Feasibility study of postoperative adjuvant chemotherapy with S-1 in patients with biliary tract cancer

Abstract

Background

The role of adjuvant chemotherapy has not yet been established for patients with resected biliary tract cancer. S-1 has been shown to exert activity against advanced biliary tract cancer. Therefore, we evaluated the feasibility of adjuvant chemotherapy with S-1 in patients with resected biliary tract cancer.

Methods

Patients with complete macroscopic resection of intrahepatic/extrahepatic bile duct, gall bladder, or ampullary cancer were eligible. S-1 was administered orally twice daily for 4 weeks every 6 weeks, up to 4 cycles. The treatment was continued up to 24 weeks or until recurrence/appearance of unacceptable toxicity. The primary endpoint was the treatment completion rate, which was defined as the percentage of patients who received a relative dose intensity of ≥ 75%. This trial was registered as UMIN000004051.

Results

Thirty-three patients were enrolled between June 2010 and March 2011. The relative dose intensity was ≥ 75% in 27 patients representing a treatment completion rate of 81.8%. The most common grade 3/4 adverse event was neutropenia (18%). Grade 2 nausea or diarrhea was observed in 12%. The 3-year relapse-free survival rate was 39.4%. The 3-year survival rate was 54.5%.

Conclusion

Adjuvant chemotherapy with S-1 is feasible treatment in patients with resected biliary tract cancer. It is necessary to conduct a phase III study to confirm the efficacy of adjuvant therapy of S-1 in patients with resected BTC.

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Thymidine phosphorylase: the unforeseen driver in colorectal cancer treatment?

Future Oncology, Ahead of Print.


https://ift.tt/2jblYzY

Trifluridine/tipiracil: an emerging strategy for the management of gastrointestinal cancers

Future Oncology, Ahead of Print.


https://ift.tt/2vQsSUF

The current landscape of early drug development for patients with sarcoma in the immunotherapy era

Future Oncology, Ahead of Print.


https://ift.tt/2jcM7yw

Thymidine phosphorylase: the unforeseen driver in colorectal cancer treatment?

Future Oncology, Ahead of Print.


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Trifluridine/tipiracil: an emerging strategy for the management of gastrointestinal cancers

Future Oncology, Ahead of Print.


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The current landscape of early drug development for patients with sarcoma in the immunotherapy era

Future Oncology, Ahead of Print.


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A rationally designed fully human EGFRvIII:CD3-targeted bispecific antibody redirects human T cells to treat patient-derived intracerebral malignant glioma

Purpose: Conventional therapy for malignant glioma (MG) fails to specifically target tumor cells. In contrast, substantial evidence indicates that if appropriately redirected, T cells can precisely eradicate tumors. Here we report the rational development of a fully-human bispecific antibody (hEGFRvIII-CD3 bi-scFv) that redirects human T cells to lyse MG expressing a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII). Experimental Design: We generated a panel of bispecific single-chain variable-fragments and optimized design through successive rounds of screening and refinement. We tested the ability of our lead construct to re-direct naïve T cells and induce target-cell specific lysis. To test for efficacy, we evaluated tumor growth and survival in xenogeneic and syngeneic models of glioma. Results: A highly-expressed bispecific antibody with specificity to CD3 and EGFRvIII was generated (hEGFRvIII-CD3 bi-scFv). Antibody-induced T cell activation, secretion of pro-inflammatory cytokines, and proliferation was robust and occurred exclusively in the presence of target antigen. hEGFRvIII-CD3 bi-scFv was potent and target-specific, mediating significant lysis of multiple MG cell lines and patient-derived MG samples. In both subcutaneous and orthotopic models, well-engrafted, patient-derived MG was effectively treated despite heterogeneity of EGFRvIII expression; intravenous hEGFRvIII-CD3 bi-scFv administration caused significant regression of tumor burden (p<0.0001) and significantly extended survival (p<0.0001). Similar efficacy was obtained in highly-infiltrative, syngeneic glioma models. Conclusions: We have developed a clinically-translatable bispecific antibody that redirects human T cells to safely and effectively treat MG. On the basis of these results, we have developed a clinical study of hEGFRvIII-CD3 bi-scFv for patients with EGFRvIII-positive MG.

https://ift.tt/2HUMJXr

New Insights from Studies of Clonal Hematopoiesis

Clonal hematopoiesis (CH) describes an asymptomatic expansion of blood cells descended from a single hematopoietic stem cell. Recent studies have shown that CH increases in frequency with aging, and is often driven by somatic mutations in genes that are recurrently mutated in hematologic malignancies. When CH is associated with a mutation in a leukemia-associated gene at a variant allele frequency of 0.02 or greater, it is termed "clonal hematopoiesis of indeterminate potential" (CHIP).  CHIP has a 0.5-1% risk per year of progression to hematological neoplasia, and increases both all-cause mortality and the risk of myocardial infarction and ischemic stroke due to a pro-inflammatory interaction between clonally-derived leukocytes and vascular endothelium. CH frequently emerges in the context of immune-mediated marrow failure syndromes such as aplastic anemia, while CH emerging after cytotoxic cancer therapy is strongly associated with subsequent development of a therapy-related myeloid neoplasm, especially if a TP53 mutation is present.  However, risk factors for developing CH other than aging, marrow failure, and cytotoxic radiotherapy or chemotherapy are poorly defined.  In this review, we discuss the epidemiology, molecular mechanisms, and clinical consequences of this common and clinically important biological state.

https://ift.tt/2Jyi1k5

Insulin-like growth factor 2 mRNA-binding protein 3 is a novel post-transcriptional regulator of Ewing sarcoma malignancy

Purpose: Large-scale sequencing studies have indicated that besides genomic alterations, the post-transcriptional regulation of gene expression or epigenetic mechanisms largely influences the clinical behavior of Ewing sarcoma (ES). We investigated the significance of the RNA-binding protein IGF2BP3 in the regulation of ES aggressiveness. Experimental Design: Explorative study was performed in 15 patients with localized ES using RNAseq. Next, 128 patients with localized ES were divided into two cohorts. In the training set, 29 ES samples were analyzed using Affymetrix GeneChip arrays. In the validation set, 99 ES samples were examined using qRT-PCR. Patient-derived cell lines and experimental models were used for functional studies.  Results: Univariate and multivariate analyses indicated IGF2BP3 as a potent indicator of poor prognosis. Furthermore, ABCF1 mRNA was identified as a novel partner of IGF2BP3. Functional studies indicated IGF2BP3 as an oncogenic driver and ABCF1 mRNA as a sponge that by binding IGF2BP3, partly repressed its functions. The combined evaluation of IGF2BP3 and ABCF1 could identify different patient outcomes-high IGF2BP3 and low ABCF1 levels indicated poor survival (25%), whereas low IGF2BP3 and high ABCF1 levels indicated favorable survival (85.5%). The bromodomain and extraterminal domain inhibitor (BETi) JQ1 decreased IGF2BP3 expression, modified the expression of its validated targets and inhibited the capability of ES cells to grow under anchorage-independent conditions.  Conclusions: The combined assessment of IGF2BP3 and ABCF1 predicts recurrence in ES patients. Thus, for patients with high expression of IGF2BP3 and poor probability of survival, the use of BETis should be clinically evaluated.

https://ift.tt/2HYQpaE

Paclitaxel Plasma Concentration After the First Infusion Predicts Treatment-Limiting Peripheral Neuropathy

Purpose: Paclitaxel exposure, specifically the maximum concentration (Cmax) and amount of time the concentration remains above 0.05 µM (Tc>0.05), have been associated with the occurrence of paclitaxel-induced peripheral neuropathy (PN). The objective of this study was to validate the relationship between paclitaxel exposure and PN.  Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m2 x 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of, and 16-26 hours after, the first infusion to estimate Cmax and Tc>0.05. Patient-reported PN was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with Tc>0.05. Secondary analyses were conducted using Cmax as an alternative exposure parameter and testing either parameter with a secondary endpoint of the occurrence of PN-induced treatment disruption.   Results: In the 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (p<0.05), but neither Tc>0.05 (p=0.27) nor Cmax (p=0.99). In analyses of the secondary endpoint, cumulative dose (odds ratio (OR)=1.46, 95% confidence interval (CI): 1.18-1.80, p=0.0008) and Tc>0.05 (OR=1.79, 95% CI: 1.06-3.01, p=0.029) or Cmax (OR=2.74, 95% CI: 1.45-5.20, p=0.002) were associated with PN-induced treatment disruption. Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting PN in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents PN in these patients. 

https://ift.tt/2JzQL4C

A rationally designed fully human EGFRvIII:CD3-targeted bispecific antibody redirects human T cells to treat patient-derived intracerebral malignant glioma

Purpose: Conventional therapy for malignant glioma (MG) fails to specifically target tumor cells. In contrast, substantial evidence indicates that if appropriately redirected, T cells can precisely eradicate tumors. Here we report the rational development of a fully-human bispecific antibody (hEGFRvIII-CD3 bi-scFv) that redirects human T cells to lyse MG expressing a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII). Experimental Design: We generated a panel of bispecific single-chain variable-fragments and optimized design through successive rounds of screening and refinement. We tested the ability of our lead construct to re-direct naïve T cells and induce target-cell specific lysis. To test for efficacy, we evaluated tumor growth and survival in xenogeneic and syngeneic models of glioma. Results: A highly-expressed bispecific antibody with specificity to CD3 and EGFRvIII was generated (hEGFRvIII-CD3 bi-scFv). Antibody-induced T cell activation, secretion of pro-inflammatory cytokines, and proliferation was robust and occurred exclusively in the presence of target antigen. hEGFRvIII-CD3 bi-scFv was potent and target-specific, mediating significant lysis of multiple MG cell lines and patient-derived MG samples. In both subcutaneous and orthotopic models, well-engrafted, patient-derived MG was effectively treated despite heterogeneity of EGFRvIII expression; intravenous hEGFRvIII-CD3 bi-scFv administration caused significant regression of tumor burden (p<0.0001) and significantly extended survival (p<0.0001). Similar efficacy was obtained in highly-infiltrative, syngeneic glioma models. Conclusions: We have developed a clinically-translatable bispecific antibody that redirects human T cells to safely and effectively treat MG. On the basis of these results, we have developed a clinical study of hEGFRvIII-CD3 bi-scFv for patients with EGFRvIII-positive MG.

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New Insights from Studies of Clonal Hematopoiesis

Clonal hematopoiesis (CH) describes an asymptomatic expansion of blood cells descended from a single hematopoietic stem cell. Recent studies have shown that CH increases in frequency with aging, and is often driven by somatic mutations in genes that are recurrently mutated in hematologic malignancies. When CH is associated with a mutation in a leukemia-associated gene at a variant allele frequency of 0.02 or greater, it is termed "clonal hematopoiesis of indeterminate potential" (CHIP).  CHIP has a 0.5-1% risk per year of progression to hematological neoplasia, and increases both all-cause mortality and the risk of myocardial infarction and ischemic stroke due to a pro-inflammatory interaction between clonally-derived leukocytes and vascular endothelium. CH frequently emerges in the context of immune-mediated marrow failure syndromes such as aplastic anemia, while CH emerging after cytotoxic cancer therapy is strongly associated with subsequent development of a therapy-related myeloid neoplasm, especially if a TP53 mutation is present.  However, risk factors for developing CH other than aging, marrow failure, and cytotoxic radiotherapy or chemotherapy are poorly defined.  In this review, we discuss the epidemiology, molecular mechanisms, and clinical consequences of this common and clinically important biological state.

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Insulin-like growth factor 2 mRNA-binding protein 3 is a novel post-transcriptional regulator of Ewing sarcoma malignancy

Purpose: Large-scale sequencing studies have indicated that besides genomic alterations, the post-transcriptional regulation of gene expression or epigenetic mechanisms largely influences the clinical behavior of Ewing sarcoma (ES). We investigated the significance of the RNA-binding protein IGF2BP3 in the regulation of ES aggressiveness. Experimental Design: Explorative study was performed in 15 patients with localized ES using RNAseq. Next, 128 patients with localized ES were divided into two cohorts. In the training set, 29 ES samples were analyzed using Affymetrix GeneChip arrays. In the validation set, 99 ES samples were examined using qRT-PCR. Patient-derived cell lines and experimental models were used for functional studies.  Results: Univariate and multivariate analyses indicated IGF2BP3 as a potent indicator of poor prognosis. Furthermore, ABCF1 mRNA was identified as a novel partner of IGF2BP3. Functional studies indicated IGF2BP3 as an oncogenic driver and ABCF1 mRNA as a sponge that by binding IGF2BP3, partly repressed its functions. The combined evaluation of IGF2BP3 and ABCF1 could identify different patient outcomes-high IGF2BP3 and low ABCF1 levels indicated poor survival (25%), whereas low IGF2BP3 and high ABCF1 levels indicated favorable survival (85.5%). The bromodomain and extraterminal domain inhibitor (BETi) JQ1 decreased IGF2BP3 expression, modified the expression of its validated targets and inhibited the capability of ES cells to grow under anchorage-independent conditions.  Conclusions: The combined assessment of IGF2BP3 and ABCF1 predicts recurrence in ES patients. Thus, for patients with high expression of IGF2BP3 and poor probability of survival, the use of BETis should be clinically evaluated.

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Paclitaxel Plasma Concentration After the First Infusion Predicts Treatment-Limiting Peripheral Neuropathy

Purpose: Paclitaxel exposure, specifically the maximum concentration (Cmax) and amount of time the concentration remains above 0.05 µM (Tc>0.05), have been associated with the occurrence of paclitaxel-induced peripheral neuropathy (PN). The objective of this study was to validate the relationship between paclitaxel exposure and PN.  Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m2 x 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of, and 16-26 hours after, the first infusion to estimate Cmax and Tc>0.05. Patient-reported PN was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with Tc>0.05. Secondary analyses were conducted using Cmax as an alternative exposure parameter and testing either parameter with a secondary endpoint of the occurrence of PN-induced treatment disruption.   Results: In the 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (p<0.05), but neither Tc>0.05 (p=0.27) nor Cmax (p=0.99). In analyses of the secondary endpoint, cumulative dose (odds ratio (OR)=1.46, 95% confidence interval (CI): 1.18-1.80, p=0.0008) and Tc>0.05 (OR=1.79, 95% CI: 1.06-3.01, p=0.029) or Cmax (OR=2.74, 95% CI: 1.45-5.20, p=0.002) were associated with PN-induced treatment disruption. Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting PN in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents PN in these patients. 

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Comparison of Hematologic and Other Prognostic Markers in Metastatic Colorectal Cancer

Abstract

Background

Associations of thrombocytosis, neutrophilia, and lymphopenia with prognosis have been confirmed in many cancers. This study aims at comparing various prognostic indices based on blood counts in metastatic colorectal adenocarcinomas.

Patients and Methods

Records from 152 patients with metastatic colorectal cancer who were treated in our center were reviewed. Demographic and disease characteristics and hematologic parameters data were extracted and patients were stratified according to their scores of several hematologic ratios. Hematologic ratios and parameters considered included the platelet-neutrophil to lymphocyte ratio (PNLR), the platelet to lymphocyte ratio (PLR), the neutrophil to lymphocyte ratio (NLR), the Abnormal Hematological Markers Index (AHMI), and the neutrophil-platelet score (NPS). Optimal cutoffs were defined with the aid of an online tool. Baseline parameters of the two groups derived for each tool were evaluated and compared with the χ² test. Univariate and multivariate Cox proportional-hazards regression analyses were performed on variables of interest.

Results

Progression-Free Survival (PFS) hazard ratios (HR) between the high-risk and low-risk groups derived from the multivariate analyses for each index were as follows: for PNLR 2.0 (95% CI 1.28–3.13), for PLR 1.74 (95% CI 1.13–2.67), for NLR 1.54 (95% CI 1.04–2.29), for AHMI 1.62 (95% CI 1.06–2.46), and for NPS 1.47 (95% CI 1.1–1.96). Overall Survival (OS) hazard ratios (HR) derived from the multivariate analyses for each index were as follows: for PNLR 2.23 (95% CI 1.36–3.66), for PLR 1.68 (95% CI 1.03–2.75), for NLR 1.62 (95% CI 1.06–2.49), for AHMI 1.7 (95% CI 1.07–2.69), and for NPS 1.53 (95% CI 1.11–2.11). Another prognostic index called PRONOPALL, which is based on ECOG PS (0–1 versus 2–3 versus 4), number of metastatic sites (≤ 1 versus ≥ 2), LDH (< 600 U/L versus ≥ 600 U/L), and albumin (≥ 33 g/L versus < 33 g/L), had HRs of 1.75 and 2.20 for PFS and OS, respectively, with a cutoff of < 4 versus ≥ 4. This score has a range of 0 to 10 and points are attributed for the presence of each of the four prognostic factors.

Conclusion

In this analysis of metastatic colorectal cancer patients, several ratios and other prognostic tools had prognostic value for both OS and PFS. While other variables held significance for poorer prognosis, PNLR had the highest HR and the highest significance in multivariate analysis for both PFS and OS. Thus, it represents a valid prognostic tool in metastatic colorectal cancer among the spectrum of hematologic parameter-constructed tools.

https://ift.tt/2JxHWbG

Comparison of Hematologic and Other Prognostic Markers in Metastatic Colorectal Cancer

Abstract

Background

Associations of thrombocytosis, neutrophilia, and lymphopenia with prognosis have been confirmed in many cancers. This study aims at comparing various prognostic indices based on blood counts in metastatic colorectal adenocarcinomas.

Patients and Methods

Records from 152 patients with metastatic colorectal cancer who were treated in our center were reviewed. Demographic and disease characteristics and hematologic parameters data were extracted and patients were stratified according to their scores of several hematologic ratios. Hematologic ratios and parameters considered included the platelet-neutrophil to lymphocyte ratio (PNLR), the platelet to lymphocyte ratio (PLR), the neutrophil to lymphocyte ratio (NLR), the Abnormal Hematological Markers Index (AHMI), and the neutrophil-platelet score (NPS). Optimal cutoffs were defined with the aid of an online tool. Baseline parameters of the two groups derived for each tool were evaluated and compared with the χ² test. Univariate and multivariate Cox proportional-hazards regression analyses were performed on variables of interest.

Results

Progression-Free Survival (PFS) hazard ratios (HR) between the high-risk and low-risk groups derived from the multivariate analyses for each index were as follows: for PNLR 2.0 (95% CI 1.28–3.13), for PLR 1.74 (95% CI 1.13–2.67), for NLR 1.54 (95% CI 1.04–2.29), for AHMI 1.62 (95% CI 1.06–2.46), and for NPS 1.47 (95% CI 1.1–1.96). Overall Survival (OS) hazard ratios (HR) derived from the multivariate analyses for each index were as follows: for PNLR 2.23 (95% CI 1.36–3.66), for PLR 1.68 (95% CI 1.03–2.75), for NLR 1.62 (95% CI 1.06–2.49), for AHMI 1.7 (95% CI 1.07–2.69), and for NPS 1.53 (95% CI 1.11–2.11). Another prognostic index called PRONOPALL, which is based on ECOG PS (0–1 versus 2–3 versus 4), number of metastatic sites (≤ 1 versus ≥ 2), LDH (< 600 U/L versus ≥ 600 U/L), and albumin (≥ 33 g/L versus < 33 g/L), had HRs of 1.75 and 2.20 for PFS and OS, respectively, with a cutoff of < 4 versus ≥ 4. This score has a range of 0 to 10 and points are attributed for the presence of each of the four prognostic factors.

Conclusion

In this analysis of metastatic colorectal cancer patients, several ratios and other prognostic tools had prognostic value for both OS and PFS. While other variables held significance for poorer prognosis, PNLR had the highest HR and the highest significance in multivariate analysis for both PFS and OS. Thus, it represents a valid prognostic tool in metastatic colorectal cancer among the spectrum of hematologic parameter-constructed tools.

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Germline IKZF1 Variants Predispose Children to Developing B-ALL [Research Watch]

Germline DNA sequencing of 4,963 B-ALLs identified 28 IKZF1 variants, with 22 determined to be damaging.

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Single-Cell RNA Sequencing Reveals H3K27M Glioma Oncogenic Programs [Research Watch]

H3K27M⁺ gliomas display a unique oncogenic program and are driven by OPC-like glioma cells.

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Neoadjuvant Endpoints, Response Criteria Proposed [News in Brief]

Profusion of preoperative lung cancer trials prompts specialists to reconsider metrics of evaluation.

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SAMHD1 Mutations Disrupt Replication Fork Progression to Induce IFN [Research Watch]

SAMHD1 activates MRE11 exonuclease activity to prevent release of ssDNA from stalled replication forks.

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Everolimus Enhances the Efficacy of Fulvestrant in ER+ Breast Cancer [Research Watch]

mTOR inhibition with everolimus extends progression-free survival in combination with fulvestrant.

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Blinatumomab Approval Expanded Based on MRD [News in Brief]

The decision marks the first time the agency has approved an ALL drug using minimal residual disease as an endpoint.

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Anti-GD2 CAR T Cells Are Potent in H3-K27M+ Diffuse Midline Gliomas [Research Watch]

The disialoganglioside GD2 is an immunotherapeutic target in H3-K27M⁺ diffuse midline gliomas.

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MYD88 L265P Mutation in Lymphoid Malignancies

Next-generation sequencing has revealed cancer genomic landscapes, in which over 100 driver genes that, when altered by intragenic mutations, can promote oncogenesis. MYD88 is a driver gene found in hematologic B-cell malignancies. A missense mutation (L265P) changing leucine at position 265 to proline in MYD88 is found in ∼90% of Waldenström macroglobulinemia (WM) cases and in significant portions of activated B-cell diffuse large B-cell lymphomas and IgM monoclonal gammopathy of undetermined significance. Few cancers such as WM have a single amino acid substitution in one gene like MYD88 L265P that occurs in ∼90% of cases, making WM paradigmatic for study of a single causative mutation in oncogenesis. In this review, we summarize the frequency and cancer spectrum of MYD88 L265P and its downstream effects in lymphoid cancers. Malignant B cells with MYD88 L265P are likely transformed from IgM-producing B cells either in response to T-cell–independent antigens or in response to protein antigens before class switching. We also discuss therapeutic strategies that include targeting Bruton tyrosine kinase and other kinases, interfering with the assembly of MYD88 and its interacting partners, and MYD88 L265P-specific peptide-based immunotherapy. Cancer Res; 78(10); 1–6. ©2018 AACR.

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Bcl-2 Protein Targeting by the p53/p21 Complex—Letter

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Bcl-2 Protein Targeting by the p53/p21 Complex—Response

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From MGUS to Multiple Myeloma, a Paradigm for Clonal Evolution of Premalignant Cells

Multiple myeloma (MM) is a treatable, but incurable, malignancy of plasma cells (PC) in the bone marrow (BM). It represents the final stage in a continuum of PC dyscrasias and is consistently preceded by a premalignant phase termed monoclonal gammopathy of undetermined significance (MGUS). The existence of this well-defined premalignant phase provides the opportunity to study clonal evolution of a premalignant condition into overt cancer. Unraveling the mechanisms of malignant transformation of PC could enable early identification of MGUS patients at high risk of progression and may point to novel therapeutic targets, thereby possibly delaying or preventing malignant transformation. The MGUS-to-MM progression requires multiple genomic events and the establishment of a permissive BM microenvironment, although it is generally not clear if the various microenvironmental events are causes or consequences of disease progression. Advances in gene-sequencing techniques and the use of serial paired analyses have allowed for a more specific identification of driver lesions. The challenge in cancer biology is to identify and target those lesions that confer selective advantage and thereby drive evolution of a premalignant clone. Here, we review recent advances in the understanding of malignant transformation of MGUS to MM. Cancer Res; 78(10); 1–8. ©2018 AACR.

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Sialic acid blockade suppresses tumor growth by enhancing T cell-mediated tumor immunity

Sialic acid sugars on the surface of cancer cells have emerged as potent immune modulators that contribute to the immunosuppressive microenvironment and tumor immune evasion. However, the mechanisms by which these sugars modulate anti-tumor immunity as well as therapeutic strategies directed against them are limited. Here we report that intratumoral injections with a sialic acid mimetic Ac53FaxNeu5Ac blocks tumor sialic acid expression in vivo and suppresses tumor growth in multiple tumor models. Sialic acid blockade had a major impact on the immune cell composition of the tumor, enhancing tumor-infiltrating natural killer cell and CD8+ T cell numbers while reducing regulatory T cell and myeloid regulatory cell numbers. Sialic acid blockade enhanced cytotoxic CD8+ T cell-mediated killing of tumor cells in part by facilitating antigen specific T cell-tumor cell clustering. Sialic acid blockade also synergized with adoptive transfer of tumor-specific CD8+ T cells in vivo and enhanced CpG immune adjuvant therapy by increasing dendritic cell activation and subsequent CD8+ T cell responses. Collectively, these data emphasize the crucial role of sialic acids in tumor immune evasion and provide proof of concept that sialic acid blockade creates an immune-permissive tumor microenvironment for CD8+ T cell-mediated tumor immunity, either as single treatment or in combination with other immune-based intervention strategies.

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MYD88 L265P Mutation in Lymphoid Malignancies

Next-generation sequencing has revealed cancer genomic landscapes, in which over 100 driver genes that, when altered by intragenic mutations, can promote oncogenesis. MYD88 is a driver gene found in hematologic B-cell malignancies. A missense mutation (L265P) changing leucine at position 265 to proline in MYD88 is found in ∼90% of Waldenström macroglobulinemia (WM) cases and in significant portions of activated B-cell diffuse large B-cell lymphomas and IgM monoclonal gammopathy of undetermined significance. Few cancers such as WM have a single amino acid substitution in one gene like MYD88 L265P that occurs in ∼90% of cases, making WM paradigmatic for study of a single causative mutation in oncogenesis. In this review, we summarize the frequency and cancer spectrum of MYD88 L265P and its downstream effects in lymphoid cancers. Malignant B cells with MYD88 L265P are likely transformed from IgM-producing B cells either in response to T-cell–independent antigens or in response to protein antigens before class switching. We also discuss therapeutic strategies that include targeting Bruton tyrosine kinase and other kinases, interfering with the assembly of MYD88 and its interacting partners, and MYD88 L265P-specific peptide-based immunotherapy. Cancer Res; 78(10); 1–6. ©2018 AACR.

https://ift.tt/2r51QmU

Bcl-2 Protein Targeting by the p53/p21 Complex—Letter

https://ift.tt/2HvSU53

Bcl-2 Protein Targeting by the p53/p21 Complex—Response

https://ift.tt/2r6pRdk

From MGUS to Multiple Myeloma, a Paradigm for Clonal Evolution of Premalignant Cells

Multiple myeloma (MM) is a treatable, but incurable, malignancy of plasma cells (PC) in the bone marrow (BM). It represents the final stage in a continuum of PC dyscrasias and is consistently preceded by a premalignant phase termed monoclonal gammopathy of undetermined significance (MGUS). The existence of this well-defined premalignant phase provides the opportunity to study clonal evolution of a premalignant condition into overt cancer. Unraveling the mechanisms of malignant transformation of PC could enable early identification of MGUS patients at high risk of progression and may point to novel therapeutic targets, thereby possibly delaying or preventing malignant transformation. The MGUS-to-MM progression requires multiple genomic events and the establishment of a permissive BM microenvironment, although it is generally not clear if the various microenvironmental events are causes or consequences of disease progression. Advances in gene-sequencing techniques and the use of serial paired analyses have allowed for a more specific identification of driver lesions. The challenge in cancer biology is to identify and target those lesions that confer selective advantage and thereby drive evolution of a premalignant clone. Here, we review recent advances in the understanding of malignant transformation of MGUS to MM. Cancer Res; 78(10); 1–8. ©2018 AACR.

https://ift.tt/2HvSM5z

Sialic acid blockade suppresses tumor growth by enhancing T cell-mediated tumor immunity

Sialic acid sugars on the surface of cancer cells have emerged as potent immune modulators that contribute to the immunosuppressive microenvironment and tumor immune evasion. However, the mechanisms by which these sugars modulate anti-tumor immunity as well as therapeutic strategies directed against them are limited. Here we report that intratumoral injections with a sialic acid mimetic Ac53FaxNeu5Ac blocks tumor sialic acid expression in vivo and suppresses tumor growth in multiple tumor models. Sialic acid blockade had a major impact on the immune cell composition of the tumor, enhancing tumor-infiltrating natural killer cell and CD8+ T cell numbers while reducing regulatory T cell and myeloid regulatory cell numbers. Sialic acid blockade enhanced cytotoxic CD8+ T cell-mediated killing of tumor cells in part by facilitating antigen specific T cell-tumor cell clustering. Sialic acid blockade also synergized with adoptive transfer of tumor-specific CD8+ T cells in vivo and enhanced CpG immune adjuvant therapy by increasing dendritic cell activation and subsequent CD8+ T cell responses. Collectively, these data emphasize the crucial role of sialic acids in tumor immune evasion and provide proof of concept that sialic acid blockade creates an immune-permissive tumor microenvironment for CD8+ T cell-mediated tumor immunity, either as single treatment or in combination with other immune-based intervention strategies.

https://ift.tt/2r4n7x5

Platinum-based neoadjuvant chemotherapy in BRCA1-positive breast cancer: a retrospective cohort analysis and literature review

Abstract

Background

There is increasing evidence of high platinum sensitivity in BRCA-associated breast cancer. However, evidence from randomized trials is lacking. The aim of this study was to analyze the results of platinum-based chemotherapy for BRCA1-positive breast cancer in a neoadjuvant setting.

Methods

A retrospective study was performed by obtaining information from patient files. The results were compared with the available data from a literature review.

Results

Twelve female patients with BRCA1 gene mutations who had stage I to III breast cancers were eligible for evaluation. They received platinum-based neoadjuvant chemotherapy between 2011 and 2016. Eleven patients received a combination of cisplatin and doxorubicin, and one patient received carboplatin and docetaxel. All patients underwent mastectomy after chemotherapy. Ten patients (83%) achieved pathological complete remission (pCR). The observed pCR rate was comparable to existing results found in similar studies.

Conclusion

The results of the study confirm the high pCR rate in BRCA1-positive breast cancer after platinum-based neoadjuvant chemotherapy. Larger randomized studies and longer follow-up times are necessary to evaluate the role of platinum-based therapies in BRCA1-positive breast cancer.

https://ift.tt/2FnrIj4

Platinum-based neoadjuvant chemotherapy in BRCA1-positive breast cancer: a retrospective cohort analysis and literature review

Abstract

Background

There is increasing evidence of high platinum sensitivity in BRCA-associated breast cancer. However, evidence from randomized trials is lacking. The aim of this study was to analyze the results of platinum-based chemotherapy for BRCA1-positive breast cancer in a neoadjuvant setting.

Methods

A retrospective study was performed by obtaining information from patient files. The results were compared with the available data from a literature review.

Results

Twelve female patients with BRCA1 gene mutations who had stage I to III breast cancers were eligible for evaluation. They received platinum-based neoadjuvant chemotherapy between 2011 and 2016. Eleven patients received a combination of cisplatin and doxorubicin, and one patient received carboplatin and docetaxel. All patients underwent mastectomy after chemotherapy. Ten patients (83%) achieved pathological complete remission (pCR). The observed pCR rate was comparable to existing results found in similar studies.

Conclusion

The results of the study confirm the high pCR rate in BRCA1-positive breast cancer after platinum-based neoadjuvant chemotherapy. Larger randomized studies and longer follow-up times are necessary to evaluate the role of platinum-based therapies in BRCA1-positive breast cancer.

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MKAD-21 suppresses the oncogenic activity of the miR-21/PPP2R2A/ERK molecular network in bladder cancer

Bladder cancer (BC) represents a disease associated with significant morbidity and mortality. MicroRNA-21 (MiR-21) has been found to have oncogenic activity in multiple cancers, including BC, while inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in BC and evaluate the effects of intravenous (I.V.) and intraperitoneal (I.P.) administration of a novel miR-21 chemical inhibitor in vivo. LNA miR-21 reduced the oncogenic potential of BC cells, while the MKAD-21 chemically-modified antisense oligo against miR-21, dose-dependently blocked xenograft growth. I.V. administration of LNA miR-21 was more effective in suppressing tumor growth than was I.P. administration. Integration of computational and transcriptomic analyses in a panel of 28 BC lines revealed a 15-gene signature that correlates with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit Balpha (PPP2R2A) was one of these 15 genes and was experimentally validated as a novel miR-21 direct target gene. Gene network and molecular analyses showed that PPP2R2A is a potent negative regulator of the ERK pathway activation and BC cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21-induced oncogenic effects in BC. Integrative analysis of human BC tumors and a large panel of human BC cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. Importantly, we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and BC cell growth. Furthermore, I.V. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A-ERK network in mice.

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Targeting the proteasome-associated deubiquitinating enzyme USP14 impairs melanoma cell survival and overcomes resistance to MAPK-targeting therapies

Advanced cutaneous melanoma is one of the most challenging cancers to treat because of its high plasticity, metastatic potential and resistance to treatment. New targeted therapies and immunotherapies have shown remarkable clinical efficacy. However, such treatments are limited to a subset of patients and relapses often occur, warranting validation of novel targeted therapies. Post-translational modification of proteins by ubiquitin coordinates essential cellular functions, including ubiquitin-proteasome system (UPS) function and protein homeostasis. Deubiquitinating enzymes (DUBs) have been associated to multiple diseases, including cancer. However, their exact involvement in melanoma development and therapeutic resistance remains poorly understood. Using a DUB trap assay to label cellular active DUBs, we have observed an increased activity of the proteasome-associated DUB, USP14 (Ubiquitin-specific peptidase 14) in melanoma cells compared to melanocytes. Our survey of public gene expression databases indicates that high expression of USP14 correlates with melanoma progression and with a poorer survival rate in metastatic melanoma patients. Knockdown or pharmacological inhibition of USP14 dramatically impairs viability of melanoma cells irrespective of the mutational status of BRAF, NRAS or TP53 and their transcriptional cell state, and overcomes resistance to MAPK-targeting therapies both in vitro and in human melanoma xenografted mice. At the molecular level, we find that inhibition of USP14 rapidly triggers accumulation of poly-ubiquitinated proteins and chaperones, mitochondrial dysfunction, ER stress, and a ROS production leading to a caspase-independent cell death. Our results provide a rationale for targeting the proteasome-associated DUB USP14 to treat and combat melanomas.

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A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model

Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system-activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only re-challenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd up-regulated CD86 expression on bone marrow-derived DCs in vitro, and that DS-8201a increased tumor-infiltrating DCs and up-regulated their CD86 expression in vivo. DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti-PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of re-challenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti-PD-1 antibody, possibly due to increased T cell activity and up-regulated PD-L1 expression induced by DS-8201a.

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MKAD-21 suppresses the oncogenic activity of the miR-21/PPP2R2A/ERK molecular network in bladder cancer

Bladder cancer (BC) represents a disease associated with significant morbidity and mortality. MicroRNA-21 (MiR-21) has been found to have oncogenic activity in multiple cancers, including BC, while inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in BC and evaluate the effects of intravenous (I.V.) and intraperitoneal (I.P.) administration of a novel miR-21 chemical inhibitor in vivo. LNA miR-21 reduced the oncogenic potential of BC cells, while the MKAD-21 chemically-modified antisense oligo against miR-21, dose-dependently blocked xenograft growth. I.V. administration of LNA miR-21 was more effective in suppressing tumor growth than was I.P. administration. Integration of computational and transcriptomic analyses in a panel of 28 BC lines revealed a 15-gene signature that correlates with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit Balpha (PPP2R2A) was one of these 15 genes and was experimentally validated as a novel miR-21 direct target gene. Gene network and molecular analyses showed that PPP2R2A is a potent negative regulator of the ERK pathway activation and BC cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21-induced oncogenic effects in BC. Integrative analysis of human BC tumors and a large panel of human BC cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. Importantly, we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and BC cell growth. Furthermore, I.V. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A-ERK network in mice.

https://ift.tt/2vPVv4l

Targeting the proteasome-associated deubiquitinating enzyme USP14 impairs melanoma cell survival and overcomes resistance to MAPK-targeting therapies

Advanced cutaneous melanoma is one of the most challenging cancers to treat because of its high plasticity, metastatic potential and resistance to treatment. New targeted therapies and immunotherapies have shown remarkable clinical efficacy. However, such treatments are limited to a subset of patients and relapses often occur, warranting validation of novel targeted therapies. Post-translational modification of proteins by ubiquitin coordinates essential cellular functions, including ubiquitin-proteasome system (UPS) function and protein homeostasis. Deubiquitinating enzymes (DUBs) have been associated to multiple diseases, including cancer. However, their exact involvement in melanoma development and therapeutic resistance remains poorly understood. Using a DUB trap assay to label cellular active DUBs, we have observed an increased activity of the proteasome-associated DUB, USP14 (Ubiquitin-specific peptidase 14) in melanoma cells compared to melanocytes. Our survey of public gene expression databases indicates that high expression of USP14 correlates with melanoma progression and with a poorer survival rate in metastatic melanoma patients. Knockdown or pharmacological inhibition of USP14 dramatically impairs viability of melanoma cells irrespective of the mutational status of BRAF, NRAS or TP53 and their transcriptional cell state, and overcomes resistance to MAPK-targeting therapies both in vitro and in human melanoma xenografted mice. At the molecular level, we find that inhibition of USP14 rapidly triggers accumulation of poly-ubiquitinated proteins and chaperones, mitochondrial dysfunction, ER stress, and a ROS production leading to a caspase-independent cell death. Our results provide a rationale for targeting the proteasome-associated DUB USP14 to treat and combat melanomas.

https://ift.tt/2jfozJo

A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model

Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system-activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only re-challenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd up-regulated CD86 expression on bone marrow-derived DCs in vitro, and that DS-8201a increased tumor-infiltrating DCs and up-regulated their CD86 expression in vivo. DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti-PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of re-challenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti-PD-1 antibody, possibly due to increased T cell activity and up-regulated PD-L1 expression induced by DS-8201a.

https://ift.tt/2vPVhdv

Telomerase regulation by the long non-coding RNA H19 in human acute promyelocytic leukemia cells

Abstract

Background

Since tumor growth requires reactivation of telomerase (hTERT), this enzyme is a challenging target for drug development. Therefore, it is of great interest to identify telomerase expression and activity regulators. Retinoids are well-known inducers of granulocytic maturation associated with hTERT repression in acute promyelocytic leukemia (APL) blasts. In a maturation-resistant APL cell line, we have previously identified a new pathway of retinoid-induced hTERT transcriptional repression independent of differentiation. Furthermore, we reported the isolation of a cell variant resistant to this repression. Those cell lines could serve as unique tools to identify new telomerase regulators.

Methods

Using a microarray approach we identified the long non-coding RNA, H19 as a potential candidate playing a role in telomerase regulation. Expression of H19, hTERT, and hTR were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Telomerase activity was quantified by quantitative telomeric repeats amplification protocol (qTRAP). In vitro and in vivo assays were performed to investigate H19 function on telomerase expression and activity.

Results

We showed both in retinoid-treated cell lines and in APL patient cells an inverse relationship between the expression of H19 and the expression and activity of hTERT. Exploring the mechanistic link between H19 and hTERT regulation, we showed that H19 is able to impede telomerase function by disruption of the hTERT-hTR interaction.

Conclusions

This study identifies a new way of telomerase regulation through H19's involvement and thereby reveals a new function for this long non-coding RNA that can be targeted for therapeutic purpose.

https://ift.tt/2HX2mhe

Telomerase regulation by the long non-coding RNA H19 in human acute promyelocytic leukemia cells

Abstract

Background

Since tumor growth requires reactivation of telomerase (hTERT), this enzyme is a challenging target for drug development. Therefore, it is of great interest to identify telomerase expression and activity regulators. Retinoids are well-known inducers of granulocytic maturation associated with hTERT repression in acute promyelocytic leukemia (APL) blasts. In a maturation-resistant APL cell line, we have previously identified a new pathway of retinoid-induced hTERT transcriptional repression independent of differentiation. Furthermore, we reported the isolation of a cell variant resistant to this repression. Those cell lines could serve as unique tools to identify new telomerase regulators.

Methods

Using a microarray approach we identified the long non-coding RNA, H19 as a potential candidate playing a role in telomerase regulation. Expression of H19, hTERT, and hTR were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Telomerase activity was quantified by quantitative telomeric repeats amplification protocol (qTRAP). In vitro and in vivo assays were performed to investigate H19 function on telomerase expression and activity.

Results

We showed both in retinoid-treated cell lines and in APL patient cells an inverse relationship between the expression of H19 and the expression and activity of hTERT. Exploring the mechanistic link between H19 and hTERT regulation, we showed that H19 is able to impede telomerase function by disruption of the hTERT-hTR interaction.

Conclusions

This study identifies a new way of telomerase regulation through H19's involvement and thereby reveals a new function for this long non-coding RNA that can be targeted for therapeutic purpose.

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A secondary analysis of FDG spatio-temporal consistency in the randomized phase II PET-boost trial in stage II–III NSCLC

FDG-PET scans have shown spatial consistency in NSCLC patients before and following chemoradiotherapy, implying radioresistance. We hypothesized that patients, who received FDG-PET redistributed dose painting, would demonstrate reduced spatial consistency when compared to registered patients or to escalated dose treatment.

https://ift.tt/2Kl3vNJ

In reply to “A Long-Awaited Guideline for the Delineation of Primary Tumor in Head and Neck Cancer, and a Few Concerns about It” by Sezin Yuce Sari et al.

We would like to thank Dr Sezin Yuce Sari and his colleagues for their interest and comments on our recent publication on Clinical Target Volume (CTV) delineation for primary Head & Neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx and larynx [1]. To avoid any misunderstanding and/or misinterpretation of our recent guidelines, we would like to reply point by point to their criticism.

https://ift.tt/2Fnzeu5

Surgical results of laparoscopic Toupet fundoplication for gastroesophageal reflux disease with special reference to recurrence

Abstract

Background

Surgical results of GERD have mainly been reported from the Western countries, with a few reports found in Japan. We examined the surgical results of laparoscopic Toupet fundoplication and clarify the characteristics of recurrent cases.

Methods

The subjects included 375 patients who underwent laparoscopic Toupet fundoplication from June 1997 to December 2016 as the initial surgery. Patient characteristics, pathophysiology, and surgical results were examined. In addition, we compared the patient characteristics and pathophysiology of recurrent cases in comparison with non-recurrent cases.

Results

Age 59 (43–70) and male 211 (56.3%). The operation time was 141 min (113–180) and intraoperative complications were found to have onset in 13 subjects (3.5%). Dysphagia after surgery was found in 18 cases (4.8%). The A factor (the degree of hiatal hernia), P factor (the degree of esophagitis), and pH < 4 holding time significantly improved after surgery compared with prior to surgery (p < 0.001 for all), while the LES lengths and abdominal LES lengths were extended (p < 0.001 for each). Recurrence was found in 48 patients (15.1%) among the 318 patients for whom we could confirm the presence or absence of recurrence. The A factor, P factor, and pH < 4 holding time prior to surgery were, respectively, higher in the recurrence group (p = 0.031, p < 0.001, p < 0.001).

Conclusions

Laparoscopic Toupet fundoplication for GERD could be performed safely, with a response rate as good as 85%. Compared with non-recurrent cases, preoperative clinical conditions such as esophageal hiatal hernia, reflux esophagitis, and acid reflux time were all advanced in recurrent cases.

https://ift.tt/2r2pt06

Surgical results of laparoscopic Toupet fundoplication for gastroesophageal reflux disease with special reference to recurrence

Abstract

Background

Surgical results of GERD have mainly been reported from the Western countries, with a few reports found in Japan. We examined the surgical results of laparoscopic Toupet fundoplication and clarify the characteristics of recurrent cases.

Methods

The subjects included 375 patients who underwent laparoscopic Toupet fundoplication from June 1997 to December 2016 as the initial surgery. Patient characteristics, pathophysiology, and surgical results were examined. In addition, we compared the patient characteristics and pathophysiology of recurrent cases in comparison with non-recurrent cases.

Results

Age 59 (43–70) and male 211 (56.3%). The operation time was 141 min (113–180) and intraoperative complications were found to have onset in 13 subjects (3.5%). Dysphagia after surgery was found in 18 cases (4.8%). The A factor (the degree of hiatal hernia), P factor (the degree of esophagitis), and pH < 4 holding time significantly improved after surgery compared with prior to surgery (p < 0.001 for all), while the LES lengths and abdominal LES lengths were extended (p < 0.001 for each). Recurrence was found in 48 patients (15.1%) among the 318 patients for whom we could confirm the presence or absence of recurrence. The A factor, P factor, and pH < 4 holding time prior to surgery were, respectively, higher in the recurrence group (p = 0.031, p < 0.001, p < 0.001).

Conclusions

Laparoscopic Toupet fundoplication for GERD could be performed safely, with a response rate as good as 85%. Compared with non-recurrent cases, preoperative clinical conditions such as esophageal hiatal hernia, reflux esophagitis, and acid reflux time were all advanced in recurrent cases.

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Immunotherapy Drugs Expand Treatment Options for Advanced Lung Cancer

Results from a large clinical trial show combining an immune checkpoint inhibitor with chemotherapy helped some patients with advanced lung cancer live longer than chemotherapy alone. How will this change the lung cancer treatment landscape?

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Type 1 Papillary Renal Cell Carcinoma Presenting as an Infected Benign Renal Cyst: an Uncommon Presentation

Abstract

We describe an unusual presentation of papillary renal cell carcinoma in a 40-year old male where radiological evaluation revealed a Bosniak type 2 cyst (probably benign), and clinical signs as well as symptoms also suggested an infected cyst l. However, on histopathological examination, an intra cystic type 1 papillary renal cell carcinoma was diagnosed. This is an extremely rare presentation of papillary renal cell carcinoma because it usually present as a heterogenous mass. Hence, even the radiologically benign cyst should be evaluated and managed cautiously.

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Immunotherapy Drugs Expand Treatment Options for Advanced Lung Cancer

Results from a large clinical trial show combining an immune checkpoint inhibitor with chemotherapy helped some patients with advanced lung cancer live longer than chemotherapy alone. How will this change the lung cancer treatment landscape?

https://ift.tt/2vUsIeY

Type 1 Papillary Renal Cell Carcinoma Presenting as an Infected Benign Renal Cyst: an Uncommon Presentation

Abstract

We describe an unusual presentation of papillary renal cell carcinoma in a 40-year old male where radiological evaluation revealed a Bosniak type 2 cyst (probably benign), and clinical signs as well as symptoms also suggested an infected cyst l. However, on histopathological examination, an intra cystic type 1 papillary renal cell carcinoma was diagnosed. This is an extremely rare presentation of papillary renal cell carcinoma because it usually present as a heterogenous mass. Hence, even the radiologically benign cyst should be evaluated and managed cautiously.

https://ift.tt/2HAtz5V

Antidepressant and anxiolytic like effects of Urtica dioica leaves in streptozotocin induced diabetic mice

Abstract

The present study was aimed to investigate the effect of Urtica dioica Linn. (UD) extract against chronic diabetes mediated anxiogenic and depressive like behavior in mice. Streptozotocin (STZ) (50 mg/kg, i.p.) for 5 consecutive days was used to induce diabetes followed by treatment with UD leaves extract (50 mg/kg, p.o.) and rosiglitazone (ROSI) (5 mg/kg, p.o.) for 8 weeks. STZ induced chronic diabetes significantly induced anxiety and depressive like behavior in mice. Chronic diabetes significantly downregulated BDNF (p < 0.001), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.05) and autophagy7 (p < 0.001), while upregulated iNOS (p < 0.05) mRNA expression in the hippocampus as compared to control mice. In addition, chronic diabetes significantly increased the expression of TNF-α in CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of hippocampus as compared to control mice. Chronic diabetes mediated neuronal damage in the CA2, CA3 and DG regions of hippocampus. Chronic administration of UD leaves extract significantly reversed diabetes mediated anxiogenic and depressive like behavior in mice. Further, UD treatment significantly upregulated BDNF (p < 0.01), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.01), autophagy5 (p < 0.01) and autophagy7 (p < 0.001), while downregulated iNOS (p < 0.05) mRNA expression in the hippocampus of diabetic mice. Concomitantly, UD administration significantly decreased the expression of TNF-α in hippocampal CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of diabetic mice. Diabetes mediated neuronal damage and DNA fragmentation in the hippocampus was substantially attenuated following UD treatment. UD leaves extract might prove to be effective for diabetes mediated anxiety and depressive like behavior.

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Antidepressant and anxiolytic like effects of Urtica dioica leaves in streptozotocin induced diabetic mice

Abstract

The present study was aimed to investigate the effect of Urtica dioica Linn. (UD) extract against chronic diabetes mediated anxiogenic and depressive like behavior in mice. Streptozotocin (STZ) (50 mg/kg, i.p.) for 5 consecutive days was used to induce diabetes followed by treatment with UD leaves extract (50 mg/kg, p.o.) and rosiglitazone (ROSI) (5 mg/kg, p.o.) for 8 weeks. STZ induced chronic diabetes significantly induced anxiety and depressive like behavior in mice. Chronic diabetes significantly downregulated BDNF (p < 0.001), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.05) and autophagy7 (p < 0.001), while upregulated iNOS (p < 0.05) mRNA expression in the hippocampus as compared to control mice. In addition, chronic diabetes significantly increased the expression of TNF-α in CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of hippocampus as compared to control mice. Chronic diabetes mediated neuronal damage in the CA2, CA3 and DG regions of hippocampus. Chronic administration of UD leaves extract significantly reversed diabetes mediated anxiogenic and depressive like behavior in mice. Further, UD treatment significantly upregulated BDNF (p < 0.01), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.01), autophagy5 (p < 0.01) and autophagy7 (p < 0.001), while downregulated iNOS (p < 0.05) mRNA expression in the hippocampus of diabetic mice. Concomitantly, UD administration significantly decreased the expression of TNF-α in hippocampal CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of diabetic mice. Diabetes mediated neuronal damage and DNA fragmentation in the hippocampus was substantially attenuated following UD treatment. UD leaves extract might prove to be effective for diabetes mediated anxiety and depressive like behavior.

https://ift.tt/2KhIcwG

Timing is everything: intraperitoneal chemotherapy after primary or interval debulking surgery for advanced ovarian cancer

Abstract

Purpose

To evaluate the outcomes of intraperitoneal chemotherapy (IP) compared with those of intravenous chemotherapy (IV) in patients with advanced ovarian cancer after neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or primary debulking surgery (PDS).

Methods

Patients with advanced epithelial ovarian carcinoma treated with PDS or NACT and IDS from 2006 to 2015 were identified. Comparative statistics were used to evaluate covariates, and survival rates were calculated using the Kaplan–Meier method and compared with log-rank tests.

Results

Sixty-six patients received NACT followed by IDS with residual disease of ≤ 1 cm; 42 of these patients (63.6%) received IP therapy; and 24 patients (36.3%) had IV therapy only after IDS. The median progression-free survival (PFS) was 16.0 months in the IP group and 13.5 months in the IV group (p = 0.13). The estimated median overall survival (OS) was 64.0 months with IP and 50.0 months with IV (p = 0.44). During the same study period, 149 patients underwent optimal PDS after which 93 patients (62.4%) received IP and 56 patients (37.6%) were given IV chemotherapy. Patients after IP demonstrated improved survival outcomes when compared to patients after IV therapy. The median PFS was 28.0 months after IP and 16.5 months after IV (p = 0.0006), and the median OS was not reached for IP and 50.0 months after IV (p < 0.0001).

Conclusions

Although IP chemotherapy after PDS is associated with improved survival, IP therapy after NACT and IDS, despite high rates of completion, may not have the same degree of survival advantage over IV therapy.

https://ift.tt/2vRyI8b

Timing is everything: intraperitoneal chemotherapy after primary or interval debulking surgery for advanced ovarian cancer

Abstract

Purpose

To evaluate the outcomes of intraperitoneal chemotherapy (IP) compared with those of intravenous chemotherapy (IV) in patients with advanced ovarian cancer after neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or primary debulking surgery (PDS).

Methods

Patients with advanced epithelial ovarian carcinoma treated with PDS or NACT and IDS from 2006 to 2015 were identified. Comparative statistics were used to evaluate covariates, and survival rates were calculated using the Kaplan–Meier method and compared with log-rank tests.

Results

Sixty-six patients received NACT followed by IDS with residual disease of ≤ 1 cm; 42 of these patients (63.6%) received IP therapy; and 24 patients (36.3%) had IV therapy only after IDS. The median progression-free survival (PFS) was 16.0 months in the IP group and 13.5 months in the IV group (p = 0.13). The estimated median overall survival (OS) was 64.0 months with IP and 50.0 months with IV (p = 0.44). During the same study period, 149 patients underwent optimal PDS after which 93 patients (62.4%) received IP and 56 patients (37.6%) were given IV chemotherapy. Patients after IP demonstrated improved survival outcomes when compared to patients after IV therapy. The median PFS was 28.0 months after IP and 16.5 months after IV (p = 0.0006), and the median OS was not reached for IP and 50.0 months after IV (p < 0.0001).

Conclusions

Although IP chemotherapy after PDS is associated with improved survival, IP therapy after NACT and IDS, despite high rates of completion, may not have the same degree of survival advantage over IV therapy.

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Recurrent upper lumbar disc herniation treated via the transforaminal approach using microendoscopy-assisted lumbar discectomy: a case report

Although microendoscopy-assisted lumbar discectomy for lateral or extraforaminal lumbar disc herniations via the lateral approach has previously been reported, microendoscopy-assisted lumbar discectomy for cen...

https://ift.tt/2Hvh1Rs

Intussusception caused by an inverted colonic diverticulum: a case report

Intussusception is an unusual disorder among the complications of diverticula in adults. This study aimed to report intussusception due to an inverted colonic diverticulum. Such a large inverted colonic divert...

https://ift.tt/2r4GLZS

Correction to: Evaluation of pharmacokinetic models of intravenous dexmedetomidine in sedated patients under spinal anesthesia

Inadvertently, the reference [8] was published incorrectly in the original publication of the article. The correct reference [8] is provided below:

https://ift.tt/2I3gFhU

Effects of megavoltage computed tomographic scan methodology on setup verification and adaptive dose calculation in helical TomoTherapy

To evaluate the effect of pretreatment megavoltage computed tomographic (MVCT) scan methodology on setup verification and adaptive dose calculation in helical TomoTherapy.

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Effects of megavoltage computed tomographic scan methodology on setup verification and adaptive dose calculation in helical TomoTherapy

To evaluate the effect of pretreatment megavoltage computed tomographic (MVCT) scan methodology on setup verification and adaptive dose calculation in helical TomoTherapy.

https://ift.tt/2HUAWbS

Racialized economic segregation and stage at diagnosis of colorectal cancer in the United States

Abstract

Purpose

In order to improve colorectal cancer outcomes in the United States, there is an urgent need for research on the drivers of geographic disparities in stage at diagnosis. Our objective was to determine the effects of racialized economic segregation on the odds of late diagnosis.

Methods

Among 187,843 adults (≥ 18 years old) with new diagnoses of colorectal cancer reported to the Surveillance, Epidemiology and End-Results program between 1st January 2009 and 31st December 2013, exposure to racialized economic segregation was measured at the county-level using Index of Concentration at the Extremes metrics. Multilevel logistic regression models including registry and county random effects were fit to examine the association between racialized economic segregation and odds of metastatic disease at time of diagnosis.

Results

Odds of late diagnosis were greatest in counties with the lowest compared to highest quintile for racial and economic privilege (OR 1.14; 95% CI 1.09–1.20). In multilevel models adjusting for individual-level covariates, odds of late diagnosis were greater for all patients except those living in counties with the highest concentration of white high-income individuals. There was significant effect modification of this relationship by age, with greater adverse effects for younger adults (OR 1.16; 95% CI 1.02–1.32) than older adults (OR 1.06; 95% CI 1.00–1.11). Racialized economic segregation was strongly associated with access to affordable healthcare.

Conclusions

Spatial social polarization, quantified in relation to racialized economic segregation, increases the odds of late diagnosis of colorectal cancer for persons residing in the least compared to most privileged counties.

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Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer

Abstract

Background

Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC.

Methods

We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided.

Results

ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival.

Conclusions

MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.

https://ift.tt/2r5lfUO

Racialized economic segregation and stage at diagnosis of colorectal cancer in the United States

Abstract

Purpose

In order to improve colorectal cancer outcomes in the United States, there is an urgent need for research on the drivers of geographic disparities in stage at diagnosis. Our objective was to determine the effects of racialized economic segregation on the odds of late diagnosis.

Methods

Among 187,843 adults (≥ 18 years old) with new diagnoses of colorectal cancer reported to the Surveillance, Epidemiology and End-Results program between 1st January 2009 and 31st December 2013, exposure to racialized economic segregation was measured at the county-level using Index of Concentration at the Extremes metrics. Multilevel logistic regression models including registry and county random effects were fit to examine the association between racialized economic segregation and odds of metastatic disease at time of diagnosis.

Results

Odds of late diagnosis were greatest in counties with the lowest compared to highest quintile for racial and economic privilege (OR 1.14; 95% CI 1.09–1.20). In multilevel models adjusting for individual-level covariates, odds of late diagnosis were greater for all patients except those living in counties with the highest concentration of white high-income individuals. There was significant effect modification of this relationship by age, with greater adverse effects for younger adults (OR 1.16; 95% CI 1.02–1.32) than older adults (OR 1.06; 95% CI 1.00–1.11). Racialized economic segregation was strongly associated with access to affordable healthcare.

Conclusions

Spatial social polarization, quantified in relation to racialized economic segregation, increases the odds of late diagnosis of colorectal cancer for persons residing in the least compared to most privileged counties.

https://ift.tt/2I15BnE

Cost‐utility analysis of meaning‐centered group psychotherapy for cancer survivors

Psycho-Oncology, EarlyView.


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Cost‐utility analysis of meaning‐centered group psychotherapy for cancer survivors

Psycho-Oncology, EarlyView.


https://ift.tt/2I4lAir

Adenocarcinoma arising in sigmoid colon neovagina 53 years after construction

Abstract

Background

In view of the rarity of vaginal agenesis, malignancy arising in the neovagina is extremely rare.

Case presentation

Here, we report a 76-year-old female with an adenocarcinoma arising in the sigmoid colon neovagina which was constructed 53 years ago for congenital vaginal agenesis. Vaginal endoscopy to examine vaginal bleeding revealed a protruding lesion occupying three quarters of the lumen in the vicinity of anastomosis of the residual vagina and sigmoid colon. Transvaginal ultrasonography revealed the muscularis propria layer (hypoechoic fourth layer) to be interrupted. CT revealed no distant metastasis. Total pelvic exenteration was performed based on the diagnosis of neovaginal cancer at the anastomosis site. The 45-mm tumor showed well-differentiated adenocarcinoma with a mucinous adenocarcinoma component. Immunohistochemistry showed no p16-overexpressing tumor cells, suggesting the lack of human papilloma virus infection.

Conclusions

Although rare, clinicians should be aware of cancer that arises in the ectopic intestine when anastomosed with other organs.

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Adenocarcinoma arising in sigmoid colon neovagina 53 years after construction

Abstract

Background

In view of the rarity of vaginal agenesis, malignancy arising in the neovagina is extremely rare.

Case presentation

Here, we report a 76-year-old female with an adenocarcinoma arising in the sigmoid colon neovagina which was constructed 53 years ago for congenital vaginal agenesis. Vaginal endoscopy to examine vaginal bleeding revealed a protruding lesion occupying three quarters of the lumen in the vicinity of anastomosis of the residual vagina and sigmoid colon. Transvaginal ultrasonography revealed the muscularis propria layer (hypoechoic fourth layer) to be interrupted. CT revealed no distant metastasis. Total pelvic exenteration was performed based on the diagnosis of neovaginal cancer at the anastomosis site. The 45-mm tumor showed well-differentiated adenocarcinoma with a mucinous adenocarcinoma component. Immunohistochemistry showed no p16-overexpressing tumor cells, suggesting the lack of human papilloma virus infection.

Conclusions

Although rare, clinicians should be aware of cancer that arises in the ectopic intestine when anastomosed with other organs.

https://ift.tt/2KlJLtt

Therapeutic experience with hepatoblastoma associated with trisomy 18

Pediatric Blood &Cancer, EarlyView.


https://ift.tt/2r5zitd

Assessment of end‐of‐treatment transition needs for pediatric cancer and hematopoietic stem cell transplant patients and their families

Pediatric Blood &Cancer, EarlyView.


https://ift.tt/2HzNMg7

Treatment of refractory germ cell tumors in children with paclitaxel, ifosfamide, and carboplatin: A report from the Children's Oncology Group AGCT0521 study

Pediatric Blood &Cancer, EarlyView.


https://ift.tt/2r2M0co

Therapeutic experience with hepatoblastoma associated with trisomy 18

Pediatric Blood &Cancer, EarlyView.


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Assessment of end‐of‐treatment transition needs for pediatric cancer and hematopoietic stem cell transplant patients and their families

Pediatric Blood &Cancer, EarlyView.


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Treatment of refractory germ cell tumors in children with paclitaxel, ifosfamide, and carboplatin: A report from the Children's Oncology Group AGCT0521 study

Pediatric Blood &Cancer, EarlyView.


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Maternal residential pesticide use and risk of childhood leukemia in Costa Rica

International Journal of Cancer, EarlyView.


https://ift.tt/2I34vWi

Pre‐diagnostic blood immune markers, incidence and progression of B‐cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses

International Journal of Cancer, EarlyView.


https://ift.tt/2Fmnw2R

Maternal residential pesticide use and risk of childhood leukemia in Costa Rica

International Journal of Cancer, EarlyView.


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Pre‐diagnostic blood immune markers, incidence and progression of B‐cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses

International Journal of Cancer, EarlyView.


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IN THIS ISSUE

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Ovarian cancer incidence rates in the world from the Cancer Incidence in Five Continents XI

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Type 1 diabetes mellitus and risk of cancer: a meta-analysis of observational studies

Abstract

Objective

Previous observational studies have focused on the link between type 2 diabetes and the risk of cancer. However, the association between type 1 diabetes and the risk of cancer has not been well addressed. This study aimed to investigate the association between type 1 diabetes and the risk of cancer by using a meta-analysis of observational studies.

Methods

We searched PubMed and EMBASE for observational studies that examined the association between type 1 diabetes and cancer in April 2017. We calculated the pooled odds ratios (ORs) or relative risks (RRs) with confidence intervals (CIs) from individual studies based on a random-effects model meta-analysis.

Results

We included a total of 15 observational studies with two case–control studies and 13 cohort studies involving 31 893 cancer patients among a total of 1 915 179 participants in the final analysis. In the random-effects meta-analysis of all studies, patients with type 1 diabetes had an increased risk of cancer (OR or RR, 1.29; 95% CI, 1.09–1.52; n = 15; I² = 95.2%). In the subgroup meta-analysis by type of cancer, type 1 diabetes significantly increased the risk of cancers of stomach, lung, pancreas, liver, ovary and kidney, whereas it significantly decreased the risk of breast cancer (OR or RR, 0.91; 95% CI, 0.86–0.95; n = 9; I² = 0%).

Conclusion

This meta-analysis suggests that type 1 diabetes is associated with the increased risk of several types of cancer and the decreased risk of breast cancer. However, the plausible mechanisms for the decreased risk of breast cancer remain unclear. Further prospective studies with proper adjustment for possible confounding factors are warranted.

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A double-blind, randomized comparative study to investigate the morphine to hydromorphone conversion ratio in Japanese cancer patients

Abstract

Objective

To confirm the morphine to hydromorphone conversion ratio for hydromorphone (DS-7113b) immediate-release tablets in cancer patients who achieved pain control with oral morphine.

Methods

This was a multicenter, active-controlled, randomized, double-blind, parallel-group, comparative study (July 2013 to December 2014) at 39 Japanese sites. Seventy-one patients (aged >20 years) who had achieved pain control with morphine 60 mg/day and 90 mg/day were randomly allocated 1:1 to hydromorphone immediate-release tablets at a dose converted at a hydromorphone:morphine ratio of 1:5 or 1:8, respectively, and treated for up to 5 days. The efficacy was evaluated as the pain control ratio.

Results

The pain control ratio in the full analysis set was 83.3% (25/30) in the conversion ratio 1:5 group and 95.0% (38/40) in the conversion ratio 1:8 group, and both groups demonstrated highly successful pain control. The incidence of adverse events was 46.7% (14/30) in the conversion ratio 1:5 group and 58.5% (24/41) in the 1:8 group; the difference was not clinically relevant. Frequently observed adverse events (incidence ≥5%) were nausea, vomiting, diarrhea, somnolence and dyspnea.

Conclusions

A high pain control ratio was maintained by a switch at either conversion ratio, and no notable difference was observed in the incidence of adverse events. A switch from morphine to hydromorphone is effective at a dose converted at ratios of 1:5 and 1:8.

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Elotuzumab-induced interstitial lung disease: the first case report

Abstract

Elotuzumab, a humanized immunoglobulin G1 monoclonal antibody targeted against signaling lymphocytic activation molecule F7 (SLAMF7), has recently been used in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma. The clinical characteristics of drug-induced interstitial lung disease (ILD) due to elotuzumab have not been clarified. In this report, we describe a patient with refractory multiple myeloma who received elotuzumab in combination with lenalidomide and dexamethasone in whom fatigue, fever and diffuse pulmonary infiltration developed. The patient had a history of long-term therapy with lenalidomide without pulmonary toxicity. Bronchoscopy with bronchoalveolar lavage was negative for infection, and transbronchial lung biopsies showed active alveolitis with lymphocytic infiltration and myxomatous change of the thick alveolar wall. After the discontinuation of elotuzumab and lenalidomide, the patient's clinical symptoms gradually improved, and spontaneous remission of the pulmonary infiltration was observed. Based on the chest CT and lung pathology findings, the exclusion of infection and pulmonary edema, and according to the clinical course, we established a diagnosis of drug-induced ILD due to elotuzumab. Clinicians should bear in mind the potential for pulmonary toxicity in patients receiving elotuzumab-containing therapy.

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Stereotactic body radiotherapy (SBRT) for Stage I lung cancer

Abstract

Stereotactic body radiation therapy (SBRT) is a newly developed technique currently in clinical use. SBRT originated from stereotactic radiosurgery (SRS) for intracranial tumors. Since the 1990s, SBRT has been widely used in clinical settings for the treatment of lung cancer. We review the history and current standard techniques. Previous clinical studies of lung cancer showed high local control rates with acceptable toxicities. Past and on-going clinical trials are also reviewed.

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Efficacy of heparinoid moisturizer as a prophylactic agent for radiation dermatitis following radiotherapy after breast-conserving surgery: a randomized controlled trial

Abstract

Background

The application of heparinoid moisturizer for 2 weeks following whole-breast radiotherapy (WBRT) was previously reported to significantly increase skin water content (WC) and help improve skin dryness and desquamation. The prospective open-label, randomized trial included an exploratory arm to investigate the preventive efficacy of heparinoid moisturizer for acute radiation dermatitis (ARD).

Methods

Between April 2011 and April 2013, patients receiving WBRT were assigned (1:2:2) to receive either: moisturizer for prophylaxis (group P), moisturizer starting 2 weeks after WBRT for treatment (group M), and no moisturizer (group C). This paper presents the results of comparison between the exploratory arm and no moisturizer group. Skin WC was measured prior to WBRT, on the last day of WBRT, and 2 weeks, 4 weeks and 3 months following WBRT. Signs and symptoms were also assessed.

Results

Comparing two groups, WC values were significantly higher in group P until 4 weeks following WBRT. At 2 weeks following WBRT, mean WC values in group P and C were 38.5 ± 6.1 arbitrary units (a.u.) and 30.2 ± 7.8 a.u., respectively (P < 0.001). In group C, dryness was more severe at 2 and 4 weeks following WBRT and desquamation more severe until 3 months following WBRT. However, the erythema score showed no difference between the two groups. Regarding symptoms, group C pain scores on the last day of WBRT were significantly higher than in group P (P < 0.030).

Conclusions

The preventive application of heparinoid moisturizer has the potential of reducing skin desquamation and dryness in patients receiving WBRT.

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Patterns of radiotherapy infrastructure in Japan and in other countries with well-developed radiotherapy infrastructures

Abstract

Background

In high-income countries, the number of radiotherapy machine per population reaches a sufficient level. However, the patterns of infrastructure of radiotherapy in high-income countries are not well known.

Methods

Among 29 high-income countries with gross national income of $25,000 or more per capita, we selected 23 countries whose total number of newly diagnosed cancer patients in 2012 was reported in the Organisation for Economic Co-operation and Development Health Statistics 2017. The numbers of radiotherapy centers and teletherapy machines in each of these 23 countries were collected using the Dictionary of Radiotherapy Centers database.

Results

The number of cancer patients per teletherapy machine was 452.35–1398.22 (median 711.66) with a three-fold variation, whereas the number of cancer patients per radiotherapy center varied even more widely, from 826.16 to 5159.86 (median 2259.83) with a six-fold variation. The average number of teletherapy machines per radiotherapy center also ranged widely, from 1.24 to 8.29 (median 3.11) with a seven-fold variation. The number of teletherapy machines in each country was almost proportional to that of cancer patients, and the number of teletherapy machines per radiotherapy center was inversely related to the number of radiotherapy centers per cancer patients. The number of teletherapy machines per radiotherapy center in Japan was 1.24, the most fragmented among the high-income countries. The percentage of large radiotherapy centers having three or more teletherapy machines in Japan was the smallest among 23 high-income countries.

Conclusions

Optimization of the radiotherapy infrastructure in Japan should be carefully considered.

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Oncological and peri-surgical outcomes of radical prostatectomy for non-metastatic prostate cancer with prostate-specific antigen level of 50 ng/ml or greater

Abstract

Background

The role of radical prostatectomy in treating non-metastatic prostate cancer patients with high prostate-specific antigen levels remains unclear. We evaluated the feasibility and oncological outcomes of radical prostatectomy in non-metastatic prostate cancer patients with prostate-specific antigen levels of 50 ng/ml or higher.

Methods

This retrospective study included 31 patients who were diagnosed as very high-risk prostate cancer (clinical stage of any T, N0-1 M0 and PSA levels ≥50 ng/ml) and underwent radical prostatectomy either as a monotherapy or as a component of multimodal therapy (RP group). Surgery-related complications were investigated. Time to castration-resistant prostate cancer, cancer-specific survival, and overall survival were estimated using the Kaplan–Meier method. A total of 47 patients with very high-risk prostate cancer who were treated with androgen deprivation therapy without local therapy served as a control group (ADT group). Survivals were compared between RP group and ADT group in exploratory analyses.

Results

The median pretreatment prostate-specific antigen was 87 ng/ml and 100 ng/ml in the RP and ADT groups, respectively (P = 0.67). Surgical complications of Clavien-Dindo Grade 3 were documented in nine patients (29%). Ten-year castration-resistant prostate cancer-free, cancer-specific and overall survivals were 78%, 81% and 77% in RP group, respectively, and they were significantly better than those of ADT group (54%, P = 0.006; 54%, P = 0.006 and 38%, P < 0.001). Exploratory multivariate analysis identified radical prostatectomy as the only significant factor associated with a better cancer-specific survival (hazard ratio: 0.25, P = 0.006).

Conclusions

Radical prostatectomy is feasible for non-metastatic prostate cancer patients with prostate-specific antigen levels of 50 ng/ml or higher. Radical prostatectomy is a viable option for select patients with non-metastatic, very high-risk prostate cancer.

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Ovarian cancer incidence rates in the world from the Cancer Incidence in Five Continents XI

https://ift.tt/2Kg6cQG

IN THIS ISSUE

https://ift.tt/2JwbGFL

Type 1 diabetes mellitus and risk of cancer: a meta-analysis of observational studies

Abstract

Objective

Previous observational studies have focused on the link between type 2 diabetes and the risk of cancer. However, the association between type 1 diabetes and the risk of cancer has not been well addressed. This study aimed to investigate the association between type 1 diabetes and the risk of cancer by using a meta-analysis of observational studies.

Methods

We searched PubMed and EMBASE for observational studies that examined the association between type 1 diabetes and cancer in April 2017. We calculated the pooled odds ratios (ORs) or relative risks (RRs) with confidence intervals (CIs) from individual studies based on a random-effects model meta-analysis.

Results

We included a total of 15 observational studies with two case–control studies and 13 cohort studies involving 31 893 cancer patients among a total of 1 915 179 participants in the final analysis. In the random-effects meta-analysis of all studies, patients with type 1 diabetes had an increased risk of cancer (OR or RR, 1.29; 95% CI, 1.09–1.52; n = 15; I² = 95.2%). In the subgroup meta-analysis by type of cancer, type 1 diabetes significantly increased the risk of cancers of stomach, lung, pancreas, liver, ovary and kidney, whereas it significantly decreased the risk of breast cancer (OR or RR, 0.91; 95% CI, 0.86–0.95; n = 9; I² = 0%).

Conclusion

This meta-analysis suggests that type 1 diabetes is associated with the increased risk of several types of cancer and the decreased risk of breast cancer. However, the plausible mechanisms for the decreased risk of breast cancer remain unclear. Further prospective studies with proper adjustment for possible confounding factors are warranted.

https://ift.tt/2I7hWoc

A double-blind, randomized comparative study to investigate the morphine to hydromorphone conversion ratio in Japanese cancer patients

Abstract

Objective

To confirm the morphine to hydromorphone conversion ratio for hydromorphone (DS-7113b) immediate-release tablets in cancer patients who achieved pain control with oral morphine.

Methods

This was a multicenter, active-controlled, randomized, double-blind, parallel-group, comparative study (July 2013 to December 2014) at 39 Japanese sites. Seventy-one patients (aged >20 years) who had achieved pain control with morphine 60 mg/day and 90 mg/day were randomly allocated 1:1 to hydromorphone immediate-release tablets at a dose converted at a hydromorphone:morphine ratio of 1:5 or 1:8, respectively, and treated for up to 5 days. The efficacy was evaluated as the pain control ratio.

Results

The pain control ratio in the full analysis set was 83.3% (25/30) in the conversion ratio 1:5 group and 95.0% (38/40) in the conversion ratio 1:8 group, and both groups demonstrated highly successful pain control. The incidence of adverse events was 46.7% (14/30) in the conversion ratio 1:5 group and 58.5% (24/41) in the 1:8 group; the difference was not clinically relevant. Frequently observed adverse events (incidence ≥5%) were nausea, vomiting, diarrhea, somnolence and dyspnea.

Conclusions

A high pain control ratio was maintained by a switch at either conversion ratio, and no notable difference was observed in the incidence of adverse events. A switch from morphine to hydromorphone is effective at a dose converted at ratios of 1:5 and 1:8.

https://ift.tt/2FnqeoK

Elotuzumab-induced interstitial lung disease: the first case report

Abstract

Elotuzumab, a humanized immunoglobulin G1 monoclonal antibody targeted against signaling lymphocytic activation molecule F7 (SLAMF7), has recently been used in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma. The clinical characteristics of drug-induced interstitial lung disease (ILD) due to elotuzumab have not been clarified. In this report, we describe a patient with refractory multiple myeloma who received elotuzumab in combination with lenalidomide and dexamethasone in whom fatigue, fever and diffuse pulmonary infiltration developed. The patient had a history of long-term therapy with lenalidomide without pulmonary toxicity. Bronchoscopy with bronchoalveolar lavage was negative for infection, and transbronchial lung biopsies showed active alveolitis with lymphocytic infiltration and myxomatous change of the thick alveolar wall. After the discontinuation of elotuzumab and lenalidomide, the patient's clinical symptoms gradually improved, and spontaneous remission of the pulmonary infiltration was observed. Based on the chest CT and lung pathology findings, the exclusion of infection and pulmonary edema, and according to the clinical course, we established a diagnosis of drug-induced ILD due to elotuzumab. Clinicians should bear in mind the potential for pulmonary toxicity in patients receiving elotuzumab-containing therapy.

https://ift.tt/2I3KzT2

Stereotactic body radiotherapy (SBRT) for Stage I lung cancer

Abstract

Stereotactic body radiation therapy (SBRT) is a newly developed technique currently in clinical use. SBRT originated from stereotactic radiosurgery (SRS) for intracranial tumors. Since the 1990s, SBRT has been widely used in clinical settings for the treatment of lung cancer. We review the history and current standard techniques. Previous clinical studies of lung cancer showed high local control rates with acceptable toxicities. Past and on-going clinical trials are also reviewed.

https://ift.tt/2Fmvklf

Efficacy of heparinoid moisturizer as a prophylactic agent for radiation dermatitis following radiotherapy after breast-conserving surgery: a randomized controlled trial

Abstract

Background

The application of heparinoid moisturizer for 2 weeks following whole-breast radiotherapy (WBRT) was previously reported to significantly increase skin water content (WC) and help improve skin dryness and desquamation. The prospective open-label, randomized trial included an exploratory arm to investigate the preventive efficacy of heparinoid moisturizer for acute radiation dermatitis (ARD).

Methods

Between April 2011 and April 2013, patients receiving WBRT were assigned (1:2:2) to receive either: moisturizer for prophylaxis (group P), moisturizer starting 2 weeks after WBRT for treatment (group M), and no moisturizer (group C). This paper presents the results of comparison between the exploratory arm and no moisturizer group. Skin WC was measured prior to WBRT, on the last day of WBRT, and 2 weeks, 4 weeks and 3 months following WBRT. Signs and symptoms were also assessed.

Results

Comparing two groups, WC values were significantly higher in group P until 4 weeks following WBRT. At 2 weeks following WBRT, mean WC values in group P and C were 38.5 ± 6.1 arbitrary units (a.u.) and 30.2 ± 7.8 a.u., respectively (P < 0.001). In group C, dryness was more severe at 2 and 4 weeks following WBRT and desquamation more severe until 3 months following WBRT. However, the erythema score showed no difference between the two groups. Regarding symptoms, group C pain scores on the last day of WBRT were significantly higher than in group P (P < 0.030).

Conclusions

The preventive application of heparinoid moisturizer has the potential of reducing skin desquamation and dryness in patients receiving WBRT.

https://ift.tt/2I338XE

Patterns of radiotherapy infrastructure in Japan and in other countries with well-developed radiotherapy infrastructures

Abstract

Background

In high-income countries, the number of radiotherapy machine per population reaches a sufficient level. However, the patterns of infrastructure of radiotherapy in high-income countries are not well known.

Methods

Among 29 high-income countries with gross national income of $25,000 or more per capita, we selected 23 countries whose total number of newly diagnosed cancer patients in 2012 was reported in the Organisation for Economic Co-operation and Development Health Statistics 2017. The numbers of radiotherapy centers and teletherapy machines in each of these 23 countries were collected using the Dictionary of Radiotherapy Centers database.

Results

The number of cancer patients per teletherapy machine was 452.35–1398.22 (median 711.66) with a three-fold variation, whereas the number of cancer patients per radiotherapy center varied even more widely, from 826.16 to 5159.86 (median 2259.83) with a six-fold variation. The average number of teletherapy machines per radiotherapy center also ranged widely, from 1.24 to 8.29 (median 3.11) with a seven-fold variation. The number of teletherapy machines in each country was almost proportional to that of cancer patients, and the number of teletherapy machines per radiotherapy center was inversely related to the number of radiotherapy centers per cancer patients. The number of teletherapy machines per radiotherapy center in Japan was 1.24, the most fragmented among the high-income countries. The percentage of large radiotherapy centers having three or more teletherapy machines in Japan was the smallest among 23 high-income countries.

Conclusions

Optimization of the radiotherapy infrastructure in Japan should be carefully considered.

https://ift.tt/2FmvcCh