independent ER-negative BC cohorts to derive and then validate the GR activity signature (GRsig). Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig comprised of n=74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predicted probability of relapse in a separate Validation cohort (HR=1.9; p= 0.012). Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive BCs most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome of these high-risk patients.

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Resistance mechanisms to targeted therapies in ROS1+ and ALK+ non-small cell lung cancer

Purpose: Experimental Design: Results: Conclusions:

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A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

Purpose: The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose escalation results of the first-in-human phase I study of LY3023414.  Experimental Design: A 3+3 dose escalation for QD and BID oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug-drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics (PK)/pharmacodynamics, and antitumor activity. Results: Forty-seven patients with solid tumors received LY3023414 at QD (20-450 mg) or BID dosing (150-250 mg). Dose-limiting toxicities were observed at 450 mg QD (thrombocytopenia, hypotension, hyperkalemia) in 3/3 patients, 250 mg BID dosing (hypophosphatemia, fatigue, mucositis) in 3/4 patients, and in 1/15 patients at 200 BID mg (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ≥ 90% target inhibition at doses ≥150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in an endometrial cancer patient harboring PIK3R1 and PTEN truncating mutations and 13 additional patients (28%) had decrease in their target lesions by up to 30%.  Conclusions: LY3023414 has a tolerable safety profile and single agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg BID based on safety, tolerability, and PK/Pharmacodynamic data.

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Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma

Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison to cluster II PCPGs that are related to kinase signaling and often present as benign tumors. Results: We found that cluster I PCPGs develop dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft. Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations.

https://ift.tt/2JCWHL9

Discovery of a glucocorticoid receptor (GR) activity signature using selective GR antagonism in ER-negative breast cancer

Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer (BC) is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive BC behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary BCs. The resulting subset of GR targeted genes was analyzed in two independent ER-negative BC cohorts to derive and then validate the GR activity signature (GRsig). Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig comprised of n=74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predicted probability of relapse in a separate Validation cohort (HR=1.9; p= 0.012). Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive BCs most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome of these high-risk patients.

https://ift.tt/2EBmgZi

Resistance mechanisms to targeted therapies in ROS1+ and ALK+ non-small cell lung cancer

Purpose: Experimental Design: Results: Conclusions:

https://ift.tt/2JCWRlJ

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

Purpose: The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose escalation results of the first-in-human phase I study of LY3023414.  Experimental Design: A 3+3 dose escalation for QD and BID oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug-drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics (PK)/pharmacodynamics, and antitumor activity. Results: Forty-seven patients with solid tumors received LY3023414 at QD (20-450 mg) or BID dosing (150-250 mg). Dose-limiting toxicities were observed at 450 mg QD (thrombocytopenia, hypotension, hyperkalemia) in 3/3 patients, 250 mg BID dosing (hypophosphatemia, fatigue, mucositis) in 3/4 patients, and in 1/15 patients at 200 BID mg (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ≥ 90% target inhibition at doses ≥150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in an endometrial cancer patient harboring PIK3R1 and PTEN truncating mutations and 13 additional patients (28%) had decrease in their target lesions by up to 30%.  Conclusions: LY3023414 has a tolerable safety profile and single agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg BID based on safety, tolerability, and PK/Pharmacodynamic data.

https://ift.tt/2IJAPwy

Automated Cervical Screening and Triage, Based on HPV Testing and Computer-Interpreted Cytology

Abstract

Background

State-of-the-art cervical cancer prevention includes human papillomavirus (HPV) vaccination among adolescents and screening/treatment of cervical precancer (CIN3/AIS and, less strictly, CIN2) among adults. HPV testing provides sensitive detection of precancer but, to reduce overtreatment, secondary "triage" is needed to predict women at highest risk. Those with the highest-risk HPV types or abnormal cytology are commonly referred to colposcopy; however, expert cytology services are critically lacking in many regions.

Methods

To permit completely automatable cervical screening/triage, we designed and validated a novel triage method, a cytologic risk score algorithm based on computer-scanned liquid-based slide features (FocalPoint, BD, Burlington, NC). We compared it with abnormal cytology in predicting precancer among 1839 women testing HPV positive (HC2, Qiagen, Germantown, MD) in 2010 at Kaiser Permanente Northern California (KPNC). Precancer outcomes were ascertained by record linkage. As additional validation, we compared the algorithm prospectively with cytology results among 243 807 women screened at KPNC (2016–2017). All statistical tests were two-sided.

Results

Among HPV-positive women, the algorithm matched the triage performance of abnormal cytology. Combined with HPV16/18/45 typing (Onclarity, BD, Sparks, MD), the automatable strategy referred 91.7% of HPV-positive CIN3/AIS cases to immediate colposcopy while deferring 38.4% of all HPV-positive women to one-year retesting (compared with 89.1% and 37.4%, respectively, for typing and cytology triage). In the 2016–2017 validation, the predicted risk scores strongly correlated with cytology (P < .001).

Conclusions

High-quality cervical screening and triage performance is achievable using this completely automated approach. Automated technology could permit extension of high-quality cervical screening/triage coverage to currently underserved regions.

https://ift.tt/2GQHuEm

Patterns of Care of Breast Cancer Patients in a Rural Cancer Center in Western India

Abstract

Breast cancer is an emerging public health problem in low- and middle-income countries. The main objective is to describe the clinical characteristics and patterns of care of breast cancer patients diagnosed and treated in a rural cancer hospital in Barshi, Western India. The results from a cross-sectional study of 99 consecutive breast cancer patients diagnosed and treated between February 2012 and November 2014 in Nargis Dutt Memorial Cancer Hospital is reported. The case records of the patients were scrutinized and reviewed to abstract data on their clinical characteristics, diagnostic, and treatment details. The mean age at diagnosis of the patients was 52.8 ± 11.6 years; 83.5% of women were married, and 60.6% were illiterate. Sixty percent of patients had tumors measuring 5 cm or less. Almost half of the patients (46.4%) had stage I or II A disease and a third (36.0%) had axillary lymph node metastasis. Estrogen, progesterone, and human epidermal growth factor receptor2 receptor status were investigated in 41 (41.4%) of patients only. The median interval between diagnosis and initiation of treatment was 11 days. Modified radical mastectomy was done in 91% of patients, and nearly a third of patients who were prescribed chemotherapy did not complete treatment. The rural-based tertiary cancer care center has made treatment more accessible to breast cancer patients and has reduced the interval between diagnosis and treatment initiation. However, there are still many challenges like non-compliance to and incomplete treatments and poor follow-up that need to be addressed.

https://ift.tt/2JCUyz5

Patterns of Care of Breast Cancer Patients in a Rural Cancer Center in Western India

Abstract

Breast cancer is an emerging public health problem in low- and middle-income countries. The main objective is to describe the clinical characteristics and patterns of care of breast cancer patients diagnosed and treated in a rural cancer hospital in Barshi, Western India. The results from a cross-sectional study of 99 consecutive breast cancer patients diagnosed and treated between February 2012 and November 2014 in Nargis Dutt Memorial Cancer Hospital is reported. The case records of the patients were scrutinized and reviewed to abstract data on their clinical characteristics, diagnostic, and treatment details. The mean age at diagnosis of the patients was 52.8 ± 11.6 years; 83.5% of women were married, and 60.6% were illiterate. Sixty percent of patients had tumors measuring 5 cm or less. Almost half of the patients (46.4%) had stage I or II A disease and a third (36.0%) had axillary lymph node metastasis. Estrogen, progesterone, and human epidermal growth factor receptor2 receptor status were investigated in 41 (41.4%) of patients only. The median interval between diagnosis and initiation of treatment was 11 days. Modified radical mastectomy was done in 91% of patients, and nearly a third of patients who were prescribed chemotherapy did not complete treatment. The rural-based tertiary cancer care center has made treatment more accessible to breast cancer patients and has reduced the interval between diagnosis and treatment initiation. However, there are still many challenges like non-compliance to and incomplete treatments and poor follow-up that need to be addressed.

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Enhanced lymphodepletion is insufficient to replace exogenous IL-2 or IL-15 therapy in augmenting the efficacy of adoptively transferred effector CD8+ T cells

Effector CD8+ T cells conditioned with IL-12 during activation mediate enhanced antitumor efficacy after adoptive transfer into lymphodepleted hosts; this is due in part to improved IL-7 responsiveness. Therefore, we hypothesized that increasing the intensity or type of lymphodepletion would deplete more IL-7-consuming host cells and improve the persistence and antitumor activity of IL-12-conditioned CD8+ T cells. Using cyclophosphamide (CTX), fludarabine (FLU), and total body irradiation (TBI, 6 Gy) either individually or in combination, we found that combined lymphodepletion best enhanced T cell engraftment in mice. This improvement was strongly related to the extent of leukopenia, as post-transfer levels of donor T cells inversely correlated to host cell counts after lymphodepletion. Despite the improvement in engraftment seen with combination lymphodepletion, dual-agent lymphodepletion did not augment the antitumor efficacy of donor T cells compared to TBI alone. Similarly, IL-7 supplementation after TBI and transfer of tumor-reactive T cells failed to improve persistence or anti-tumor immunity. However, IL-15 or IL-2 supplementation greatly augmented the persistence and antitumor efficacy of donor tumor-reactive T cells. Our results indicate that the amount of host IL-7 induced after single agent lymphodepletion is sufficient to potentiate the expansion and antitumor activity of donor T cells, and that the efficacy of future regimens may be improved by providing post-transfer support with IL-2 or IL-15.

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Enhanced lymphodepletion is insufficient to replace exogenous IL-2 or IL-15 therapy in augmenting the efficacy of adoptively transferred effector CD8+ T cells

Effector CD8+ T cells conditioned with IL-12 during activation mediate enhanced antitumor efficacy after adoptive transfer into lymphodepleted hosts; this is due in part to improved IL-7 responsiveness. Therefore, we hypothesized that increasing the intensity or type of lymphodepletion would deplete more IL-7-consuming host cells and improve the persistence and antitumor activity of IL-12-conditioned CD8+ T cells. Using cyclophosphamide (CTX), fludarabine (FLU), and total body irradiation (TBI, 6 Gy) either individually or in combination, we found that combined lymphodepletion best enhanced T cell engraftment in mice. This improvement was strongly related to the extent of leukopenia, as post-transfer levels of donor T cells inversely correlated to host cell counts after lymphodepletion. Despite the improvement in engraftment seen with combination lymphodepletion, dual-agent lymphodepletion did not augment the antitumor efficacy of donor T cells compared to TBI alone. Similarly, IL-7 supplementation after TBI and transfer of tumor-reactive T cells failed to improve persistence or anti-tumor immunity. However, IL-15 or IL-2 supplementation greatly augmented the persistence and antitumor efficacy of donor tumor-reactive T cells. Our results indicate that the amount of host IL-7 induced after single agent lymphodepletion is sufficient to potentiate the expansion and antitumor activity of donor T cells, and that the efficacy of future regimens may be improved by providing post-transfer support with IL-2 or IL-15.

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Commentary on: Thoughts on the American Board of Radiology Examinations and the Resident Experience in Radiation Oncology

Publication date: Available online 10 April 2018
Source:Practical Radiation Oncology
Author(s): Paul E. Wallner, Lisa A. Kachnic, Anthony M. Gerdeman




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Local Control for Clinical Stage I Non-small Cell Lung Cancer Treated with Five Fraction Stereotactic Body Radiation Therapy is Not Associated with Treatment Schedule

Publication date: Available online 10 April 2018
Source:Practical Radiation Oncology
Author(s): Pamela Samson, Sana Rehman, Aditya Juloori, Todd DeWees, Michael Roach, Jeffrey Bradley, Gregory M.M. Videtic, Kevin Stephans, Clifford Robinson
PurposeClinical concern remains regarding the relationship between consecutive (QD) versus non-consecutive (QoD) lung SBRT treatment schedules and outcomes for clinical Stage I NSCLC. We examined a multi-institutional series of patients receiving five fraction lung SBRT to compare the local failure rates and overall survival between patients receiving QD versus QoD treatment.Methods and MaterialsLung SBRT databases from two high-volume institutions were combined, and patients receiving five fraction SBRT for a solitary Stage I NSCLC were identified. QD treatment was defined as completing SBRT in ≤7days, while QoD treatment was defined as completing treatment in >7days. To control for patient characteristics between the two institutions, a 1:1 propensity matched analysis was performed. Multivariable logistic regression was performed to identify variables independently associated with local failure, and Cox proportional hazards modeling to identify variables independently associated with increased mortality.ResultsFrom 2005–2016, 245 clinical Stage I NSCLC patients receiving five fraction SBRT were identified. 117 (47.8%) patients received QD treatment and 128 (52.2%) patients received QoD treatment. On propensity matched analysis, no association was seen between QD treatment and local failure (Odds Ratio for QD treatment 0.48, 95% CI 0.12–1.99, p=0.5). On multivariable logistic regression central tumors were independently associated with increased likelihood of local recurrence (OR 5.2, 95% CI 1.11–24.2, p=0.04). Kaplan–Meier analysis identified no difference in median overall survival between QD versus QoD treatments (38.0months versus 38.0months, log-rank p=0.7), respectively. QD treatment was not associated with an increased mortality hazard (HR 1.08, 95% CI 0.67–1.75, p=0.75).ConclusionsThis analysis demonstrated no association between QD versus QoD treatment scheduling and local control or overall survival for early stage NSCLC.



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The long-term sequelae of palliative radiotherapy to Lumbo-sacral spine using conventional PA-single portal technique

Publication date: Available online 10 April 2018
Source:Practical Radiation Oncology
Author(s): Kuan-Yin Hsiao, Hui-Chuan Wang, Steve H Fung, Waqar Haque, E Brian Butler, Bin S Teh




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Commentary on: Thoughts on the American Board of Radiology Examinations and the Resident Experience in Radiation Oncology

Publication date: Available online 10 April 2018
Source:Practical Radiation Oncology
Author(s): Paul E. Wallner, Lisa A. Kachnic, Anthony M. Gerdeman




https://ift.tt/2Hc6h9l

Local Control for Clinical Stage I Non-small Cell Lung Cancer Treated with Five Fraction Stereotactic Body Radiation Therapy is Not Associated with Treatment Schedule

Publication date: Available online 10 April 2018
Source:Practical Radiation Oncology
Author(s): Pamela Samson, Sana Rehman, Aditya Juloori, Todd DeWees, Michael Roach, Jeffrey Bradley, Gregory M.M. Videtic, Kevin Stephans, Clifford Robinson
PurposeClinical concern remains regarding the relationship between consecutive (QD) versus non-consecutive (QoD) lung SBRT treatment schedules and outcomes for clinical Stage I NSCLC. We examined a multi-institutional series of patients receiving five fraction lung SBRT to compare the local failure rates and overall survival between patients receiving QD versus QoD treatment.Methods and MaterialsLung SBRT databases from two high-volume institutions were combined, and patients receiving five fraction SBRT for a solitary Stage I NSCLC were identified. QD treatment was defined as completing SBRT in ≤7days, while QoD treatment was defined as completing treatment in >7days. To control for patient characteristics between the two institutions, a 1:1 propensity matched analysis was performed. Multivariable logistic regression was performed to identify variables independently associated with local failure, and Cox proportional hazards modeling to identify variables independently associated with increased mortality.ResultsFrom 2005–2016, 245 clinical Stage I NSCLC patients receiving five fraction SBRT were identified. 117 (47.8%) patients received QD treatment and 128 (52.2%) patients received QoD treatment. On propensity matched analysis, no association was seen between QD treatment and local failure (Odds Ratio for QD treatment 0.48, 95% CI 0.12–1.99, p=0.5). On multivariable logistic regression central tumors were independently associated with increased likelihood of local recurrence (OR 5.2, 95% CI 1.11–24.2, p=0.04). Kaplan–Meier analysis identified no difference in median overall survival between QD versus QoD treatments (38.0months versus 38.0months, log-rank p=0.7), respectively. QD treatment was not associated with an increased mortality hazard (HR 1.08, 95% CI 0.67–1.75, p=0.75).ConclusionsThis analysis demonstrated no association between QD versus QoD treatment scheduling and local control or overall survival for early stage NSCLC.



https://ift.tt/2GQ6Imp

The long-term sequelae of palliative radiotherapy to Lumbo-sacral spine using conventional PA-single portal technique

Publication date: Available online 10 April 2018
Source:Practical Radiation Oncology
Author(s): Kuan-Yin Hsiao, Hui-Chuan Wang, Steve H Fung, Waqar Haque, E Brian Butler, Bin S Teh




https://ift.tt/2HcwxR2

Management of older adults with acute lymphoblastic leukemia: challenges & current approaches

International Journal of Hematologic Oncology, Ahead of Print.


https://ift.tt/2HpYS47

Management of older adults with acute lymphoblastic leukemia: challenges & current approaches

International Journal of Hematologic Oncology, Ahead of Print.


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Thyroid FNA biopsies comprised of abundant, mature squamous cells can be reported as benign: A cytologic study of 18 patients with clinical correlation

Cancer Cytopathology, EarlyView.


https://ift.tt/2ql21e7

Thyroid FNA biopsies comprised of abundant, mature squamous cells can be reported as benign: A cytologic study of 18 patients with clinical correlation

Cancer Cytopathology, EarlyView.


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Collaborating with Adolescents and Young Adults with Cancer as Advisors

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


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Sleep Quality, Fatigue, and Quality of Life Among Teenage and Young Adult Cancer Survivors

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


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Germ Cell Tumor Ovary: an Institutional Experience of Treatment and Survival Outcomes

Abstract

Malignant germ cell tumors (GCT) of the ovary account for 2–3% of all ovarian neoplasms and occur mostly in the second and third decade of life. Over the past three decades, survival rates for germ cell tumors have dramatically improved, coincident with more aggressive surgical staging and combination chemotherapy. Although there are several studies describing ovarian GCT and fertility-preserving surgery in the western population, there is very little Indian data. We present our experience of germ cell tumor ovary in the Department of Surgical Oncology, King George's Medical University over the last 5 years with special emphasis on treatment outcome and role of fertility preservation surgery. A retrospective review of medical records of patients with ovarian germ cell tumors, treated at our center from January 2012 to December 2016, was performed. Epidemiological and clinical profile of patients was reviewed. Clinical stage of presentation, neoadjuvant treatment, surgical treatment, and adjuvant treatment data were analyzed, and treatment outcome data was recorded. Patient follow-up was done to ascertain disease-free interval, treatment outcome, ability to conceive following fertility-preserving surgery, and quality of life. A total of 39 patients with ovarian germ cell tumor were treated during this period. Their median age at diagnosis was 22 years (range 11–65 years) and most common mode of presentation was abdominal lump without ascites. Around 36.8% (n = 14) patients had conservative surgery with preservation of opposite ovary and uterus. Most patients (71.1% n = 27) received neoadjuvant chemotherapy due to advanced disease in form of ascites or large mass, and five of these patients were amenable to fertility-preserving surgery after chemotherapy. Nine out of the fourteen patients have had return of menstrual function after a mean period of 3.5 + 0.5 months. One patient who underwent fertility-preserving surgery has delivered healthy children after treatment. Stage distribution for stage I to IV was as follows: 15.4% (n = 6), 35.9% (n = 14), 46.2% (n = 18), and 2.6% (n = 1), respectively. Dysgerminoma was the commonest histology (37.1% n = 13) followed by teratoma (22.9% n = 8). 17.1% (n = 6) patients had recurrence, with a median time to recurrence 16 months (range 5.5 to 37 months) and they were treated with second-line chemotherapy. Germ cell tumor of the ovary is an eminently treatable disease and selected patients can be managed with fertility-preserving surgery. BEP is the most effective chemotherapy regimen. Disease-free survival rates in these patients are quite high and recurrences can be managed with second-line chemotherapy.

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Collaborating with Adolescents and Young Adults with Cancer as Advisors

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


https://ift.tt/2qlk1VU

Sleep Quality, Fatigue, and Quality of Life Among Teenage and Young Adult Cancer Survivors

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


https://ift.tt/2EyGbYN

Germ Cell Tumor Ovary: an Institutional Experience of Treatment and Survival Outcomes

Abstract

Malignant germ cell tumors (GCT) of the ovary account for 2–3% of all ovarian neoplasms and occur mostly in the second and third decade of life. Over the past three decades, survival rates for germ cell tumors have dramatically improved, coincident with more aggressive surgical staging and combination chemotherapy. Although there are several studies describing ovarian GCT and fertility-preserving surgery in the western population, there is very little Indian data. We present our experience of germ cell tumor ovary in the Department of Surgical Oncology, King George's Medical University over the last 5 years with special emphasis on treatment outcome and role of fertility preservation surgery. A retrospective review of medical records of patients with ovarian germ cell tumors, treated at our center from January 2012 to December 2016, was performed. Epidemiological and clinical profile of patients was reviewed. Clinical stage of presentation, neoadjuvant treatment, surgical treatment, and adjuvant treatment data were analyzed, and treatment outcome data was recorded. Patient follow-up was done to ascertain disease-free interval, treatment outcome, ability to conceive following fertility-preserving surgery, and quality of life. A total of 39 patients with ovarian germ cell tumor were treated during this period. Their median age at diagnosis was 22 years (range 11–65 years) and most common mode of presentation was abdominal lump without ascites. Around 36.8% (n = 14) patients had conservative surgery with preservation of opposite ovary and uterus. Most patients (71.1% n = 27) received neoadjuvant chemotherapy due to advanced disease in form of ascites or large mass, and five of these patients were amenable to fertility-preserving surgery after chemotherapy. Nine out of the fourteen patients have had return of menstrual function after a mean period of 3.5 + 0.5 months. One patient who underwent fertility-preserving surgery has delivered healthy children after treatment. Stage distribution for stage I to IV was as follows: 15.4% (n = 6), 35.9% (n = 14), 46.2% (n = 18), and 2.6% (n = 1), respectively. Dysgerminoma was the commonest histology (37.1% n = 13) followed by teratoma (22.9% n = 8). 17.1% (n = 6) patients had recurrence, with a median time to recurrence 16 months (range 5.5 to 37 months) and they were treated with second-line chemotherapy. Germ cell tumor of the ovary is an eminently treatable disease and selected patients can be managed with fertility-preserving surgery. BEP is the most effective chemotherapy regimen. Disease-free survival rates in these patients are quite high and recurrences can be managed with second-line chemotherapy.

https://ift.tt/2HpcZXt

Genomics and pharmacogenomics of Pediatric Acute Lymphoblastic Leukemia

Publication date: Available online 10 April 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Chuan Wu, Wei Li
Acute lymphoblastic leukaemia (ALL) is a prevalent form of pediatric cancer that accounts for 70-80% of all leukemias. Genome-based analysis, exome sequencing, transcriptomics and proteomics have provided insight into genetic classification of ALL and helped identify novel subtypes of the disease. B and T cell-based ALL are two well-characterized genomic subtypes, significantly marked by bone marrow disorders, along with mutations in trisomy 21 and T53. The other ALLs include Early T-cell precursor ALL, Philadelphia chromosome-like ALL, Down syndrome-associated ALL and Relapsed ALL. Chromosomal number forms a basis of classification, such as, hypodiploid ALL, near-haploid, low-hypodiploid, high-hypodiploid and hypodiploid-ALL. Advances in therapies targeting ALL have been noteworthy, with significant pre-clinical and clinical studies on drug pharmacokinetics and pharmacodynamics. Methotrexate and 6-mercaptopurine are leading drugs with best demonstrated efficacies against childhood ALL. The drugs in combination, following dose titration, have also been used for maintenance therapy. Methotrexate-polyglutamate is a key metabolite that specifically targets the disease pathogenesis, and 6-thioguanine nucleotides, derived from 6-mercaptopurine, impede replication and transcription processes, inducing cytotoxicity. Additionally, glucocorticoids, asparaginase, anthracycline, vincristine and cytarabine that trans-repress gene expression, deprives cells of asparagine, triggers cell cycle arrest, influences cytochrome-P450 polymorphism and inhibits DNA polymerase, respectively, have been used in chemotherapy in ALL patients. Overall, this review covers the progress in genome technology related to different sub-types of ALL and pharmacokinetics and pharmacodynamics of its medications. It also enlightens adverse effects of current drugs, and emphasizes the necessity of genome-wide association studies for restricting childhood ALL.



https://ift.tt/2JyIQ8C

Organization, Quality and Cost of Oncological Home-Hospitalization: A Systematic Review

Publication date: Available online 10 April 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Lieselot Cool, Dominique Vandijck, Philip Debruyne, Melissa Desmedt, Tessa Lefebvre, Michelle Lycke, Pieter Jan De Jonghe, Hans Pottel, Veerle Foulon, Koen Van Eygen
BackgroundHome-hospitalization might be a patient-centred approach facing the increasing burden of cancer on societies. This systematic review assessed how oncological home-hospitalization has been organized and to what extend its quality and costs were evaluated.ResultsTwenty-four papers describing parenteral cancer drug administration to adult patients in their homes were included. Most papers concluded oncological home-hospitalization had no significant effect on patient-reported quality of life (7/8=88%), but large majority of patients were satisfied (12/13, 92%) and preferred home treatment (7/8, 88%). No safety risks were associated with home-hospitalization (10/10, 100%). The cost of home-hospitalization was found beneficial in five trials (5/9, 56%); others reported no financial impact (2/9, 22%) or additional costs (2/9, 22%).ConclusionDespite heterogeneity, majority of reported models for oncological home-hospitalisation demonstrated that this is a safe, equivalent and acceptable alternative to ambulatory hospital care. More well-designed trials are needed to evaluate its economic impact.



https://ift.tt/2IHdHP1

Genomics and pharmacogenomics of Pediatric Acute Lymphoblastic Leukemia

Publication date: Available online 10 April 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Chuan Wu, Wei Li
Acute lymphoblastic leukaemia (ALL) is a prevalent form of pediatric cancer that accounts for 70-80% of all leukemias. Genome-based analysis, exome sequencing, transcriptomics and proteomics have provided insight into genetic classification of ALL and helped identify novel subtypes of the disease. B and T cell-based ALL are two well-characterized genomic subtypes, significantly marked by bone marrow disorders, along with mutations in trisomy 21 and T53. The other ALLs include Early T-cell precursor ALL, Philadelphia chromosome-like ALL, Down syndrome-associated ALL and Relapsed ALL. Chromosomal number forms a basis of classification, such as, hypodiploid ALL, near-haploid, low-hypodiploid, high-hypodiploid and hypodiploid-ALL. Advances in therapies targeting ALL have been noteworthy, with significant pre-clinical and clinical studies on drug pharmacokinetics and pharmacodynamics. Methotrexate and 6-mercaptopurine are leading drugs with best demonstrated efficacies against childhood ALL. The drugs in combination, following dose titration, have also been used for maintenance therapy. Methotrexate-polyglutamate is a key metabolite that specifically targets the disease pathogenesis, and 6-thioguanine nucleotides, derived from 6-mercaptopurine, impede replication and transcription processes, inducing cytotoxicity. Additionally, glucocorticoids, asparaginase, anthracycline, vincristine and cytarabine that trans-repress gene expression, deprives cells of asparagine, triggers cell cycle arrest, influences cytochrome-P450 polymorphism and inhibits DNA polymerase, respectively, have been used in chemotherapy in ALL patients. Overall, this review covers the progress in genome technology related to different sub-types of ALL and pharmacokinetics and pharmacodynamics of its medications. It also enlightens adverse effects of current drugs, and emphasizes the necessity of genome-wide association studies for restricting childhood ALL.



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Organization, Quality and Cost of Oncological Home-Hospitalization: A Systematic Review

Publication date: Available online 10 April 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Lieselot Cool, Dominique Vandijck, Philip Debruyne, Melissa Desmedt, Tessa Lefebvre, Michelle Lycke, Pieter Jan De Jonghe, Hans Pottel, Veerle Foulon, Koen Van Eygen
BackgroundHome-hospitalization might be a patient-centred approach facing the increasing burden of cancer on societies. This systematic review assessed how oncological home-hospitalization has been organized and to what extend its quality and costs were evaluated.ResultsTwenty-four papers describing parenteral cancer drug administration to adult patients in their homes were included. Most papers concluded oncological home-hospitalization had no significant effect on patient-reported quality of life (7/8=88%), but large majority of patients were satisfied (12/13, 92%) and preferred home treatment (7/8, 88%). No safety risks were associated with home-hospitalization (10/10, 100%). The cost of home-hospitalization was found beneficial in five trials (5/9, 56%); others reported no financial impact (2/9, 22%) or additional costs (2/9, 22%).ConclusionDespite heterogeneity, majority of reported models for oncological home-hospitalisation demonstrated that this is a safe, equivalent and acceptable alternative to ambulatory hospital care. More well-designed trials are needed to evaluate its economic impact.



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Biomarqueurs inflammatoires et immunologiques de réponse à la radiothérapie

Publication date: Available online 10 April 2018
Source:Cancer/Radiothérapie
Author(s): J.P. Nesseler, D. Schaue, W.H. McBride, P. Nickers




https://ift.tt/2GMXH1I

Biomarqueurs inflammatoires et immunologiques de réponse à la radiothérapie

Publication date: Available online 10 April 2018
Source:Cancer/Radiothérapie
Author(s): J.P. Nesseler, D. Schaue, W.H. McBride, P. Nickers




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Stacked generalization: an introduction to super learning

Abstract

Stacked generalization is an ensemble method that allows researchers to combine several different prediction algorithms into one. Since its introduction in the early 1990s, the method has evolved several times into a host of methods among which is the "Super Learner". Super Learner uses V-fold cross-validation to build the optimal weighted combination of predictions from a library of candidate algorithms. Optimality is defined by a user-specified objective function, such as minimizing mean squared error or maximizing the area under the receiver operating characteristic curve. Although relatively simple in nature, use of Super Learner by epidemiologists has been hampered by limitations in understanding conceptual and technical details. We work step-by-step through two examples to illustrate concepts and address common concerns.

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Safety, efficacy and survival of patients with primary malignant brain tumours (PMBT) in phase I (Ph1) trials: the 12-year Royal Marsden experience

Abstract

Background

Primary malignant brain tumours (PMBT) constitute less than 2% of all malignancies and carry a dismal prognosis. Treatment options at relapse are limited. First-in-human solid tumour studies have historically excluded patients with PMBT due to the poor prognosis, concomitant drug interactions and concerns regarding toxicities.

Methods

Retrospective data were collected on clinical and tumour characteristics of patients referred for consideration of Ph1 trials in the Royal Marsden Hospital between June 2004 and August 2016. Survival analyses were performed using the Kaplan–Meier method, Cox proportional hazards model. Chi squared test was used to measure bivariate associations between categorical variables.

Results

100pts with advanced PMBT were referred. At initial consultation, patients had a median ECOG PS 1, median age 48 years (range 18–70); 69% were men, 76% had glioblastoma; 68% were on AEDs, 63% required steroid therapy; median number of prior treatments was two. Median OS for patients treated on a Ph1 trials was 9.3 months (95% CI 5.9–12.9) versus 5.3 months (95% CI 4.1–6.1) for patients that did not proceed with a Ph1 trial, p = 0.0094. Steroid use, poor PS, neutrophil-to-lymphocyte ratio and treatment on a Ph1 trial were shown to independently influence OS.

Conclusions

We report a survival benefit for patients with PMBT treated on Ph1 trials. Toxicity and efficacy outcomes were comparable to the general Ph1 population. In the absence of an internationally recognized standard second line treatment for patients with recurrent PMBT, more Ph1 trials should allow enrolment of patients with refractory PMBT and Ph1 trial participation should be considered at an earlier stage.

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Information needs and requirements in patients with brain tumours

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Safety, efficacy and survival of patients with primary malignant brain tumours (PMBT) in phase I (Ph1) trials: the 12-year Royal Marsden experience

Abstract

Background

Primary malignant brain tumours (PMBT) constitute less than 2% of all malignancies and carry a dismal prognosis. Treatment options at relapse are limited. First-in-human solid tumour studies have historically excluded patients with PMBT due to the poor prognosis, concomitant drug interactions and concerns regarding toxicities.

Methods

Retrospective data were collected on clinical and tumour characteristics of patients referred for consideration of Ph1 trials in the Royal Marsden Hospital between June 2004 and August 2016. Survival analyses were performed using the Kaplan–Meier method, Cox proportional hazards model. Chi squared test was used to measure bivariate associations between categorical variables.

Results

100pts with advanced PMBT were referred. At initial consultation, patients had a median ECOG PS 1, median age 48 years (range 18–70); 69% were men, 76% had glioblastoma; 68% were on AEDs, 63% required steroid therapy; median number of prior treatments was two. Median OS for patients treated on a Ph1 trials was 9.3 months (95% CI 5.9–12.9) versus 5.3 months (95% CI 4.1–6.1) for patients that did not proceed with a Ph1 trial, p = 0.0094. Steroid use, poor PS, neutrophil-to-lymphocyte ratio and treatment on a Ph1 trial were shown to independently influence OS.

Conclusions

We report a survival benefit for patients with PMBT treated on Ph1 trials. Toxicity and efficacy outcomes were comparable to the general Ph1 population. In the absence of an internationally recognized standard second line treatment for patients with recurrent PMBT, more Ph1 trials should allow enrolment of patients with refractory PMBT and Ph1 trial participation should be considered at an earlier stage.

https://ift.tt/2qlKLVj

Information needs and requirements in patients with brain tumours

https://ift.tt/2GN2WOJ

Clinical value of miR-182-5p in lung squamous cell carcinoma: a study combining data from TCGA, GEO, and RT-qPCR validation

Abstract

Background

MiR-182-5p, as a member of miRNA family, can be detected in lung cancer and plays an important role in lung cancer. To explore the clinical value of miR-182-5p in lung squamous cell carcinoma (LUSC) and to unveil the molecular mechanism of LUSC.

Methods

The clinical value of miR-182-5p in LUSC was investigated by collecting and calculating data from The Cancer Genome Atlas (TCGA) database, the Gene Expression Omnibus (GEO) database, and real-time quantitative polymerase chain reaction (RT-qPCR). Twelve prediction platforms were used to predict the target genes of miR-182-5p. Protein-protein interaction (PPI) networks and gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to explore the molecular mechanism of LUSC.

Results

The expression of miR-182-5p was significantly over-expressed in LUSC than in non-cancerous tissues, as evidenced by various approaches, including the TCGA database, GEO microarrays, RT-qPCR, and a comprehensive meta-analysis of 501 LUSC cases and 148 non-cancerous cases. Furthermore, a total of 81 potential target genes were chosen from the union of predicted genes and the TCGA database. GO and KEGG analyses demonstrated that the target genes are involved in pathways related to biological processes. PPIs revealed the relationships between these genes, with EPAS1, PRKCE, NR3C1, and RHOB being located in the center of the PPI network.

Conclusions

MiR-182-5p upregulation greatly contributes to LUSC and may serve as a biomarker in LUSC.

https://ift.tt/2He44KO

Clinical value of miR-182-5p in lung squamous cell carcinoma: a study combining data from TCGA, GEO, and RT-qPCR validation

Abstract

Background

MiR-182-5p, as a member of miRNA family, can be detected in lung cancer and plays an important role in lung cancer. To explore the clinical value of miR-182-5p in lung squamous cell carcinoma (LUSC) and to unveil the molecular mechanism of LUSC.

Methods

The clinical value of miR-182-5p in LUSC was investigated by collecting and calculating data from The Cancer Genome Atlas (TCGA) database, the Gene Expression Omnibus (GEO) database, and real-time quantitative polymerase chain reaction (RT-qPCR). Twelve prediction platforms were used to predict the target genes of miR-182-5p. Protein-protein interaction (PPI) networks and gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to explore the molecular mechanism of LUSC.

Results

The expression of miR-182-5p was significantly over-expressed in LUSC than in non-cancerous tissues, as evidenced by various approaches, including the TCGA database, GEO microarrays, RT-qPCR, and a comprehensive meta-analysis of 501 LUSC cases and 148 non-cancerous cases. Furthermore, a total of 81 potential target genes were chosen from the union of predicted genes and the TCGA database. GO and KEGG analyses demonstrated that the target genes are involved in pathways related to biological processes. PPIs revealed the relationships between these genes, with EPAS1, PRKCE, NR3C1, and RHOB being located in the center of the PPI network.

Conclusions

MiR-182-5p upregulation greatly contributes to LUSC and may serve as a biomarker in LUSC.

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Cancers, Vol. 10, Pages 114: Immune Response against ALK in Children with ALK-Positive Anaplastic Large Cell Lymphoma

Cancers, Vol. 10, Pages 114: Immune Response against ALK in Children with ALK-Positive Anaplastic Large Cell Lymphoma

Cancers doi: 10.3390/cancers10040114

Authors: Serena Stadler Vijay Singh Fabian Knörr Christine Damm-Welk Wilhelm Woessmann

Patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount a humoral and cellular immune response against ALK. More than 90% of children and adolescents with ALK-positive ALCL have detectable anti-ALK antibodies in serum or plasma, and the antibody titer inversely correlates with the risk of relapse. ALK-specific CD8 and CD4 T cell responses have been described in patients with ALK-positive ALCL. Vaccination with ALK DNA led to protection against lymphoma growth in a murine model. Collectively, these data suggest that the ALK-specific immune response is involved in the control of the disease. The characteristics of the humoral and cellular immune response against ALK as well as tumor immune escape mechanisms have been increasingly investigated. However, tumor and host factors contributing to the individual immune response against ALK are still largely unknown. Depending on the individual strength of the immune response and its determinants, individualized immunological approaches might be appropriate for the consolidation of ALCL patients. Strategies such as ALK vaccination could be effective for those with a pre-existing anti-tumor immunity, while an allogeneic blood stem cell transplantation or check-point inhibition could be effective for others.

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Cancers, Vol. 10, Pages 115: YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Cancers, Vol. 10, Pages 115: YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Cancers doi: 10.3390/cancers10040115

Authors: Janine Warren Yuxuan Xiao John Lamar

Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.

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Cancers, Vol. 10, Pages 116: Proton Beam Therapy Alone for Intermediate- or High-Risk Prostate Cancer: An Institutional Prospective Cohort Study

Cancers, Vol. 10, Pages 116: Proton Beam Therapy Alone for Intermediate- or High-Risk Prostate Cancer: An Institutional Prospective Cohort Study

Cancers doi: 10.3390/cancers10040116

Authors: Takeshi Arimura Takashi Yoshiura Kyoko Matsukawa Naoaki Kondo Ikumi Kitano Takashi Ogino

The role of proton beam therapy (PBT) as monotherapy for localized prostate cancer (PCa) remains unclear. The purpose of this study was to evaluate the efficacy and adverse events of PBT alone for these patients. Between January 2011 and July 2014, 218 patients with intermediate- and high-risk PCa who declined androgen deprivation therapy (ADT) were enrolled to the study and were treated with PBT following one of the following protocols: 74 Gray (GyE) with 37 fractions (fr) (74 GyE/37 fr), 78 GyE/39 fr, and 70 GyE/28 fr. The 5-year progression-free survival rate in the intermediate- and high-risk groups was 97% and 83%, respectively (p = 0.002). The rate of grade 2 or higher late gastrointestinal toxicity was 3.9%, and a significant increased incidence was noted in those who received the 78 GyE/39 fr protocol (p &lt; 0.05). Grade 2 or higher acute and late genitourinary toxicities were observed in 23.5% and 3.4% of patients, respectively. Our results indicated that PBT monotherapy can be a beneficial treatment for localized PCa. Furthermore, it can preserve the quality of life of these patients. We believe that this study provides crucial hypotheses for further study and for establishing new treatment strategies.

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Cancers, Vol. 10, Pages 115: YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Cancers, Vol. 10, Pages 115: YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Cancers doi: 10.3390/cancers10040115

Authors: Janine Warren Yuxuan Xiao John Lamar

Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.

https://ift.tt/2HnONED

Cancers, Vol. 10, Pages 114: Immune Response against ALK in Children with ALK-Positive Anaplastic Large Cell Lymphoma

Cancers, Vol. 10, Pages 114: Immune Response against ALK in Children with ALK-Positive Anaplastic Large Cell Lymphoma

Cancers doi: 10.3390/cancers10040114

Authors: Serena Stadler Vijay Singh Fabian Knörr Christine Damm-Welk Wilhelm Woessmann

Patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount a humoral and cellular immune response against ALK. More than 90% of children and adolescents with ALK-positive ALCL have detectable anti-ALK antibodies in serum or plasma, and the antibody titer inversely correlates with the risk of relapse. ALK-specific CD8 and CD4 T cell responses have been described in patients with ALK-positive ALCL. Vaccination with ALK DNA led to protection against lymphoma growth in a murine model. Collectively, these data suggest that the ALK-specific immune response is involved in the control of the disease. The characteristics of the humoral and cellular immune response against ALK as well as tumor immune escape mechanisms have been increasingly investigated. However, tumor and host factors contributing to the individual immune response against ALK are still largely unknown. Depending on the individual strength of the immune response and its determinants, individualized immunological approaches might be appropriate for the consolidation of ALCL patients. Strategies such as ALK vaccination could be effective for those with a pre-existing anti-tumor immunity, while an allogeneic blood stem cell transplantation or check-point inhibition could be effective for others.

https://ift.tt/2uZsAdO

Cancers, Vol. 10, Pages 116: Proton Beam Therapy Alone for Intermediate- or High-Risk Prostate Cancer: An Institutional Prospective Cohort Study

Cancers, Vol. 10, Pages 116: Proton Beam Therapy Alone for Intermediate- or High-Risk Prostate Cancer: An Institutional Prospective Cohort Study

Cancers doi: 10.3390/cancers10040116

Authors: Takeshi Arimura Takashi Yoshiura Kyoko Matsukawa Naoaki Kondo Ikumi Kitano Takashi Ogino

The role of proton beam therapy (PBT) as monotherapy for localized prostate cancer (PCa) remains unclear. The purpose of this study was to evaluate the efficacy and adverse events of PBT alone for these patients. Between January 2011 and July 2014, 218 patients with intermediate- and high-risk PCa who declined androgen deprivation therapy (ADT) were enrolled to the study and were treated with PBT following one of the following protocols: 74 Gray (GyE) with 37 fractions (fr) (74 GyE/37 fr), 78 GyE/39 fr, and 70 GyE/28 fr. The 5-year progression-free survival rate in the intermediate- and high-risk groups was 97% and 83%, respectively (p = 0.002). The rate of grade 2 or higher late gastrointestinal toxicity was 3.9%, and a significant increased incidence was noted in those who received the 78 GyE/39 fr protocol (p &lt; 0.05). Grade 2 or higher acute and late genitourinary toxicities were observed in 23.5% and 3.4% of patients, respectively. Our results indicated that PBT monotherapy can be a beneficial treatment for localized PCa. Furthermore, it can preserve the quality of life of these patients. We believe that this study provides crucial hypotheses for further study and for establishing new treatment strategies.

https://ift.tt/2EzKbIM

Nucleoside diphosphate kinase B promotes osteosarcoma proliferation through c-Myc.

Nucleoside diphosphate kinase B promotes osteosarcoma proliferation through c-Myc.

Cancer Biol Ther. 2018 Apr 09;:0

Authors: Li S, Hu T, Yuan T, Cheng D, Yang Q

Abstract
Osteosarcoma (OS) is one of the most common primary bone tumors and has a high disablity rate and case-fatality rate. The protracted stagnancy of the chemotherapy program and surgical technology for OS treatment prompted us to focus on the mechanisms of cancer carcinogenesis progression in OS. Nucleoside diphosphate kinase B (NME2) is a type of nucleoside diphosphate kinase that plays an important role in cellular processes. In this study, we report overexpression of NME2 in OS cell lines and correlate this overexpression with the clinicopathologic features of osteosarcoma. We used si-NME2 to downregulate expression of NME2 in OS cell lines. The results of the CCK8 and clone forming assays show that NME2 promotes OS cell line proliferation. Western blot assays show that deregulation of NME2 results in enhanced the expression of c-Myc, which promotes OS proliferation.

PMID: 29630434 [PubMed - as supplied by publisher]

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Alternative splicing of human telomerase reverse transcriptase in gliomas and its modulation mediated by CX-5461

Glioma is a heterogeneous, invasive primary brain tumor with a wide range of patient survival and a lack of reliable prognostic biomarkers. Human telomerase reverse transcriptase (hTERT) has been reported in t...

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Nucleoside diphosphate kinase B promotes osteosarcoma proliferation through c-Myc.

Nucleoside diphosphate kinase B promotes osteosarcoma proliferation through c-Myc.

Cancer Biol Ther. 2018 Apr 09;:0

Authors: Li S, Hu T, Yuan T, Cheng D, Yang Q

Abstract
Osteosarcoma (OS) is one of the most common primary bone tumors and has a high disablity rate and case-fatality rate. The protracted stagnancy of the chemotherapy program and surgical technology for OS treatment prompted us to focus on the mechanisms of cancer carcinogenesis progression in OS. Nucleoside diphosphate kinase B (NME2) is a type of nucleoside diphosphate kinase that plays an important role in cellular processes. In this study, we report overexpression of NME2 in OS cell lines and correlate this overexpression with the clinicopathologic features of osteosarcoma. We used si-NME2 to downregulate expression of NME2 in OS cell lines. The results of the CCK8 and clone forming assays show that NME2 promotes OS cell line proliferation. Western blot assays show that deregulation of NME2 results in enhanced the expression of c-Myc, which promotes OS proliferation.

PMID: 29630434 [PubMed - as supplied by publisher]

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PPI use and oesophageal cancer: What if the results are true?

Publication date: Available online 9 April 2018
Source:Cancer Epidemiology
Author(s): Nele Brusselaers, Lars Engstrand, Jesper Lagergren




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PPI use and oesophageal cancer: What if the results are true?

Publication date: Available online 9 April 2018
Source:Cancer Epidemiology
Author(s): Nele Brusselaers, Lars Engstrand, Jesper Lagergren




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Antenatal Spontaneous Renal Forniceal Rupture Presenting as an Acute Abdomen

Background. Renal forniceal rupture is a lesser-known cause of acute abdomen in pregnancy. The ureteral compression by the gravid uterus places pregnant women at a higher risk. Sequelae in pregnancy could include intractable pain, acute kidney injury, and preterm birth. Case. A 22-year-old primigravida with no prior medical history presented with an acute abdomen in her second trimester. The diagnosis of renal forniceal rupture was made by a radiologist using MRI. A percutaneous nephrostomy catheter was placed, and the patient's pain was relieved. She subsequently delivered at term. Conclusion. Upon presentation of an acute abdomen in pregnancy, providers may not include renal forniceal rupture in their differential as readily as obstetric or gynecologic causes, resulting in delayed diagnosis, unnecessary invasive interventions, and potentially adverse maternal and neonatal outcomes. Increasing provider awareness could result in improved outcomes.

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Cancers, Vol. 10, Pages 113: ALK in Neuroblastoma: Biological and Therapeutic Implications

Cancers, Vol. 10, Pages 113: ALK in Neuroblastoma: Biological and Therapeutic Implications

Cancers doi: 10.3390/cancers10040113

Authors: Ricky Trigg Suzanne Turner

Neuroblastoma (NB) is the most common and deadly solid tumour in children. Despite the development of new treatment options for high-risk NB, over half of patients relapse and five-year survival remains at 40–50%. Therefore, novel treatment strategies aimed at providing long-term disease remission are urgently sought. ALK, encoding the anaplastic lymphoma kinase receptor, is altered by gain-of-function point mutations in around 14% of high-risk NB and represents an ideal therapeutic target given its low or absent expression in healthy tissue postnatally. Small-molecule inhibitors of Anaplastic Lymphoma Kinase (ALK) approved in ALK fusion-positive lung cancer are currently undergoing clinical assessment in patients with ALK-mutant NB. Parallel pre-clinical studies are demonstrating the efficacy of ALK inhibitors against common ALK variants in NB; however, a complex picture of therapeutic resistance is emerging. It is anticipated that long-term use of these compounds will require combinatorial targeting of pathways downstream of ALK, functionally-related 'bypass' mechanisms and concomitant oncogenic pathways.

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Cancers, Vol. 10, Pages 113: ALK in Neuroblastoma: Biological and Therapeutic Implications

Cancers, Vol. 10, Pages 113: ALK in Neuroblastoma: Biological and Therapeutic Implications

Cancers doi: 10.3390/cancers10040113

Authors: Ricky Trigg Suzanne Turner

Neuroblastoma (NB) is the most common and deadly solid tumour in children. Despite the development of new treatment options for high-risk NB, over half of patients relapse and five-year survival remains at 40–50%. Therefore, novel treatment strategies aimed at providing long-term disease remission are urgently sought. ALK, encoding the anaplastic lymphoma kinase receptor, is altered by gain-of-function point mutations in around 14% of high-risk NB and represents an ideal therapeutic target given its low or absent expression in healthy tissue postnatally. Small-molecule inhibitors of Anaplastic Lymphoma Kinase (ALK) approved in ALK fusion-positive lung cancer are currently undergoing clinical assessment in patients with ALK-mutant NB. Parallel pre-clinical studies are demonstrating the efficacy of ALK inhibitors against common ALK variants in NB; however, a complex picture of therapeutic resistance is emerging. It is anticipated that long-term use of these compounds will require combinatorial targeting of pathways downstream of ALK, functionally-related 'bypass' mechanisms and concomitant oncogenic pathways.

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Ichthyosis: A Harbinger of Lymphoma

Description

A 60-year-old, previously healthy woman presented with patchy skin colour change and dryness for 3 months duration. She also gave a history of recurrent boils requiring local and oral antibiotics. On examination, patchy hyperpigmented skin with scaly appearance was apparent along with features of healed and active infection (figure 1). She also had multiple, firm, lymph nodes (largest 2 cm) in the bilateral axillae. On evaluation, haemoglobin was 115 g/L, white blood cells 7.8x10⁹/L, platelets 248x10⁹/L; peripheral blood smear was normal. Representative skin biopsy showed loss of granular layer characteristic of ichthyosis (figure 2). Right axillary lymph node excision biopsy and immunohistochemistry confirmed the diagnosis of T-cell non-Hodgkin's lymphoma (not otherwise specified). HIV ELISA, thyroid function tests and coeliac serology were inconclusive. She was treated with cyclophosphamide, doxorubicin, vincristine  and prednisolone chemotherapy along with moisturisers (urea-based), regular skin cleansing and salty water bath. After six cycles...

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Blind spot: blindness as initial presentation of subarachnoid haemorrhage

A 47-year-old Caucasian man with arterial hypertension was admitted after a seizure. At the emergency department, he presented with high blood pressure, bilateral vision loss (evidenced by unresponsiveness to threatening stimuli), right hemiplegia and severe agitation. The brain CT angiography showed a diffuse basal cisterns subarachnoid haemorrhage with a ruptured basilar aneurysm. He was admitted for neurovascular procedure and embolisation. The patient's neurological examination improved but blindness persisted. A funduscopic examination revealed a left eye vitreous haemorrhage and diffuse retinal haemorrhages in the posterior pole. Assuming the haemorrhages were the cause of blindness, Terson syndrome was diagnosed. The patient underwent vitrectomy surgery being discharged 5 days later maintaining left eye blindness and able to count fingers from 1 m distance with the right eye. Two months after discharge, he was re-evaluated at our clinic with left eye blurred vision and almost normal right eye visual acuity.

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Bland-White-Garland syndrome on coronary CT angiography

Description

A 2-month-old infant presented with poor weight gain, feeding intolerance and cardiomegaly on chest radiography. Transthoracic echocardiography showed severe left ventricular dilatation and dysfunction, left atrial dilatation, moderate mitral regurgitation and doubtful origin of left coronary artery (LCA). Cardiac catheterisation did not identify the origin of LCA from the aorta. Coronary CT angiography (128-multidetector CT, retrospective ECG-gated with restrictive dose modulation, 70 kVs, 1.2 mSv) revealed the origin of the LCA from the pulmonary artery trunk/root junction, immediately above the sinus of Valsalva and was consistent with remaining echocardiography findings (figure 1). The right coronary artery had normal origin. After surgical reimplantation of the LCA in the ascending aorta there was good clinical evolution, with significant weight gain and gradual left ventricular function improvement.

Figure 1

Anomalous left coronary artery from the pulmonary artery (PA) trunk/root junction on multidetector coronary CT angiography. (A) Origin of the...

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Rocuronium for control of muscle spasms in a tetanus patient with chronic methamphetamine use disorder

This is a case of a 31-year-old Filipino man with chronic methamphetamine use disorder who developed tetanus from a necrotic skin graft over his left calcaneus, which was fractured after a motor vehicular accident. During the course of his illness, the patient's muscle spasms were unusually refractory to benzodiazepine, which is the first-line drug used in the management of muscle spasms. The muscle spasms were successfully controlled on the seventh day of illness with rocuronium at a dose of 10 μg/kg/min and midazolam at 0.30 mg/kg/hour. Both infusions were tapered off until the 23rd day of illness. The patient was discharged on the 30th day of illness, improved and stable.

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Wellens syndrome: a pattern to remember

Description

Electrocardiographic changes in asymptomatic individuals may be a diagnostic challenge. The knowledge and early identification of these patterns and their correct association with clinical picture shall have an urgent and specific management.

A 75-year-old Caucasian man with medical history of hypertension and peripheral arterial disease presented at the emergency department, transported by the prehospital emergency team, complaining of an intense chest pain, which woke him up, with irradiation to the left upper limb and diaphoresis. The patient denied nausea, vomiting, palpitations and previous complaints of angina as well. It was administered, during transport, sublingual nitroglycerine, with resolution of the pain.

The patient was vigil, oriented and haemodynamically stable. Physical examination was unremarkable.

The admission ECG, without pain, showed sinus rhythm, heart rate of 60 bpm, right bundle branch block pattern and deep negative symmetrical T waves in the precordial derivations (V2 to V6) suggestive of type 2 Wellens'...

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An unusual cause of thunderclap headache after eating the hottest pepper in the world - "The Carolina Reaper"

Description

A 34-year-old man with no significant medical history presented to the emergency room (ER) after an episode of thunderclap headache. His symptoms began with dry heaves but no vomiting immediately after participation in a hot pepper contest where he ate one 'Carolina Reaper,' the hottest chili pepper in the world. He then developed intense neck and occipital head pain that became holocephalic. During the next few days, on at least two occasions and in retrospect he thought probably more often, he experienced brief intense thunderclap headaches lasting seconds. The pain was excruciating and thus he came to the ER. He denied any focal tingling sensation or weakness, slurred speech, or transient loss of vision. Physical examination revealed blood pressure of 134/69 mm Hg and no neurological deficits. Urine drug screen and non-contrast CT head and neck were unremarkable. CT angiography revealed no aneurysm but demonstrated unexpected multifocal luminal...

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A Window to Internet-Based Information Seeking of US Fourth-Year Medical Students: Are Radiation Oncology Residency Program Websites Comprehensive?

Publication date: Available online 10 April 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Arpan V. Prabhu, Pooja Karukonda, David R. Hansberry, Dwight E. Heron, Charles R. Thomas




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A Window to Internet-Based Information Seeking of US Fourth-Year Medical Students: Are Radiation Oncology Residency Program Websites Comprehensive?

Publication date: Available online 10 April 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Arpan V. Prabhu, Pooja Karukonda, David R. Hansberry, Dwight E. Heron, Charles R. Thomas




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Intraoperative linguistic performance during awake brain surgery predicts postoperative linguistic deficits

Abstract

Introduction

Awake craniotomy pursues a balance between extensive tumor resection and preservation of postoperative language function. A dilemma exists in patients whose tumor resection is restricted due to signs of language impairment observed during awake craniotomy. In order to determine the degree to which recovery of language function caused by tumor resection can be achieved by spontaneous neuroplasticity, the change in postoperative language function was compared to quantified intraoperative linguistic performance.

Methods

The modified, short-form Boston Diagnostic Aphasia Examination (sfBDAE) was used to assess pre- and postoperative language functions; visual object naming (DO 80) and semantic-association (Pyramid and Palm Tree Test, PPTT) tests assessed intraoperative linguistic performance. DO 80 and PPTT were performed alternatively during subcortical functional monitoring while performing tumor resection and sfBDAE was assessed 1-week postoperatively.

Results

Most patients with observed language impairment during awake surgery showed improved language function postoperatively. Both intraoperative DO 80 and PPTT showed significant correlation to postoperative sfBDAE domain scores (p < 0.05), with a higher correlation observed with PPTT. A linear regression model showed that only PPTT predicted the postoperative sfBDAE domain scores with the adjusted R² ranging from 0.51 to 0.89 (all p < 0.01). Receiver operating characteristic analysis showed a cutoff value of PPTT that yielded a sensitivity of 80% and specificity of 100%.

Conclusion

PPTT may be a feasible tool for intraoperative linguistic evaluation that can predict postoperative language outcomes. Further studies are needed to determine the extent of tumor resection that optimizes the postoperative language following neuroplasticity.

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Intraoperative linguistic performance during awake brain surgery predicts postoperative linguistic deficits

Abstract

Introduction

Awake craniotomy pursues a balance between extensive tumor resection and preservation of postoperative language function. A dilemma exists in patients whose tumor resection is restricted due to signs of language impairment observed during awake craniotomy. In order to determine the degree to which recovery of language function caused by tumor resection can be achieved by spontaneous neuroplasticity, the change in postoperative language function was compared to quantified intraoperative linguistic performance.

Methods

The modified, short-form Boston Diagnostic Aphasia Examination (sfBDAE) was used to assess pre- and postoperative language functions; visual object naming (DO 80) and semantic-association (Pyramid and Palm Tree Test, PPTT) tests assessed intraoperative linguistic performance. DO 80 and PPTT were performed alternatively during subcortical functional monitoring while performing tumor resection and sfBDAE was assessed 1-week postoperatively.

Results

Most patients with observed language impairment during awake surgery showed improved language function postoperatively. Both intraoperative DO 80 and PPTT showed significant correlation to postoperative sfBDAE domain scores (p < 0.05), with a higher correlation observed with PPTT. A linear regression model showed that only PPTT predicted the postoperative sfBDAE domain scores with the adjusted R² ranging from 0.51 to 0.89 (all p < 0.01). Receiver operating characteristic analysis showed a cutoff value of PPTT that yielded a sensitivity of 80% and specificity of 100%.

Conclusion

PPTT may be a feasible tool for intraoperative linguistic evaluation that can predict postoperative language outcomes. Further studies are needed to determine the extent of tumor resection that optimizes the postoperative language following neuroplasticity.

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Anesthesiology’s Future with Specialists in Population Health

Publication date: Available online 9 April 2018
Source:Anesthesiology Clinics
Author(s): Mike Schweitzer

Teaser

In population health medicine, often it is not primary care, but rather the specialists' care teams that are responsible for the most overall spending for health care. Engaging specialists in population health medicine is a prerequisite to be successful in improving the quality of care by reducing complications, unnecessary utilization, avoidable Emergency Department visits/readmissions, and total cost of care. Creating patient-centric, physician-lead, interdisciplinary care teams to redesign the delivery of care across the continuum of the episode of care (eg, shadow bundle) is a successful approach to commercial or Centers for Medicare and Medicaid Services value-based payments.


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Perioperative Surgical Home for the Patient with Chronic Pain

Publication date: Available online 9 April 2018
Source:Anesthesiology Clinics
Author(s): Talal W. Khan, Smith Manion

Teaser

The management of acute pain for the phenotypically different patient who suffers from chronic pain is challenging. The care of these patients is expensive and siloed. The physician-led, multidisciplinary, patient-centric, care coordination framework of the perioperative surgical home is an optimal vehicle for the management of these patients. The engagement of physician anesthesiologists in the optimization, in-hospital management, and postdischarge care of the patient with chronic pain will lead to improved outcomes, reduced health care expenditures, and improve the health of this challenging population.


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Challenges in Outcome Reporting

Publication date: Available online 9 April 2018
Source:Anesthesiology Clinics
Author(s): Avery Tung

Teaser

Although measuring outcomes is an integral part of medical quality improvement, large-scale outcome reporting efforts face several challenges. Among these are difficulties in establishing consensus definitions for outcome measurement; classifying gray outcomes, such as postoperative respiratory failure; and adequately adjusting for patient comorbidities and severity of illness. Unintended consequences of outcome reporting can also distort care in undesirable ways, and clinician reluctance to care for high-risk patients may occur with reporting programs. Ultimately, clinicians need not compare outcomes to improve and should recognize that even outcomes that cannot be precisely quantitated can still be improved.


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Bundled Payments and Hidden Costs

Publication date: Available online 9 April 2018
Source:Anesthesiology Clinics
Author(s): Stanley W. Stead, Sharon K. Merrick

Teaser

In a fee-for-service environment, anesthesiologists are paid for the volume of services billed, with little relation to the cost of delivering the services. In bundled payments, anesthesiologists are paid a set fee for an episode of care inclusive of all the anesthesia, pain medicine, and related services for the surgical episode and a period of time after the initial procedure to cover complications and redo procedures. When calculating a bundled payment, all the services typically used by a patient must be counted when calculating both the costs and expected payment.


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Measuring Clinical Productivity

Publication date: Available online 9 April 2018
Source:Anesthesiology Clinics
Author(s): Mark E. Hudson, Evan E. Lebovitz

Teaser

Productivity measurements have been used to evaluate and compare physicians and physician practices. Anesthesiology is unique in that factors outside anesthesiologist control impact opportunity for revenue generation and make comparisons between providers and facilities challenging. This article uses data from the multicenter University of Pittsburgh Physicians Department of Anesthesiology to demonstrate factors influencing productivity opportunity by surgical facility, between department divisions and subspecialties within multispecialty divisions, and by individuals within divisions. The complexities of benchmarking anesthesiology productivity are demonstrated, and the potential value of creating a productivity profile for facilities and groups is illustrated.


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Integrating Academic and Private Practices

Publication date: Available online 9 April 2018
Source:Anesthesiology Clinics
Author(s): Aviva Regev, Aman Mahajan

Teaser

As health care reform shifts toward value over volume, academic medical centers, known for highly specialized, high-cost care, will suffer from erosion of their traditional funding sources. Academic medical centers have undertaken mergers and partnerships with community medical centers, to maintain a more diversified, cost-effective, and competitive presence in their markets. These consolidations have seen varying results. Cultural factors are frequently cited as a cause of dysfunction and disintegration. Anesthesiology groups integrating academic and private practice physicians are likely to face many of the same challenges. Appropriate attention to culture and other key issues may help realize numerous benefits.


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Measuring Quality for Individual Anesthesia Clinicians

Publication date: Available online 9 April 2018
Source:Anesthesiology Clinics
Author(s): John Allyn, Craig Curry

Teaser

A robust quality management system (QMS) will provide value to patients, providers, and hospitals or systems by focusing on system performance. The QMS must remain independent of provider-specific measures used for privileging. Some outcome measures may be used to assess system performance; they must not be used to assess individual provider performance. All anesthesia providers, especially leaders, must be guardians of an organization's safety culture.


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Value Proposition and Anesthesiology

Publication date: Available online 9 April 2018
Source:Anesthesiology Clinics
Author(s): Joseph W. Szokol, Keith J. Chamberlin

Teaser

Health care in general and anesthesia in particular have seen dramatic changes in the economic landscape. It is vital if anesthesia groups wish to survive and prosper in this new environment to understand the changes occurring in health care and be flexible and proactive in taking on these challenges. More than ever anesthesia groups must be good corporate citizens and seek ways in which to enhance their value to the organization, whether in the operating room or out of operating room locations, and be a proactive partner with the hospital.


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Congenital Partial Absence of Pericardium: A Mimic of Arrhythmogenic Right Ventricular Cardiomyopathy

Congenital absence of pericardium is a rare condition with electrocardiogram, chest X-ray, and echocardiographic findings which may mimic those of other cardiac conditions. We present a case of a 19-year-old asymptomatic female with incidental cardiomegaly on chest X-ray and electrocardiographic and echocardiographic changes, which meet the revised task force criteria for definite arrhythmogenic right ventricular cardiomyopathy but subsequently confirmed to have congenital partial absence of pericardium on cardiac magnetic resonance imaging.

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Building a Culture of Excellence in Cancer Education: a Message from Your President

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Building a Culture of Excellence in Cancer Education: a Message from Your President

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Real-world healthcare costs of ipilimumab in patients with advanced cutaneous melanoma in The Netherlands

There is limited evidence on the costs associated with ipilimumab. We investigated healthcare costs of all Dutch patients with advanced cutaneous melanoma who were treated with ipilimumab. Data were retrieved from the nation-wide Dutch Melanoma Treatment Registry. Costs were determined by applying unit costs to individual patient resource use. A total of 807 patients who were diagnosed between July 2012 and July 2015 received ipilimumab in Dutch practice. The mean (median) episode duration was 6.27 (4.61) months (computed from the start of ipilimumab until the start of a next treatment, death, or the last date of follow-up). The average total healthcare costs amounted to €81 484, but varied widely (range: €18 131–€160 002). Ipilimumab was by far the most important cost driver (€73 739). Other costs were related to hospital admissions (€3323), hospital visits (€1791), diagnostics and imaging (€1505), radiotherapy (€828), and surgery (€297). Monthly costs for resource use other than ipilimumab were €1997 (SD: €2629). Treatment-naive patients (n=344) had higher total costs compared with previously-treated patients (n=463; €85 081 vs. €78 811). Although patients with colitis (n=106) had higher costs for resource use other than ipilimumab (€11 426) compared with patients with other types of immune-related adverse events (n=90; €9850) and patients with no immune-related adverse event (n=611; €6796), they had lower total costs (€76 075 vs. €87 882 and €81 480, respectively). In conclusion, this nation-wide study provides valuable insights into the healthcare costs of advanced cutaneous melanoma patients who were treated with ipilimumab in clinical practice. Most of the costs were attributable to ipilimumab, but the costs and its distribution varied considerably across subgroups. Correspondence to Margreet G. Franken, PhD, Institute for Medical Technology Assesment, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands Tel: +31 104 081 372; e-mail: franken@imta.eur.nl Received October 5, 2017 Accepted March 15, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Real-world healthcare costs of ipilimumab in patients with advanced cutaneous melanoma in The Netherlands

There is limited evidence on the costs associated with ipilimumab. We investigated healthcare costs of all Dutch patients with advanced cutaneous melanoma who were treated with ipilimumab. Data were retrieved from the nation-wide Dutch Melanoma Treatment Registry. Costs were determined by applying unit costs to individual patient resource use. A total of 807 patients who were diagnosed between July 2012 and July 2015 received ipilimumab in Dutch practice. The mean (median) episode duration was 6.27 (4.61) months (computed from the start of ipilimumab until the start of a next treatment, death, or the last date of follow-up). The average total healthcare costs amounted to €81 484, but varied widely (range: €18 131–€160 002). Ipilimumab was by far the most important cost driver (€73 739). Other costs were related to hospital admissions (€3323), hospital visits (€1791), diagnostics and imaging (€1505), radiotherapy (€828), and surgery (€297). Monthly costs for resource use other than ipilimumab were €1997 (SD: €2629). Treatment-naive patients (n=344) had higher total costs compared with previously-treated patients (n=463; €85 081 vs. €78 811). Although patients with colitis (n=106) had higher costs for resource use other than ipilimumab (€11 426) compared with patients with other types of immune-related adverse events (n=90; €9850) and patients with no immune-related adverse event (n=611; €6796), they had lower total costs (€76 075 vs. €87 882 and €81 480, respectively). In conclusion, this nation-wide study provides valuable insights into the healthcare costs of advanced cutaneous melanoma patients who were treated with ipilimumab in clinical practice. Most of the costs were attributable to ipilimumab, but the costs and its distribution varied considerably across subgroups. Correspondence to Margreet G. Franken, PhD, Institute for Medical Technology Assesment, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands Tel: +31 104 081 372; e-mail: franken@imta.eur.nl Received October 5, 2017 Accepted March 15, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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When is crossover desirable in cancer drug trials and when is it problematic?

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