Ultrasonography-driven combination antibiotic therapy with tigecycline significantly increases survival among patients with neutropenic enterocolitis following cytarabine-containing chemotherapy for the remission induction of acute myeloid leukemia

Abstract

Neutropenic enterocolitis (NEC) is an abdominal infection reported primarily in patients with acute myeloid leukemia (AML) following chemotherapy, especially cytarabine, a notable efficacious cytotoxic agent for AML remission. Specific data regarding the impact of different cytarabine schedules and/or antibacterial regimens for NEC are sparse. The aim of the study was to identify the predictors of outcome within 30 days of NEC onset. NEC episodes were retrospectively pinpointed among 440 patients with newly diagnosed AML hospitalized in our Institution, over a 10-year period, for receiving chemotherapy protocols with 100–6000 mg/m² daily of cytarabine. Two subgroups, survivors versus nonsurvivors, were compared by using logistic regression analysis. NEC was documented in 100 of 420 (23.8%) analyzed patients: 42.5% had received high-dose cytarabine, whereas 19% and 15% intermediate-dose and standard-dose cytarabine, respectively (P < 0.001). The 30-day NEC attributable mortality rate was 23%. In univariate analysis, antileukemic protocols containing robust dosages of cytarabine were significantly associated with high mortality (P < 0.001); whereas, standard-dose cytarabine and prompt initiation (at the ultrasonographic appearance of intestinal mural thickening) of NEC therapy with antibiotic combinations including tigecycline were significantly associated with low mortality. In multivariate analysis, high-dose cytarabine-containing chemotherapy was the independent predictor of poor outcome (odds ratio [OR]: 0.109; 95% confidence interval [CI]: 0.032–0.364; P < 0.001), whereas ultrasonography-driven NEC therapy with antibiotic regimens including tigecycline was associated with a favorable outcome (OR: 13.161; 95% CI: 1.587–109.17; P = 0.017). Chemotherapy schedules with robust dosages of cytarabine for AML remission are associated with a high rate of NEC incidence and attributable. Vigorous antibacterial therapy, triggered off pathologic ultrasonographic findings, with drug combinations which have broad antimicrobial coverage and good gut penetration, specifically those also including tigecycline, may be effective in improving 30-day survival rate after NEC onset.

Prompt ultrasonography-driven combination antibiotic therapy for NEC improved survival among acute myeloid leukemia (AML) patient. Chemotherapy schedules with robust dosages of cytarabine for AML remission are associated with a high rate of NEC incidence and attributable mortality. Vigorous antibacterial therapy, specifically those also including tigecycline, may be effective in improving 30-day survival rate after NEC onset. This text corresponds to the final part of the abstract and it doesn't represent the legend to this figure.

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Ultrasonography-driven combination antibiotic therapy with tigecycline significantly increases survival among patients with neutropenic enterocolitis following cytarabine-containing chemotherapy for the remission induction of acute myeloid leukemia

Abstract

Neutropenic enterocolitis (NEC) is an abdominal infection reported primarily in patients with acute myeloid leukemia (AML) following chemotherapy, especially cytarabine, a notable efficacious cytotoxic agent for AML remission. Specific data regarding the impact of different cytarabine schedules and/or antibacterial regimens for NEC are sparse. The aim of the study was to identify the predictors of outcome within 30 days of NEC onset. NEC episodes were retrospectively pinpointed among 440 patients with newly diagnosed AML hospitalized in our Institution, over a 10-year period, for receiving chemotherapy protocols with 100–6000 mg/m² daily of cytarabine. Two subgroups, survivors versus nonsurvivors, were compared by using logistic regression analysis. NEC was documented in 100 of 420 (23.8%) analyzed patients: 42.5% had received high-dose cytarabine, whereas 19% and 15% intermediate-dose and standard-dose cytarabine, respectively (P < 0.001). The 30-day NEC attributable mortality rate was 23%. In univariate analysis, antileukemic protocols containing robust dosages of cytarabine were significantly associated with high mortality (P < 0.001); whereas, standard-dose cytarabine and prompt initiation (at the ultrasonographic appearance of intestinal mural thickening) of NEC therapy with antibiotic combinations including tigecycline were significantly associated with low mortality. In multivariate analysis, high-dose cytarabine-containing chemotherapy was the independent predictor of poor outcome (odds ratio [OR]: 0.109; 95% confidence interval [CI]: 0.032–0.364; P < 0.001), whereas ultrasonography-driven NEC therapy with antibiotic regimens including tigecycline was associated with a favorable outcome (OR: 13.161; 95% CI: 1.587–109.17; P = 0.017). Chemotherapy schedules with robust dosages of cytarabine for AML remission are associated with a high rate of NEC incidence and attributable. Vigorous antibacterial therapy, triggered off pathologic ultrasonographic findings, with drug combinations which have broad antimicrobial coverage and good gut penetration, specifically those also including tigecycline, may be effective in improving 30-day survival rate after NEC onset.

Prompt ultrasonography-driven combination antibiotic therapy for NEC improved survival among acute myeloid leukemia (AML) patient. Chemotherapy schedules with robust dosages of cytarabine for AML remission are associated with a high rate of NEC incidence and attributable mortality. Vigorous antibacterial therapy, specifically those also including tigecycline, may be effective in improving 30-day survival rate after NEC onset. This text corresponds to the final part of the abstract and it doesn't represent the legend to this figure.

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Trends in Surgical Research in Head and Neck Cancer

Opinion statement

The task of surgical research is to improve the efficacy of available surgical therapeutic modalities, develop new ones, and balance this well with favorable functional outcome. Therefore, surgical research is composed of a translational and a clinical component. In translational surgical research, animal models are used to better understand the biology of head and neck cancers, but even more importantly, the biology of changes to the disease and the microenvironment created by surgical interventions. Animal models additionally allow for the development of image-guided surgery systems, novel strategies of intraoperative adjuvant treatment, and patient "avatars" to test innovative anticancer drug combinations. In clinical surgical research, surgical techniques are validated in clinical trials for effectiveness of tumor control and improvement of functional recovery of the patient. In conclusion, surgical research for head and neck cancer is an active field spanning across the entire breadth of basic and clinical science devoted to a better understanding of what surgery does to the disease and to the patient.

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Trends in Surgical Research in Head and Neck Cancer

Opinion statement

The task of surgical research is to improve the efficacy of available surgical therapeutic modalities, develop new ones, and balance this well with favorable functional outcome. Therefore, surgical research is composed of a translational and a clinical component. In translational surgical research, animal models are used to better understand the biology of head and neck cancers, but even more importantly, the biology of changes to the disease and the microenvironment created by surgical interventions. Animal models additionally allow for the development of image-guided surgery systems, novel strategies of intraoperative adjuvant treatment, and patient "avatars" to test innovative anticancer drug combinations. In clinical surgical research, surgical techniques are validated in clinical trials for effectiveness of tumor control and improvement of functional recovery of the patient. In conclusion, surgical research for head and neck cancer is an active field spanning across the entire breadth of basic and clinical science devoted to a better understanding of what surgery does to the disease and to the patient.

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Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Sanzana Fareen Rivu, Mohd Nazmul Hasan Apu, Samia Shabnaz, Noor Ahmed Nahid, Md. Reazul Islam, Mir Md. Abdullah Al-Mamun, Zabun Nahar, Sikder Nahidul Islam Rabbi, Maizbha Uddin Ahmed, Mohammad Safiqul Islam, Abul Hasnat
Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160C<A) genes has been reported on Bangladeshi population relating those with colorectal cancer. So the aim of the study is to determine whether there is an elevated risk of colorectal cancer development with TP53 codon 72 and CDH1 rs16260 genetic polymorphism in Bangladeshi population for the first time. To investigate the association of these two SNPs, we conducted a case-control study with 288 colorectal cancer patients and 295 healthy volunteers by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We found an increased risk of association between Arg/Pro heterozygosity (adjusted OR=2.58, 95% CI=1.77–3.77, p<0.05) and Pro/Pro mutant homozygosity (adjusted OR=2.92, 95% CI=1.78–4.78, p<0.05) along with the combined genotype (Arg/Pro+Pro/Pro) (adjusted OR=2.70, 95% CI=1.90–3.82, p<0.05) and colorectal cancer predisposition. In case of CDH1 rs16260 polymorphism, C/A heterozygous and A/A mutant homozygous are significantly (p<0.05) found to be associated with colorectal cancer risk with adjusted OR of 1.94 and 2.63, respectively. The combined genotype of C/A and A/A was also found to be strongly associated with colorectal cancer risk compared to C/C genotype (adjusted OR=2.02, 95% CI=1.42–2.87, p<0.05). In conclusion, heterozygosity and mutant homozygosity as well as the combination of both TP53 Arg72Pro and CDH1 rs16260 polymorphisms are responsible to increase the risk of colorectal cancer development in Bangladeshi population.



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Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies

Summary

The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open-label, multicenter phase I trial of the selective, small-molecule hedgehog signaling inhibitor glasdegib (PF-04449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once-daily oral doses (25, 50, and 100 mg) in 28-day cycles after a lead-in dose on Day –5. The primary objectives were to determine first-cycle dose-limiting toxicities, safety, vital signs, and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and preliminary evidence of clinical activity of glasdegib. No dose-limiting toxicities were noted in the 13 patients in this study. All patients experienced at least one treatment-emergent, all-causality adverse event. The most frequent treatment-related adverse events (observed in ≥3 patients) were dysgeusia (n=9), muscle spasms (n=5), alopecia, decreased appetite (n=4 each), and increased blood creatinine phosphokinase, constipation, and diarrhea (n=3 each). Two deaths occurred during the study and were deemed not to be treatment-related due to disease progression. Glasdegib demonstrated dose-proportional pharmacokinetics, marked downregulation of the glioma-associated transcriptional regulator GLI1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100-mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial.

This article is protected by copyright. All rights reserved.

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Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Sanzana Fareen Rivu, Mohd Nazmul Hasan Apu, Samia Shabnaz, Noor Ahmed Nahid, Md. Reazul Islam, Mir Md. Abdullah Al-Mamun, Zabun Nahar, Sikder Nahidul Islam Rabbi, Maizbha Uddin Ahmed, Mohammad Safiqul Islam, Abul Hasnat
Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160C<A) genes has been reported on Bangladeshi population relating those with colorectal cancer. So the aim of the study is to determine whether there is an elevated risk of colorectal cancer development with TP53 codon 72 and CDH1 rs16260 genetic polymorphism in Bangladeshi population for the first time. To investigate the association of these two SNPs, we conducted a case-control study with 288 colorectal cancer patients and 295 healthy volunteers by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We found an increased risk of association between Arg/Pro heterozygosity (adjusted OR=2.58, 95% CI=1.77–3.77, p<0.05) and Pro/Pro mutant homozygosity (adjusted OR=2.92, 95% CI=1.78–4.78, p<0.05) along with the combined genotype (Arg/Pro+Pro/Pro) (adjusted OR=2.70, 95% CI=1.90–3.82, p<0.05) and colorectal cancer predisposition. In case of CDH1 rs16260 polymorphism, C/A heterozygous and A/A mutant homozygous are significantly (p<0.05) found to be associated with colorectal cancer risk with adjusted OR of 1.94 and 2.63, respectively. The combined genotype of C/A and A/A was also found to be strongly associated with colorectal cancer risk compared to C/C genotype (adjusted OR=2.02, 95% CI=1.42–2.87, p<0.05). In conclusion, heterozygosity and mutant homozygosity as well as the combination of both TP53 Arg72Pro and CDH1 rs16260 polymorphisms are responsible to increase the risk of colorectal cancer development in Bangladeshi population.



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Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies

Summary

The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open-label, multicenter phase I trial of the selective, small-molecule hedgehog signaling inhibitor glasdegib (PF-04449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once-daily oral doses (25, 50, and 100 mg) in 28-day cycles after a lead-in dose on Day –5. The primary objectives were to determine first-cycle dose-limiting toxicities, safety, vital signs, and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and preliminary evidence of clinical activity of glasdegib. No dose-limiting toxicities were noted in the 13 patients in this study. All patients experienced at least one treatment-emergent, all-causality adverse event. The most frequent treatment-related adverse events (observed in ≥3 patients) were dysgeusia (n=9), muscle spasms (n=5), alopecia, decreased appetite (n=4 each), and increased blood creatinine phosphokinase, constipation, and diarrhea (n=3 each). Two deaths occurred during the study and were deemed not to be treatment-related due to disease progression. Glasdegib demonstrated dose-proportional pharmacokinetics, marked downregulation of the glioma-associated transcriptional regulator GLI1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100-mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial.

This article is protected by copyright. All rights reserved.

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Clinical implications of c-maf expression in plasma cells from patients with multiple myeloma

Abstract

Background

Multiple myeloma (MM) is a type of hematological malignancy with significant heterogeneity in clinical features and prognosis. Cytogenetic abnormalities are the major factors affecting patient outcomes. Studies have shown that immunohistochemistry (IHC)-based detection of cancer-related genes expression could be alternative indicators for the prognosis of MM.

Methods

Nuclear expression of c-maf protein in the bone marrow plasma cells of 128 multiple myeloma patients were examined by IHC, and its association with the clinicopathological features of MM patients was analyzed as well.

Results

Among the 128 patients, the positive rate of c-maf protein expression was up to 30.5%, which had no correlation with patient age, M protein type, Durie-Salmon staging system, the International Staging System, abnormal plasma cell ratio in the bone marrow, or the level of peripheral blood hemoglobin, serum calcium or lactate dehydrogenase. However, the c-maf-positive patients had a significantly higher rate of hypoproteinemia (p = 0.026) and higher serum β2-microglobulin levels (>2500 μg/L) (p = 0.007). Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on progression-free survival or overall survival was observed.

Conclusion

Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on survival was observed. A further large-scale prospective study is required to verify these findings.

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Clinical implications of c-maf expression in plasma cells from patients with multiple myeloma

Abstract

Background

Multiple myeloma (MM) is a type of hematological malignancy with significant heterogeneity in clinical features and prognosis. Cytogenetic abnormalities are the major factors affecting patient outcomes. Studies have shown that immunohistochemistry (IHC)-based detection of cancer-related genes expression could be alternative indicators for the prognosis of MM.

Methods

Nuclear expression of c-maf protein in the bone marrow plasma cells of 128 multiple myeloma patients were examined by IHC, and its association with the clinicopathological features of MM patients was analyzed as well.

Results

Among the 128 patients, the positive rate of c-maf protein expression was up to 30.5%, which had no correlation with patient age, M protein type, Durie-Salmon staging system, the International Staging System, abnormal plasma cell ratio in the bone marrow, or the level of peripheral blood hemoglobin, serum calcium or lactate dehydrogenase. However, the c-maf-positive patients had a significantly higher rate of hypoproteinemia (p = 0.026) and higher serum β2-microglobulin levels (>2500 μg/L) (p = 0.007). Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on progression-free survival or overall survival was observed.

Conclusion

Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on survival was observed. A further large-scale prospective study is required to verify these findings.

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Reply to the Letter to the Editor by Vargo et al.

We appreciate the supportive comment from Vargo and Beriwal about our finding [1]. Certainly, we share similar concerns regarding the absence of international consensus guidelines for target volume delineation. The optimal implications and future applications of the patterns-of-failure studies are probably more complicated than what we think, as previously reviewed [2–4]. Patterns-of-failure will continue to be changed over time as patients are diagnosed in early stages and undergo lesser invasive surgery, and as systemic therapy improves.

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PGBD5 Is a DNA Transposase Sufficient for Malignant Transformation [Research Watch]

PGBD5 binds to PSS sequences to promote somatic genomic rearrangements in rhabdoid tumor cells.

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Distinct Chromatin States Underlie Tumor-Specific T-cell Dysfunction [Research Watch]

Tumor T cells differentiate through a plastic dysfunctional state and a fixed dysfunctional state.

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Loss of Hippo Signaling Promotes Polyploidy and Tumorigenesis [Research Watch]

YAP activates AKT signaling to promote mitotic arrest, polyploidy, and hepatocellular carcinoma.

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PD-1 Expression on TAMs Suppresses Tumor Cell Phagocytosis [Research Watch]

PD-1/PD-L1 blockade increases TAM phagocytosis of tumor cells to extend survival in mouse cancer models.

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BATF3 Dendritic Cells Drive Adoptive Effector T-Cell Trafficking [Research Watch]

Trafficking of adoptively transferred effector T cells requires CD103⁺ dendritic cell–derived CXCL9/10.

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Whole breast and regional nodal irradiation in prone versus supine position in left sided breast cancer

Abstract

Background

Prone whole breast irradiation (WBI) leads to reduced heart and lung doses in breast cancer patients receiving adjuvant radiotherapy. In this feasibility trial, we investigated the prone position for whole breast + lymph node irradiation (WB + LNI).

Methods

A new support device was developed for optimal target coverage, on which patients are positioned in a position resembling a phase from the crawl swimming technique (prone crawl position). Five left sided breast cancer patients were included and simulated in supine and prone position. For each patient, a treatment plan was made in prone and supine position for WB + LNI to the whole axilla and the unoperated part of the axilla. Patients served as their own controls for comparing dosimetry of target volumes and organs at risk (OAR) in prone versus in supine position.

Results

Target volume coverage differed only slightly between prone and supine position. Doses were significantly reduced (P < 0.05) in prone position for ipsilateral lung (Dmean, D2, V5, V10, V20, V30), contralateral lung (Dmean, D2), contralateral breast (Dmean, D2 and for total axillary WB + LNI also V5), thyroid (Dmean, D2, V5, V10, V20, V30), oesophagus (Dmean and for partial axillary WB + LNI also D2 and V5), skin (D2 and for partial axillary WB + LNI V105 and V107). There were no significant differences for heart and humeral head doses.

Conclusions

Prone crawl position in WB + LNI allows for good breast and nodal target coverage with better sparing of ipsilateral lung, thyroid, contralateral breast, contralateral lung and oesophagus when compared to supine position. There is no difference in heart and humeral head doses.

Trial registration

No trial registration was performed because there were no therapeutic interventions.

http://ift.tt/2r7chb3

Whole breast and regional nodal irradiation in prone versus supine position in left sided breast cancer

Abstract

Background

Prone whole breast irradiation (WBI) leads to reduced heart and lung doses in breast cancer patients receiving adjuvant radiotherapy. In this feasibility trial, we investigated the prone position for whole breast + lymph node irradiation (WB + LNI).

Methods

A new support device was developed for optimal target coverage, on which patients are positioned in a position resembling a phase from the crawl swimming technique (prone crawl position). Five left sided breast cancer patients were included and simulated in supine and prone position. For each patient, a treatment plan was made in prone and supine position for WB + LNI to the whole axilla and the unoperated part of the axilla. Patients served as their own controls for comparing dosimetry of target volumes and organs at risk (OAR) in prone versus in supine position.

Results

Target volume coverage differed only slightly between prone and supine position. Doses were significantly reduced (P < 0.05) in prone position for ipsilateral lung (Dmean, D2, V5, V10, V20, V30), contralateral lung (Dmean, D2), contralateral breast (Dmean, D2 and for total axillary WB + LNI also V5), thyroid (Dmean, D2, V5, V10, V20, V30), oesophagus (Dmean and for partial axillary WB + LNI also D2 and V5), skin (D2 and for partial axillary WB + LNI V105 and V107). There were no significant differences for heart and humeral head doses.

Conclusions

Prone crawl position in WB + LNI allows for good breast and nodal target coverage with better sparing of ipsilateral lung, thyroid, contralateral breast, contralateral lung and oesophagus when compared to supine position. There is no difference in heart and humeral head doses.

Trial registration

No trial registration was performed because there were no therapeutic interventions.

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MicroRNA-608 inhibits proliferation of bladder cancer via AKT/FOXO3a signaling pathway

Abstract

Background

Current evidence indicates that miR-608 is widely down-regulated in various malignant tumors including liver cancer, colon cancer, lung cancer and glioma, and acts as a tumor suppressor by inhibiting cell proliferation, invasion and migration or by promoting apoptosis. The specific biological function of miR-608 in bladder cancer is still unknown.

Methods

qRT-PCR and Chromogenic in Situ Hybridization (CISH) was conducted to assess the expression of miR-608 in paired BCa tissues and adjacent non-tumor bladder urothelial tissues. Bisulfite sequencing PCR was used for DNA methylation analysis. CCK-8, colony formation and flow cytometry assays were performed, and a xenograft model was studied. Immunohistochemistry staining was performed with peroxidase and DAB. The target of miR-608 was validated with a dual-luciferase reporter assay, quantitative RT-PCR, and Western blotting.

Results

miR-608 is frequently down-regulated in human BCa tissues. The methylation status of CpG islands is involved in the regulation of miR-608 expression. Overexpression of miR-608 inhibits the proliferation and tumorigenesis of BCa cells in vitro and in vivo. Additionally, up-regulation of miR-608 in BCa cells induces G1-phase arrest through AKT/FOXO3a signaling. In contrast, down-regulation of miR-608 promotes proliferation and cell cycle progression in BCa cells. Moreover, the expression of FLOT1 was directly inhibited by miR-608, the down-regulation of FLOT1 induced by siFLOT1 could be significantly reversed by miR-608 inhibitor. Similarly, the up-regulation of FLOT1 by FLOT1 overexpression plasmid (pFLOT1) could also reverse the suppressed cell proliferation caused by miR-608.

Conclusions

miR-608 is a potential tumor suppressor in BCa, and the restoration of miR-608 might be a promising therapeutic option for BCa.

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MicroRNA-608 inhibits proliferation of bladder cancer via AKT/FOXO3a signaling pathway

Abstract

Background

Current evidence indicates that miR-608 is widely down-regulated in various malignant tumors including liver cancer, colon cancer, lung cancer and glioma, and acts as a tumor suppressor by inhibiting cell proliferation, invasion and migration or by promoting apoptosis. The specific biological function of miR-608 in bladder cancer is still unknown.

Methods

qRT-PCR and Chromogenic in Situ Hybridization (CISH) was conducted to assess the expression of miR-608 in paired BCa tissues and adjacent non-tumor bladder urothelial tissues. Bisulfite sequencing PCR was used for DNA methylation analysis. CCK-8, colony formation and flow cytometry assays were performed, and a xenograft model was studied. Immunohistochemistry staining was performed with peroxidase and DAB. The target of miR-608 was validated with a dual-luciferase reporter assay, quantitative RT-PCR, and Western blotting.

Results

miR-608 is frequently down-regulated in human BCa tissues. The methylation status of CpG islands is involved in the regulation of miR-608 expression. Overexpression of miR-608 inhibits the proliferation and tumorigenesis of BCa cells in vitro and in vivo. Additionally, up-regulation of miR-608 in BCa cells induces G1-phase arrest through AKT/FOXO3a signaling. In contrast, down-regulation of miR-608 promotes proliferation and cell cycle progression in BCa cells. Moreover, the expression of FLOT1 was directly inhibited by miR-608, the down-regulation of FLOT1 induced by siFLOT1 could be significantly reversed by miR-608 inhibitor. Similarly, the up-regulation of FLOT1 by FLOT1 overexpression plasmid (pFLOT1) could also reverse the suppressed cell proliferation caused by miR-608.

Conclusions

miR-608 is a potential tumor suppressor in BCa, and the restoration of miR-608 might be a promising therapeutic option for BCa.

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Erratum to: Evaluation of the Efficacy of Sorafenib on Overall Survival in Patients with Hepatocellular Carcinoma using FT Rate: A Devised Index

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Erratum to: Evaluation of the Efficacy of Sorafenib on Overall Survival in Patients with Hepatocellular Carcinoma using FT Rate: A Devised Index

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Phase I/II study of induction chemotherapy using carboplatin plus irinotecan and sequential thoracic radiotherapy (TRT) for elderly patients with limited-disease small-cell lung cancer (LD-SCLC): TORG 0604

Abstract

Background

The role of irinotecan for elderly patients with LD-SCLC has been unclear, and the timing of TRT combined with chemotherapy has not been fully evaluated.

Methods

Patients aged > 70 years with untreated, measurable, LD-SCLC, performance status (PS) 0–2, and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8, every 21 days for 4 cycles, and sequential TRT (54Gy in 27 fractions). Carboplatin doses were based on AUC of 4 and 5 (levels 1 and 2, respectively), with a fixed irinotecan dose (50 mg/m²). Primary objective of the phase II study was overall responce rate.

Results

Forty-three patients were enrolled and forty-one were finally analyzed (median age: 75 years [range 70–86 years); males 31; PS 0/1/2, n = 22/18/1]. Two patients were excluded because of protocol violation (ascertained to be extensive disease). Twelve patients were accrued at phase I and the number of patients with carboplatin dose-limiting toxicities at levels-1 (n = 6) and −2 (n = 6) were 1(grade 3 hypertension) and 2 (grade 4 thrombocytopenia), respectively. The phase II trial was expanded to 29 additional patients receiving the level 1 carboplatin dose, total of 35 patients. The median number of chemotherapy cycles was 4 (range 1–4), and the median radiation dose was 54Gy (range 36–60). Toxicities were generally mild. There were 4 complete and 27 partial responses (response rate 88.6%). With a median follow-up of 52 months, the median progression-free and overall survival times of phase II were 11.2 and 27.1 months, respectively.

Conclusions

Induction chemotherapy of carboplatin plus irinotecan and sequential TRT was well tolerated and effective for elderly patients with LD-SCLC. Additional confirmatory studies are warranted.

Trial registration

Trial registration number: UMIN000007352

Name of registry: UMIN.

Date of registration: 1/Dec/2006.

Date of enrolment of the first participant to the trial: 6/Feb/2007.

Clinical trial registration date: 1/Feb/2006 (prospective).

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Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration

Abstract

Background

Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process.

Methods

For our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes in cell migration and cell morphology. We also used these PAD2-modulated cells to test whether PAD2 may be required for EGF-induced cell migration. To determine how PAD2 might promote tumor cell migration in vivo, we tested the effects of PAD2 inhibition on the expression of several cell migration mediators in MCF10DCIS.com xenograft tumors. In addition, we tested the effect of PAD2 inhibition on EGF-induced ductal invasion and elongation in primary mouse mammary organoids. Lastly, using a transgenic mouse model, we investigated the effects of PAD2 overexpression on mammary gland development.

Results

Our results indicate that PAD2 depletion or inhibition suppresses cell migration and alters the morphology of MCF10DCIS.com cells. In addition, we found that PAD2 depletion suppresses the expression of the cytoskeletal regulatory proteins RhoA, Rac1, and Cdc42 and also promotes a mesenchymal to epithelial-like transition in tumor cells with an associated increase in the cell adhesion marker, E-cadherin. Our mammary gland organoid study found that inhibition of PAD2 activity suppresses EGF-induced ductal invasion. In vivo, we found that PAD2 overexpression causes hyperbranching in the developing mammary gland.

Conclusion

Together, these results suggest that PAD2 plays a critical role in breast cancer cell migration. Our findings that EGF treatment increases protein citrullination and that PAD2 inhibition blocks EGF-induced cell migration suggest that PAD2 likely functions within the EGF signaling pathway to mediate cell migration.

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JS-K, a nitric oxide pro-drug, regulates growth and apoptosis through the ubiquitin-proteasome pathway in prostate cancer cells

Abstract

Background

In view of the fact that JS-K might regulate ubiquitin E3 ligase and that ubiquitin E3 ligase plays an important role in the mechanism of CRPC formation, the goal was to investigate the probable mechanism by which JS-K regulates prostate cancer cells.

Methods

Proliferation inhibition by JS-K on prostate cancer cells was examined usingCCK-8 assays. Caspase 3/7 activity assays and flow cytometry were performed to examine whether JS-K induced apoptosis in prostate cancer cells. Western blotting and co-immunoprecipitation analyses investigated JS-K's effects on the associated apoptosis mechanism. Real time-PCR and Western blotting were performed to assess JS-K's effect on transcription of specific AR target genes. Western blotting was also performed to detect Siah2 and AR protein concentrations and co-immunoprecipitation to detect interactions of Siah2 and AR, NCoR1 and AR, and p300 and AR.

Results

JS-K inhibited proliferation and induced apoptosis in prostate cancer cells. JS-K increased p53 and Mdm2 concentrations and regulated the caspase cascade reaction-associated protein concentrations. JS-K inhibited transcription of AR target genes and down-regulated PSA protein concentrations. JS-K inhibited Siah2 interactions and also inhibited the ubiquitination of AR. With further investigation, JS-K was found to stabilize AR and NCoR1 interactions and diminish AR and p300 interactions.

Conclusions

The present results suggested that JS-K might have been able to inhibit proliferation and induce apoptosis via regulation of the ubiquitin-proteasome degradation pathway, which represented a promising platform for the development of new compounds for PCa treatments.

from Cancer via ola Kala on Inoreader http://ift.tt/2r5YTUH
via IFTTT

Expression of von Hippel–Lindau tumor suppressor protein (pVHL) characteristic of tongue cancer and proliferative lesions in tongue epithelium

Abstract

Background

Patients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel–Lindau (VHL) tumor suppressor gene. However, expression of VHL protein (pVHL) in tongue cancer has rarely been investigated and remains largely unknown. We performed immunohistochemical staining of pVHL in tongue tissues and dysplasia, and examined the association with LOH and its clinical significance.

Methods

Immunohistochemical staining of pVHL in formalin-fixed, paraffin-embedded sections of cancerous and other tissues from 19 tongue cancer patients showed positivity for LOH of VHL in four samples, negativity in four samples, and was non-informative in 11 samples. The staining pattern of pVHL was also compared with those of cytokeratin (CK) 13 and CK17.

Results

In normal tongue tissues, pVHL staining was localized to the cytoplasm of cells in the basal layer and the area of the spinous layer adjacent to the basal layer of stratified squamous epithelium. Positive staining for pVHL was observed in the cytoplasm of cancer cells from all 19 tongue cancer patients. No differences as a result of the presence or absence of LOH were found. Notably, cytoplasm of poorly differentiated invasive cancer cells was less intensely stained than that of well and moderately differentiated invasive cancer cells. pVHL staining was also evident in epithelial dysplasia lesions with pVHL-positive cells expanding from the basal layer to the middle of the spinous layer. However, no CK13 staining was noted in regions of the epithelium, which were positive for pVHL. In contrast, regions with positive staining for CK17 closely coincided with those positive for pVHL.

Conclusions

Positive staining for pVHL was observed in cancerous areas but not in normal tissues. pVHL expression was also detected in lesions of epithelial dysplasia. These findings suggest that pVHL may be a useful marker for proliferative lesions.

from Cancer via ola Kala on Inoreader http://ift.tt/2s4cN6T
via IFTTT

Switch in KRAS mutational status during an unusual course of disease in a patient with advanced pancreatic adenocarcinoma: implications for translational research

Abstract

Background

Despite the introduction of novel effective treatment regimens like gemcitabine plus nab-paclitaxel and FOLFIRINOX, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive epithelial tumors. Among the genetic alterations frequently found in PDAC, mutations in the KRAS gene might play a prognostic role regarding overall survival and may also have the potential to predict the efficacy of anti-EGFR treatment.

Case presentation

We report the clinical case of a 69 year old Caucasian female that was diagnosed with histologically confirmed locally advanced PDAC with lymph node involvement in August 2010. At the time of first diagnosis, tumor tissue obtained from an open regional lymph node biopsy showed a poorly differentiated adenocarcinoma with a wild type sequence within exon 2 (codon 12/13) of the KRAS gene. The patient initially received single-agent gemcitabine and a subsequent 5-FU-based chemoradiotherapy with a sequential maintenance chemotherapy with oral capecitabine resulting in a long term disease control. Local disease progression occurred in May 2014 and the patient underwent pancreaticoduodenectomy in September 2014. A novel KRAS gene mutation (c.35G > T, p.G12 V) in exon 2 (codon 12) was detected within the surgical specimen. As of January 2016 the patient is still alive and without evidence of the underlying disease.

Conclusions

Specifically in the context of clinical trials and translational research in PDAC a re-assessment of molecular biomarkers, i. e. KRAS, at defined time points (e. g. relapse, disease progression, unusual clinical course) may be indicated in order to detect a potential switch in biomarker status during the course of disease.

from Cancer via ola Kala on Inoreader http://ift.tt/2r6bVBo
via IFTTT

Prognostic significance of tumor infiltrating immune cells in oral squamous cell carcinoma

Abstract

Background

Prognostic factors aid in the stratification and treatment of cancer. This study evaluated prognostic importance of tumor infiltrating immune cell in patients with oral squamous cell carcinoma.

Methods

Profiles of infiltrating immune cells and clinicopathological data were available for 78 OSCC patients with a median follow-up of 48 months. The infiltrating intensity of CD8, CD4, T-bet, CD68 and CD57 positive cells were assessed by immunohistochemistry. Chi-square test was used to compare immune markers expression and clinicopathological parameters. Univariate and multivariate COX proportional hazard models were used to assess the prognostic discriminator power of immune cells. The predictive potential of immune cells for survival of OSCC patients was determined using ROC and AUC.

Results

The mean value of CD8, CD4, T-bet, CD68 and CD57 expression were 28.99, 62.06, 8.97, 21.25 and 15.75 cells per high-power field respectively. The patient cohort was separated into low and high expression groups by the mean value. Higher CD8 expression was associated with no regional lymph node metastasis (p = 0.033). Patients with more abundant stroma CD57⁺ cells showed no metastasis into regional lymph node (p = 0.005), and early clinical stage (p = 0.016). The univariate COX regression analyses showed that no lymph node involvement (p < 0.001), early clinical stage (TNM staging I/II vs III/IV, p = 0.007), higher CD8 and CD57 expression (p < 0.001) were all positively correlated with longer overall survival. Multivariate COX regression analysis showed that no lymph node involvement (p = 0.008), higher CD8 (p = 0.03) and CD57 (p < 0.001) expression could be independent prognostic indicators of better survival. None of CD4, T-bet or CD68 was associated with survival in ether univariate or multivariate analysis. ROC and AUC showed that the predictive accuracy of CD8 and CD57 were all superior compared with TNM staging. CD57 (AUC = 0.868; 95% CI, 0.785–0.950) and CD8 (AUC = 0.784; 95% CI, 0.680–0.889) both provided high predictive accuracy, of which, CD57 was the best predictor.

Conclusion

Tumor stroma CD57 and CD8 expression was associated with lymphnode status and independently predicts survival of OSCC patients. Our results suggest an active immune microenvironment in OSCC that may be targetable by immune drugs.

from Cancer via ola Kala on Inoreader http://ift.tt/2s4nd6y
via IFTTT

GABPA predicts prognosis and inhibits metastasis of hepatocellular carcinoma

Abstract

Background

Increasing evidence indicates that abnormal expression of GABPA is associated with tumor development and progression. However, the function and clinicopathological significance of GABPA in hepatocellular carcinoma (HCC) remain obscure.

Methods

The mRNA and protein expression of GABPA in HCC clinical specimens and cell lines was examined by real-time PCR and western blotting, respectively. Follow-up data were used to uncover the relationship between GABPA expression and the prognosis of HCC patients. HCC cell lines stably overexpressing or silencing GABPA were established to explore the function of GABPA in HCC cell migration and invasion by Transwell and wound healing assays in vitro and in a xenograft model in vivo. Restoration of function analysis was used to examine the underlying molecular mechanisms.

Results

GABPA was downregulated at the protein and mRNA levels in HCC tissues compared with adjacent normal tissues. Decreased GABPA expression was correlated with alpha-fetoprotein levels (P = 0.001), tumor grade (P = 0.017), and distant metastasis (P = 0.021). Kaplan-Meier survival analysis showed that patients with lower GABPA expression had significantly shorter survival times than those with higher GABPA (P = 0.031). In vivo and in vitro assays demonstrated that GABPA negatively regulated HCC cell migration and invasion, and the effect of GABPA on HCC cell migration was mediated at least partly by the regulation of E-cadherin.

Conclusions

Collectively, our data indicate that GABPA inhibits HCC cell migration by modulating E-cadherin and could serve as a novel biomarker for HCC prognosis. GABPA may act as a tumor suppressor during HCC progression and metastasis, and is a potential therapeutic target in HCC.

from Cancer via ola Kala on Inoreader http://ift.tt/2r6aZ01
via IFTTT

Survival and axillary recurrence following sentinel node-positive breast cancer without completion axillary lymph node dissection: the randomized controlled SENOMAC trial

Abstract

Background

The role of axillary lymph node dissection (ALND) has increasingly been called into question among patients with positive sentinel lymph nodes. Two recent trials have failed to show a survival difference in sentinel node-positive breast cancer patients who were randomized either to undergo completion ALND or not. Neither of the trials, however, included breast cancer patients undergoing mastectomy or those with tumors larger than 5 cm, and power was debatable to show a small survival difference.

Methods

The prospective randomized SENOMAC trial includes clinically node-negative breast cancer patients with up to two macrometastases in their sentinel lymph node biopsy. Patients with T1-T3 tumors are eligible as well as patients prior to systemic neoadjuvant therapy. Both breast-conserving surgery and mastectomy, with or without breast reconstruction, are eligible interventions. Patients are randomized 1:1 to either undergo completion ALND or not by a web-based randomization tool. This trial is designed as a non-inferiority study with breast cancer-specific survival at 5 years as the primary endpoint. Target accrual is 3500 patients to achieve 80% power in being able to detect a potential 2.5% deterioration of the breast cancer-specific 5-year survival rate. Follow-up is by annual clinical examination and mammography during 5 years, and additional controls after 10 and 15 years. Secondary endpoints such as arm morbidity and health-related quality of life are measured by questionnaires at 1, 3 and 5 years.

Discussion

Several large subgroups of breast cancer patients, such as patients undergoing mastectomy or those with larger tumors, have not been included in key trials; however, the use of ALND is being questioned even in these groups without the support of high-quality evidence. Therefore, the SENOMAC Trial will investigate the need of completion ALND in case of limited spread to the sentinel lymph nodes not only in patients undergoing any breast surgery, but also in neoadjuvantly treated patients and patients with larger tumors.

Trial registration

NCT 02240472, retrospective registration date September 14, 2015 after trial initiation on January 31, 2015.

from Cancer via ola Kala on Inoreader http://ift.tt/2s4plLF
via IFTTT

An increase in long non-coding RNA PANDAR is associated with poor prognosis in clear cell renal cell carcinoma

Abstract

Background

Nearly 30% of clear cell renal cell carcinoma (ccRCC) patients present with metastasis at the time of diagnosis, and the prognosis for these patients is poor. Therefore, novel potential prognostic biomarkers and therapeutic targets for ccRCC could be helpful. Emerging evidence indicates that lncRNAs play important roles in cancer tumorigenesis and could be used as potential biomarkers or therapeutic targets. PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) is a relatively novel lncRNA that plays an important role in the development of multiple cancers. However, the clinical significance and molecular mechanism of PANDAR in ccRCC are still elusive. In the present study, we attempted to elucidate the role of PANDAR in ccRCC.

Methods

The relative expression level of lncRNA PANDAR was quantified by real-time qPCR in 62 paired ccRCC tissues and in renal cancer cell lines, and its association with overall survival was assessed by statistical analysis. The biological functions of lncRNA PANDAR on ccRCC cells were determined both in vitro and in vivo.

Results

PANDAR expression was significantly upregulated in tumor tissues and cell lines compared with normal counterparts. Moreover, PANDAR served as an independent predictor of overall survival, and increased PANDAR expression was positively correlated with an advanced TNM stage. Further experiments demonstrated that PANDAR silencing can significantly inhibit cell proliferation and invasion, induce cell cycle arrest in the G1 phase and significantly promote apoptosis in 7860 and Caki-1 cell lines. In addition, in vivo experiments confirmed that downregulation of PANDAR inhibited the tumorigenic ability of 7860 cells in nude mice. Silencing of PANDAR also inhibited the expression of Bcl-2 and Mcl-1 and upregulated the expression of Bax in vivo.

Conclusions

Our results suggest that PANDAR is involved in ccRCC progression and may serve as a potential prognostic biomarker and therapeutic target.

from Cancer via ola Kala on Inoreader http://ift.tt/2s4jqq6
via IFTTT

Phase I/II study of induction chemotherapy using carboplatin plus irinotecan and sequential thoracic radiotherapy (TRT) for elderly patients with limited-disease small-cell lung cancer (LD-SCLC): TORG 0604

Abstract

Background

The role of irinotecan for elderly patients with LD-SCLC has been unclear, and the timing of TRT combined with chemotherapy has not been fully evaluated.

Methods

Patients aged > 70 years with untreated, measurable, LD-SCLC, performance status (PS) 0–2, and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8, every 21 days for 4 cycles, and sequential TRT (54Gy in 27 fractions). Carboplatin doses were based on AUC of 4 and 5 (levels 1 and 2, respectively), with a fixed irinotecan dose (50 mg/m²). Primary objective of the phase II study was overall responce rate.

Results

Forty-three patients were enrolled and forty-one were finally analyzed (median age: 75 years [range 70–86 years); males 31; PS 0/1/2, n = 22/18/1]. Two patients were excluded because of protocol violation (ascertained to be extensive disease). Twelve patients were accrued at phase I and the number of patients with carboplatin dose-limiting toxicities at levels-1 (n = 6) and −2 (n = 6) were 1(grade 3 hypertension) and 2 (grade 4 thrombocytopenia), respectively. The phase II trial was expanded to 29 additional patients receiving the level 1 carboplatin dose, total of 35 patients. The median number of chemotherapy cycles was 4 (range 1–4), and the median radiation dose was 54Gy (range 36–60). Toxicities were generally mild. There were 4 complete and 27 partial responses (response rate 88.6%). With a median follow-up of 52 months, the median progression-free and overall survival times of phase II were 11.2 and 27.1 months, respectively.

Conclusions

Induction chemotherapy of carboplatin plus irinotecan and sequential TRT was well tolerated and effective for elderly patients with LD-SCLC. Additional confirmatory studies are warranted.

Trial registration

Trial registration number: UMIN000007352

Name of registry: UMIN.

Date of registration: 1/Dec/2006.

Date of enrolment of the first participant to the trial: 6/Feb/2007.

Clinical trial registration date: 1/Feb/2006 (prospective).

http://ift.tt/2s4dAEQ

Role of peptidylarginine deiminase 2 (PAD2) in mammary carcinoma cell migration

Abstract

Background

Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process.

Methods

For our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes in cell migration and cell morphology. We also used these PAD2-modulated cells to test whether PAD2 may be required for EGF-induced cell migration. To determine how PAD2 might promote tumor cell migration in vivo, we tested the effects of PAD2 inhibition on the expression of several cell migration mediators in MCF10DCIS.com xenograft tumors. In addition, we tested the effect of PAD2 inhibition on EGF-induced ductal invasion and elongation in primary mouse mammary organoids. Lastly, using a transgenic mouse model, we investigated the effects of PAD2 overexpression on mammary gland development.

Results

Our results indicate that PAD2 depletion or inhibition suppresses cell migration and alters the morphology of MCF10DCIS.com cells. In addition, we found that PAD2 depletion suppresses the expression of the cytoskeletal regulatory proteins RhoA, Rac1, and Cdc42 and also promotes a mesenchymal to epithelial-like transition in tumor cells with an associated increase in the cell adhesion marker, E-cadherin. Our mammary gland organoid study found that inhibition of PAD2 activity suppresses EGF-induced ductal invasion. In vivo, we found that PAD2 overexpression causes hyperbranching in the developing mammary gland.

Conclusion

Together, these results suggest that PAD2 plays a critical role in breast cancer cell migration. Our findings that EGF treatment increases protein citrullination and that PAD2 inhibition blocks EGF-induced cell migration suggest that PAD2 likely functions within the EGF signaling pathway to mediate cell migration.

http://ift.tt/2s4kaeN

JS-K, a nitric oxide pro-drug, regulates growth and apoptosis through the ubiquitin-proteasome pathway in prostate cancer cells

Abstract

Background

In view of the fact that JS-K might regulate ubiquitin E3 ligase and that ubiquitin E3 ligase plays an important role in the mechanism of CRPC formation, the goal was to investigate the probable mechanism by which JS-K regulates prostate cancer cells.

Methods

Proliferation inhibition by JS-K on prostate cancer cells was examined usingCCK-8 assays. Caspase 3/7 activity assays and flow cytometry were performed to examine whether JS-K induced apoptosis in prostate cancer cells. Western blotting and co-immunoprecipitation analyses investigated JS-K's effects on the associated apoptosis mechanism. Real time-PCR and Western blotting were performed to assess JS-K's effect on transcription of specific AR target genes. Western blotting was also performed to detect Siah2 and AR protein concentrations and co-immunoprecipitation to detect interactions of Siah2 and AR, NCoR1 and AR, and p300 and AR.

Results

JS-K inhibited proliferation and induced apoptosis in prostate cancer cells. JS-K increased p53 and Mdm2 concentrations and regulated the caspase cascade reaction-associated protein concentrations. JS-K inhibited transcription of AR target genes and down-regulated PSA protein concentrations. JS-K inhibited Siah2 interactions and also inhibited the ubiquitination of AR. With further investigation, JS-K was found to stabilize AR and NCoR1 interactions and diminish AR and p300 interactions.

Conclusions

The present results suggested that JS-K might have been able to inhibit proliferation and induce apoptosis via regulation of the ubiquitin-proteasome degradation pathway, which represented a promising platform for the development of new compounds for PCa treatments.

http://ift.tt/2r5YTUH

Expression of von Hippel–Lindau tumor suppressor protein (pVHL) characteristic of tongue cancer and proliferative lesions in tongue epithelium

Abstract

Background

Patients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel–Lindau (VHL) tumor suppressor gene. However, expression of VHL protein (pVHL) in tongue cancer has rarely been investigated and remains largely unknown. We performed immunohistochemical staining of pVHL in tongue tissues and dysplasia, and examined the association with LOH and its clinical significance.

Methods

Immunohistochemical staining of pVHL in formalin-fixed, paraffin-embedded sections of cancerous and other tissues from 19 tongue cancer patients showed positivity for LOH of VHL in four samples, negativity in four samples, and was non-informative in 11 samples. The staining pattern of pVHL was also compared with those of cytokeratin (CK) 13 and CK17.

Results

In normal tongue tissues, pVHL staining was localized to the cytoplasm of cells in the basal layer and the area of the spinous layer adjacent to the basal layer of stratified squamous epithelium. Positive staining for pVHL was observed in the cytoplasm of cancer cells from all 19 tongue cancer patients. No differences as a result of the presence or absence of LOH were found. Notably, cytoplasm of poorly differentiated invasive cancer cells was less intensely stained than that of well and moderately differentiated invasive cancer cells. pVHL staining was also evident in epithelial dysplasia lesions with pVHL-positive cells expanding from the basal layer to the middle of the spinous layer. However, no CK13 staining was noted in regions of the epithelium, which were positive for pVHL. In contrast, regions with positive staining for CK17 closely coincided with those positive for pVHL.

Conclusions

Positive staining for pVHL was observed in cancerous areas but not in normal tissues. pVHL expression was also detected in lesions of epithelial dysplasia. These findings suggest that pVHL may be a useful marker for proliferative lesions.

http://ift.tt/2s4cN6T

Switch in KRAS mutational status during an unusual course of disease in a patient with advanced pancreatic adenocarcinoma: implications for translational research

Abstract

Background

Despite the introduction of novel effective treatment regimens like gemcitabine plus nab-paclitaxel and FOLFIRINOX, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive epithelial tumors. Among the genetic alterations frequently found in PDAC, mutations in the KRAS gene might play a prognostic role regarding overall survival and may also have the potential to predict the efficacy of anti-EGFR treatment.

Case presentation

We report the clinical case of a 69 year old Caucasian female that was diagnosed with histologically confirmed locally advanced PDAC with lymph node involvement in August 2010. At the time of first diagnosis, tumor tissue obtained from an open regional lymph node biopsy showed a poorly differentiated adenocarcinoma with a wild type sequence within exon 2 (codon 12/13) of the KRAS gene. The patient initially received single-agent gemcitabine and a subsequent 5-FU-based chemoradiotherapy with a sequential maintenance chemotherapy with oral capecitabine resulting in a long term disease control. Local disease progression occurred in May 2014 and the patient underwent pancreaticoduodenectomy in September 2014. A novel KRAS gene mutation (c.35G > T, p.G12 V) in exon 2 (codon 12) was detected within the surgical specimen. As of January 2016 the patient is still alive and without evidence of the underlying disease.

Conclusions

Specifically in the context of clinical trials and translational research in PDAC a re-assessment of molecular biomarkers, i. e. KRAS, at defined time points (e. g. relapse, disease progression, unusual clinical course) may be indicated in order to detect a potential switch in biomarker status during the course of disease.

http://ift.tt/2r6bVBo

Prognostic significance of tumor infiltrating immune cells in oral squamous cell carcinoma

Abstract

Background

Prognostic factors aid in the stratification and treatment of cancer. This study evaluated prognostic importance of tumor infiltrating immune cell in patients with oral squamous cell carcinoma.

Methods

Profiles of infiltrating immune cells and clinicopathological data were available for 78 OSCC patients with a median follow-up of 48 months. The infiltrating intensity of CD8, CD4, T-bet, CD68 and CD57 positive cells were assessed by immunohistochemistry. Chi-square test was used to compare immune markers expression and clinicopathological parameters. Univariate and multivariate COX proportional hazard models were used to assess the prognostic discriminator power of immune cells. The predictive potential of immune cells for survival of OSCC patients was determined using ROC and AUC.

Results

The mean value of CD8, CD4, T-bet, CD68 and CD57 expression were 28.99, 62.06, 8.97, 21.25 and 15.75 cells per high-power field respectively. The patient cohort was separated into low and high expression groups by the mean value. Higher CD8 expression was associated with no regional lymph node metastasis (p = 0.033). Patients with more abundant stroma CD57⁺ cells showed no metastasis into regional lymph node (p = 0.005), and early clinical stage (p = 0.016). The univariate COX regression analyses showed that no lymph node involvement (p < 0.001), early clinical stage (TNM staging I/II vs III/IV, p = 0.007), higher CD8 and CD57 expression (p < 0.001) were all positively correlated with longer overall survival. Multivariate COX regression analysis showed that no lymph node involvement (p = 0.008), higher CD8 (p = 0.03) and CD57 (p < 0.001) expression could be independent prognostic indicators of better survival. None of CD4, T-bet or CD68 was associated with survival in ether univariate or multivariate analysis. ROC and AUC showed that the predictive accuracy of CD8 and CD57 were all superior compared with TNM staging. CD57 (AUC = 0.868; 95% CI, 0.785–0.950) and CD8 (AUC = 0.784; 95% CI, 0.680–0.889) both provided high predictive accuracy, of which, CD57 was the best predictor.

Conclusion

Tumor stroma CD57 and CD8 expression was associated with lymphnode status and independently predicts survival of OSCC patients. Our results suggest an active immune microenvironment in OSCC that may be targetable by immune drugs.

http://ift.tt/2s4nd6y

GABPA predicts prognosis and inhibits metastasis of hepatocellular carcinoma

Abstract

Background

Increasing evidence indicates that abnormal expression of GABPA is associated with tumor development and progression. However, the function and clinicopathological significance of GABPA in hepatocellular carcinoma (HCC) remain obscure.

Methods

The mRNA and protein expression of GABPA in HCC clinical specimens and cell lines was examined by real-time PCR and western blotting, respectively. Follow-up data were used to uncover the relationship between GABPA expression and the prognosis of HCC patients. HCC cell lines stably overexpressing or silencing GABPA were established to explore the function of GABPA in HCC cell migration and invasion by Transwell and wound healing assays in vitro and in a xenograft model in vivo. Restoration of function analysis was used to examine the underlying molecular mechanisms.

Results

GABPA was downregulated at the protein and mRNA levels in HCC tissues compared with adjacent normal tissues. Decreased GABPA expression was correlated with alpha-fetoprotein levels (P = 0.001), tumor grade (P = 0.017), and distant metastasis (P = 0.021). Kaplan-Meier survival analysis showed that patients with lower GABPA expression had significantly shorter survival times than those with higher GABPA (P = 0.031). In vivo and in vitro assays demonstrated that GABPA negatively regulated HCC cell migration and invasion, and the effect of GABPA on HCC cell migration was mediated at least partly by the regulation of E-cadherin.

Conclusions

Collectively, our data indicate that GABPA inhibits HCC cell migration by modulating E-cadherin and could serve as a novel biomarker for HCC prognosis. GABPA may act as a tumor suppressor during HCC progression and metastasis, and is a potential therapeutic target in HCC.

http://ift.tt/2r6aZ01

Survival and axillary recurrence following sentinel node-positive breast cancer without completion axillary lymph node dissection: the randomized controlled SENOMAC trial

Abstract

Background

The role of axillary lymph node dissection (ALND) has increasingly been called into question among patients with positive sentinel lymph nodes. Two recent trials have failed to show a survival difference in sentinel node-positive breast cancer patients who were randomized either to undergo completion ALND or not. Neither of the trials, however, included breast cancer patients undergoing mastectomy or those with tumors larger than 5 cm, and power was debatable to show a small survival difference.

Methods

The prospective randomized SENOMAC trial includes clinically node-negative breast cancer patients with up to two macrometastases in their sentinel lymph node biopsy. Patients with T1-T3 tumors are eligible as well as patients prior to systemic neoadjuvant therapy. Both breast-conserving surgery and mastectomy, with or without breast reconstruction, are eligible interventions. Patients are randomized 1:1 to either undergo completion ALND or not by a web-based randomization tool. This trial is designed as a non-inferiority study with breast cancer-specific survival at 5 years as the primary endpoint. Target accrual is 3500 patients to achieve 80% power in being able to detect a potential 2.5% deterioration of the breast cancer-specific 5-year survival rate. Follow-up is by annual clinical examination and mammography during 5 years, and additional controls after 10 and 15 years. Secondary endpoints such as arm morbidity and health-related quality of life are measured by questionnaires at 1, 3 and 5 years.

Discussion

Several large subgroups of breast cancer patients, such as patients undergoing mastectomy or those with larger tumors, have not been included in key trials; however, the use of ALND is being questioned even in these groups without the support of high-quality evidence. Therefore, the SENOMAC Trial will investigate the need of completion ALND in case of limited spread to the sentinel lymph nodes not only in patients undergoing any breast surgery, but also in neoadjuvantly treated patients and patients with larger tumors.

Trial registration

NCT 02240472, retrospective registration date September 14, 2015 after trial initiation on January 31, 2015.

http://ift.tt/2s4plLF

An increase in long non-coding RNA PANDAR is associated with poor prognosis in clear cell renal cell carcinoma

Abstract

Background

Nearly 30% of clear cell renal cell carcinoma (ccRCC) patients present with metastasis at the time of diagnosis, and the prognosis for these patients is poor. Therefore, novel potential prognostic biomarkers and therapeutic targets for ccRCC could be helpful. Emerging evidence indicates that lncRNAs play important roles in cancer tumorigenesis and could be used as potential biomarkers or therapeutic targets. PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) is a relatively novel lncRNA that plays an important role in the development of multiple cancers. However, the clinical significance and molecular mechanism of PANDAR in ccRCC are still elusive. In the present study, we attempted to elucidate the role of PANDAR in ccRCC.

Methods

The relative expression level of lncRNA PANDAR was quantified by real-time qPCR in 62 paired ccRCC tissues and in renal cancer cell lines, and its association with overall survival was assessed by statistical analysis. The biological functions of lncRNA PANDAR on ccRCC cells were determined both in vitro and in vivo.

Results

PANDAR expression was significantly upregulated in tumor tissues and cell lines compared with normal counterparts. Moreover, PANDAR served as an independent predictor of overall survival, and increased PANDAR expression was positively correlated with an advanced TNM stage. Further experiments demonstrated that PANDAR silencing can significantly inhibit cell proliferation and invasion, induce cell cycle arrest in the G1 phase and significantly promote apoptosis in 7860 and Caki-1 cell lines. In addition, in vivo experiments confirmed that downregulation of PANDAR inhibited the tumorigenic ability of 7860 cells in nude mice. Silencing of PANDAR also inhibited the expression of Bcl-2 and Mcl-1 and upregulated the expression of Bax in vivo.

Conclusions

Our results suggest that PANDAR is involved in ccRCC progression and may serve as a potential prognostic biomarker and therapeutic target.

http://ift.tt/2s4jqq6

Microglia-glioblastoma interactions: New role for Wnt signaling

Publication date: Available online 26 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): D. Matias, D. Predes, P. Niemeyer Filho, J.G. Abreu, F.R.S. Lima, V. Moura Neto
Glioblastoma, the most aggressive and fatal type of brain tumor, is capable of interacting with brain immune cells such as microglia, which contributes to the growth of these tumors. Various molecules, including growth factors and cytokines, have been identified as regulators of microglia-glioblastoma interaction. Recent studies suggest that the Wnt family of lipoglycoproteins plays an important role, not only in biological events during development, but also in cancer progression, and can be part of microglia recruitment to glioblastoma as well as of tumor growth and invasion. Here, we discuss recent interesting findings that support a role for Wnt signaling pathways in the microglia-glioblastoma crosstalk.



http://ift.tt/2qX3OGX

Human cytomegalovirus-mediated immunomodulation: effects on glioblastoma progression

Publication date: Available online 26 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Haidn Foster, Ilya V. Ulasov, Charles S. Cobbs
The presence of human cytomegalovirus (HCMV) and glioblastoma multiforme (GBM), first established in 2002, has developed into an area of considerable interest and controversy. Numerous studies have found evidence of possible HCMV infection of GBM tumor cells as well as myriad onco- and immunomodulatory properties exhibited by HCMV antigens and transcripts, while recent reports have failed to detect HCMV particles in GBM and question the virus' role in tumor progression. This review highlights the known immunomodulatory properties of HCMV, independent of GBM infection status, that help drive the virus from peripheral blood into the vital tissues and subsequently dampen local immune response, assisting GBM tumors in evading immune surveillance and contributing to the disease's poor prognosis. Emerging antiviral approaches to treating GBM, including antiviral drugs and immunotherapies directed against HCMV, are also examined.



http://ift.tt/2qrAKEd

Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands

Summary

Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase such as imatinib and dasatinib exhibit remarkable therapeutic effects, though emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to down-regulate the BCR-ABL protein. We have devised a protein knockdown system by hybrid molecules named SNIPERs (Specific and Non-genetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers), which is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR-ABL protein has been developed recently. In this study, we tested various combinations of ABL inhibitors and IAP ligands, and the linker was optimized for protein knockdown activity of SNIPER(ABL). The resulting SNIPER(ABL)-39, in which dasatinib is conjugated to an IAP ligand LCL161 derivative by polyethylene glycol (PEG) × 3 linker, shows a potent activity to degrade the BCR-ABL protein. Mechanistic analysis suggested that both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP) play a role in the degradation of BCR-ABL protein. Consistent with the degradation of BCR-ABL protein, the SNIPER(ABL)-39 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and Crk like proto-oncogene (CrkL), and suppressed the growth of BCR-ABL-positive CML cells. These results suggest that SNIPER(ABL)-39 could be a lead for a degradation-based novel anti-cancer drug against BCR-ABL-positive CML.

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Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands

Summary

Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase such as imatinib and dasatinib exhibit remarkable therapeutic effects, though emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to down-regulate the BCR-ABL protein. We have devised a protein knockdown system by hybrid molecules named SNIPERs (Specific and Non-genetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers), which is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR-ABL protein has been developed recently. In this study, we tested various combinations of ABL inhibitors and IAP ligands, and the linker was optimized for protein knockdown activity of SNIPER(ABL). The resulting SNIPER(ABL)-39, in which dasatinib is conjugated to an IAP ligand LCL161 derivative by polyethylene glycol (PEG) × 3 linker, shows a potent activity to degrade the BCR-ABL protein. Mechanistic analysis suggested that both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP) play a role in the degradation of BCR-ABL protein. Consistent with the degradation of BCR-ABL protein, the SNIPER(ABL)-39 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and Crk like proto-oncogene (CrkL), and suppressed the growth of BCR-ABL-positive CML cells. These results suggest that SNIPER(ABL)-39 could be a lead for a degradation-based novel anti-cancer drug against BCR-ABL-positive CML.

This article is protected by copyright. All rights reserved.

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Paraneoplastic neuromyotonia due to lung carcinoma and invisible muscle cramps evaluated using ultrasonography

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Neuro-oncology family caregivers’ view on keeping track of care issues using eHealth systems: it’s a question of time

Abstract

Primary brain tumors (PBTs) are rare but have a great impact on both patient and family caregiver wellbeing. Supporting caregivers can help them to continue their caregiving activities to maintain the patients' best possible level of quality of life. Efforts to improve PBT caregiver wellbeing should take into account country- or culture-specific differences in care issues and supportive care needs to serve larger caregiver groups. We aimed to explore PBT caregivers' satisfaction with the current supportive care provision, as well as their thoughts on monitoring their care issues with both paper-based and digital instruments. Twelve PBT caregivers were interviewed in the United States. The semi-structured interviews were transcribed verbatim and analyzed by two coders independently. Data were combined with those collected in the Netherlands, following similar methodology (N = 15). We found that PBT caregivers utilize both formal and informal support services, but that those who experience more care issues would prefer more support, particularly in the early disease phase. Keeping track of care issues was thought to provide more insight into unmet needs and help them find professional help, but it requires investment of time and takes discipline. Caregivers preferred a brief and easy-to-use 'blended care' instrument that combines digital monitoring with personal feedback. The present study shows that the preferences of family caregivers in neuro-oncology toward keeping track of care issues are likely not heavily influenced by country- or culture-specific differences. The development of any instrument thus has the potential to benefit a large group of family caregivers.

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Novel Treatment Options for Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are not as rare as once thought, with a current prevalence that is estimated to be higher than that of many other gastrointestinal tumors. Multiple treatment options are available for these tumors, which are categorized according to their histology and site of origin. For patients with metastatic disease, somatostatin analogues are often the initial treatment, with other options considered when these drugs fail.

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What, When, and How of Biomarker Testing in Non-Small Cell Lung Cancer

Biomarker testing is recommended for all patients diagnosed with non–small cell lung cancer. At a minimum, testing should include the mutations/fusions EGFR, ALK, ROS1, and the protein programmed death ligand-1 (PD-L1), because FDA-approved therapies are available for these alterations. Other actionable molecular findings include RET rearrangements, BRAF^V600E mutations, and MET exon 14 alterations. If adequate testing was not performed at treatment initiation, molecular testing should be performed before administration of subsequent lines of therapy. In patients with EGFR-mutant lung cancer, when resistance develops, physicians should seek to identify the T790M mutation using plasma and tissue assays, because osimertinib therapy is available for this mutation.

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The NCCN 22nd Annual Conference: Discussing Treatment Disparities, the Doctor-Patient Relationship, the Latest NCCN Guidelines Updates, and More

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Biomarker-Based Treatment Selection in Non-Small Cell Lung Cancer

Patients with non–small cell lung cancer must be tested for biomarkers. Currently, treatments directed against EGFR, ALK, and ROS1 mutations are standard of care. A number of emerging new targets and treatments are on the horizon.

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Chronic Lymphocytic Leukemia: Individualizing Treatment Approach

A host of new therapies are now available for treating patients with chronic lymphocytic leukemia (CLL) in both the upfront and relapsed or refractory settings. Although the optimal use of these agents is still being defined, established and emerging prognostic markers aid in the selection of appropriate treatment with the best chance of success. At the NCCN 22nd Annual Conference, Dr. Andrew Zelenetz discussed the role of the CLL-International Prognostic Index for risk stratification, reviewed optimal first-line therapy options, and then presented updated clinical trial data on the novel agents being used in the relapsed or refractory setting. The hope is that chronic therapy will be replaced by combinations that provide high rates of minimal residual disease negativity with durable remissions.

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Immunotherapies for Lung Cancer

In 2017, immunotherapy is the standard of care for patients with non–small cell lung cancer (NSCLC) either in the first or second line depending on programmed death ligand-1 (PD-L1) and mutation status. For first-line therapy, pembrolizumab is currently the standard of care for patients whose tumors express PD-L1 >50%. All patients with NSCLC should undergo PD-L1 testing before initiating treatment on pembrolizumab. For patients not eligible in the first line, immunotherapy is the standard of care for most in the second line. Nivolumab and atezolizumab are approved in all patients as second-line therapies after platinum-based doublet failure regardless PD-L1 expression level, although pembrolizumab is approved as second-line therapy for those whose tumors express PD-L1 >1%.

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NCCN Debuts New Guidelines for Myeloproliferative Neoplasms

For the first time, NCCN has published guidelines specifically geared toward treating myeloproliferative neoplasms (MPNs). The first set of guidelines was developed for myelofibrosis (MF), and was presented at the NCCN 22nd Annual Conference. Future guidelines will be issued for polycythemia vera, essential thrombocytopenia, and atypical MPNs. Patients with MF can have an unpredictable course, one that is largely dependent on the presence of certain molecular alterations. Models are currently emerging that take into account molecular factors. Only one drug is currently approved for MF, the oral JAK1/2 inhibitor ruxolitinib, which has been shown to significantly reduce splenomegaly and improve symptoms.

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Keynote Address: When Breath Becomes Air--As Physician Becomes Patient

As part of the NCCN 22nd Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care, Lucy Kalanithi, MD, wife of now-deceased best-selling author Paul Kalanithi (When Breath Becomes Air), and Heather Wakelee, MD, Paul's oncologist, discussed—for the first time together in a public forum—Paul's experience of going from a neurosurgery resident to a patient with cancer with a terminal diagnosis. Robert Carlson, MD, moderated the discussion.

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Opportunities and Challenges: Human Papillomavirus and Cancer

Mucosal exposure to human papillomavirus (HPV) can lead to anogenital and head and neck (H&N) cancer. Vaccination at a young age can be almost 100% effective in preventing HPV infection with the viral subtypes in both men and women, at least for disease in the anogenital tract. Therapeutic strategies targeting HPV in cervical dysplasia and cancer are showing promise as well in regressing dysplasia and controlling disease. That HPV-positive H&N cancer is a different disease from HPV-negative disease, with different molecular and clinical features and prognosis, is becoming better appreciated. At this time, however, the NCCN Guidelines for H&N Cancers do not distinguish between the types. This is expected to change.

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Systemic Management of Colorectal Cancer

Advances have been made in the systemic treatment of colorectal cancer, with approximately 12 chemotherapy or biologic agents approved for use as a single agent or in a combination. However, numerous gaps in our understanding of the disease remain, such as the lack of benefit with biologics in the adjuvant setting, the absence of biomarkers for most systemic therapies, and the reason why left-sided and right-sided tumors behave differently. At the 22nd NCCN Annual Conference, Dr. Wells A. Messersmith presented several impactful updates to the 2017 NCCN Clinical Practice Guidelines in Oncology for Colon Cancer and reviewed the outcomes with a host of therapies used for both early-stage and metastatic disease.

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Strategies for Management of Relapsed or Refractory Hodgkin Lymphoma

The advent of effective therapies has improved outcomes for those with newly diagnosed Hodgkin lymphoma (HL), with a resulting cure rate of at least 80%. However, with limited data on therapeutic options in the setting of advanced disease, individualized treatment is recommended, and potential long-term effects of therapy remain a key consideration. At the NCCN 22nd Annual Conference, Dr. Leo I. Gordon explored strategies for systemic therapy in the relapsed or refractory setting, focusing primarily on the standard of high-dose therapy/autologous stem cell rescue, the CD30-targeted antibody drug conjugate brentuximab vedotin, and checkpoint inhibition.

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Abstracts From the NCCN 22nd Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care™

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Life After Treatment: Quality-of-Life Concerns in Patients Treated for Cancer

Traditionally, the physical, psychological, and psychosocial long-term needs of cancer survivors have received little attention compared with screening for cancer recurrence and secondary cancers. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Survivorship offer recommendations for various survivorship concerns, and those for improving menopausal symptoms were presented at the NCCN 22nd Annual Conference. Key considerations in managing menopausal symptoms in cancer survivors were reviewed, with chemotherapy-induced amenorrhea, fertility concerns, and both hormonal and nonhormonal therapeutic options featured.

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NCCN Roundtable Tackles Disparities in Cancer Care

During a roundtable on disparities in cancer care at the recent NCCN 22nd Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care, panelists from a variety of disciplines brought professional and personal experiences to the discussion of eliminating cancer disparities and reducing differences in incidence and mortality rates among minority populations. The panel agreed that these issues must be addressed through research in prevention, screening, clinical trials, and equal access to quality care.

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Minimally Invasive Techniques for Treating Gynecologic Malignancies

For many women with endometrial and cervical cancers, minimally invasive surgery represents an alternative standard of care to open abdominal procedures, with fewer complications, better postoperative quality of life, and overall lower cost. At the NCCN 22nd Annual Conference, Amanda N. Fader, MD, reviewed several minimally invasive strategies for treating gynecologic cancers, including conventional laparoscopy, robotic-assisted laparoscopy, sentinel lymph node technology, and single-port surgery; highlighted some of the contemporary literature on the role of these procedures; and explored some of the challenges and barriers to their successful performance.

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Use of Biomarkers and Multigene Assays in Breast Cancer

All patients with early breast cancer should be classified by subgroup through testing estrogen receptor, progesterone receptor, and HER2 status, with or without Ki-67 proliferation percentage. Genomic expression profiling aids clinical decision-making in most patients, because most are estrogen receptor–positive. The commercially available classifiers are prognostic for distant recurrence in node-negative and also node-positive patients. Patients at genomically low risk have excellent 5-year outcomes with endocrine therapy alone. Some assays also predict for benefit from adjuvant endocrine therapy and chemotherapy in node-negative and node-positive patients, but with varying levels of evidence. Genomic classifiers are also prognostic of late relapse and may predict benefit from extended adjuvant endocrine therapy.

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New Treatment Options for the Management of Multiple Myeloma

Multiple myeloma (MM) is a complex disease characterized by considerable genetic heterogeneity. The updated NCCN Guidelines for MM have added new "preferred" regimens for transplant and nontransplant candidates, and have moved some formerly "preferred" regimens to the "other" category. Supportive care has improved outcomes for patients, and new treatments in combination have extended survival for patients with MM. Novel agents on the horizon are poised to raise the bar even further.

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New Approaches to Endocrine Therapy for Breast Cancer

The management of advanced hormone receptor–positive disease has evolved with the emergence of CDK4/6 inhibitors. Improvements in progression-free survival of approximately 10 months were noted in pivotal trials of palbociclib. Strong efficacy was also seen with ribociclib, which was recently approved by the FDA. In the adjuvant treatment setting of hormone receptor–positive disease, an important issue for consideration is the duration of endocrine therapy.

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Active Systemic Treatment of Pancreatic Cancer

By 2020, pancreatic cancer is expected to be the second most common cause of cancer-related death, exceeded only by lung cancer. During her presentation at the NCCN 22nd Annual Conference, Dr. Margaret Tempero offered an update on the current state of systemic treatment of pancreatic cancer, focusing on resectable/borderline resectable, locally advanced, and metastatic disease.

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NCCN Guidelines Update: Evolving Radiation Therapy Recommendations for Breast Cancer

In the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, among adjuvant radiotherapy options for whole-breast irradiation after breast-conserving surgery, hypofractionation is preferred. For the use of accelerated partial-breast irradiation, the NCCN Guidelines have adopted the updated definition of "suitability" used by the American Society for Radiation Oncology. Regional nodal irradiation is indicated—either in the setting of breast-conserving surgery or after mastectomy—for women with ≥4 positive nodes and should be strongly considered for 1 to 3 positive lymph nodes and select patients with node-negative disease deemed at high risk for recurrence.

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Novel Treatment Options for Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are not as rare as once thought, with a current prevalence that is estimated to be higher than that of many other gastrointestinal tumors. Multiple treatment options are available for these tumors, which are categorized according to their histology and site of origin. For patients with metastatic disease, somatostatin analogues are often the initial treatment, with other options considered when these drugs fail.

http://ift.tt/2pWPhr5

What, When, and How of Biomarker Testing in Non-Small Cell Lung Cancer

Biomarker testing is recommended for all patients diagnosed with non–small cell lung cancer. At a minimum, testing should include the mutations/fusions EGFR, ALK, ROS1, and the protein programmed death ligand-1 (PD-L1), because FDA-approved therapies are available for these alterations. Other actionable molecular findings include RET rearrangements, BRAF^V600E mutations, and MET exon 14 alterations. If adequate testing was not performed at treatment initiation, molecular testing should be performed before administration of subsequent lines of therapy. In patients with EGFR-mutant lung cancer, when resistance develops, physicians should seek to identify the T790M mutation using plasma and tissue assays, because osimertinib therapy is available for this mutation.

http://ift.tt/2qs0lQl

The NCCN 22nd Annual Conference: Discussing Treatment Disparities, the Doctor-Patient Relationship, the Latest NCCN Guidelines Updates, and More

http://ift.tt/2pWZW5j

Biomarker-Based Treatment Selection in Non-Small Cell Lung Cancer

Patients with non–small cell lung cancer must be tested for biomarkers. Currently, treatments directed against EGFR, ALK, and ROS1 mutations are standard of care. A number of emerging new targets and treatments are on the horizon.

http://ift.tt/2qs1UOA

Chronic Lymphocytic Leukemia: Individualizing Treatment Approach

A host of new therapies are now available for treating patients with chronic lymphocytic leukemia (CLL) in both the upfront and relapsed or refractory settings. Although the optimal use of these agents is still being defined, established and emerging prognostic markers aid in the selection of appropriate treatment with the best chance of success. At the NCCN 22nd Annual Conference, Dr. Andrew Zelenetz discussed the role of the CLL-International Prognostic Index for risk stratification, reviewed optimal first-line therapy options, and then presented updated clinical trial data on the novel agents being used in the relapsed or refractory setting. The hope is that chronic therapy will be replaced by combinations that provide high rates of minimal residual disease negativity with durable remissions.

http://ift.tt/2pWZkwk

Immunotherapies for Lung Cancer

In 2017, immunotherapy is the standard of care for patients with non–small cell lung cancer (NSCLC) either in the first or second line depending on programmed death ligand-1 (PD-L1) and mutation status. For first-line therapy, pembrolizumab is currently the standard of care for patients whose tumors express PD-L1 >50%. All patients with NSCLC should undergo PD-L1 testing before initiating treatment on pembrolizumab. For patients not eligible in the first line, immunotherapy is the standard of care for most in the second line. Nivolumab and atezolizumab are approved in all patients as second-line therapies after platinum-based doublet failure regardless PD-L1 expression level, although pembrolizumab is approved as second-line therapy for those whose tumors express PD-L1 >1%.

http://ift.tt/2pX0rfn

NCCN Debuts New Guidelines for Myeloproliferative Neoplasms

For the first time, NCCN has published guidelines specifically geared toward treating myeloproliferative neoplasms (MPNs). The first set of guidelines was developed for myelofibrosis (MF), and was presented at the NCCN 22nd Annual Conference. Future guidelines will be issued for polycythemia vera, essential thrombocytopenia, and atypical MPNs. Patients with MF can have an unpredictable course, one that is largely dependent on the presence of certain molecular alterations. Models are currently emerging that take into account molecular factors. Only one drug is currently approved for MF, the oral JAK1/2 inhibitor ruxolitinib, which has been shown to significantly reduce splenomegaly and improve symptoms.

http://ift.tt/2qrUJWs

Keynote Address: When Breath Becomes Air--As Physician Becomes Patient

As part of the NCCN 22nd Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care, Lucy Kalanithi, MD, wife of now-deceased best-selling author Paul Kalanithi (When Breath Becomes Air), and Heather Wakelee, MD, Paul's oncologist, discussed—for the first time together in a public forum—Paul's experience of going from a neurosurgery resident to a patient with cancer with a terminal diagnosis. Robert Carlson, MD, moderated the discussion.

http://ift.tt/2pX0isu

Opportunities and Challenges: Human Papillomavirus and Cancer

Mucosal exposure to human papillomavirus (HPV) can lead to anogenital and head and neck (H&N) cancer. Vaccination at a young age can be almost 100% effective in preventing HPV infection with the viral subtypes in both men and women, at least for disease in the anogenital tract. Therapeutic strategies targeting HPV in cervical dysplasia and cancer are showing promise as well in regressing dysplasia and controlling disease. That HPV-positive H&N cancer is a different disease from HPV-negative disease, with different molecular and clinical features and prognosis, is becoming better appreciated. At this time, however, the NCCN Guidelines for H&N Cancers do not distinguish between the types. This is expected to change.

http://ift.tt/2qs1k34

Systemic Management of Colorectal Cancer

Advances have been made in the systemic treatment of colorectal cancer, with approximately 12 chemotherapy or biologic agents approved for use as a single agent or in a combination. However, numerous gaps in our understanding of the disease remain, such as the lack of benefit with biologics in the adjuvant setting, the absence of biomarkers for most systemic therapies, and the reason why left-sided and right-sided tumors behave differently. At the 22nd NCCN Annual Conference, Dr. Wells A. Messersmith presented several impactful updates to the 2017 NCCN Clinical Practice Guidelines in Oncology for Colon Cancer and reviewed the outcomes with a host of therapies used for both early-stage and metastatic disease.

http://ift.tt/2pXbfdo

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis

Publication date: Available online 25 May 2017
Source:Cancer Cell
Author(s): Christian Grommes, Anas Younes
In this issue of Cancer Cell, Lionakis et al. demonstrate that the combination of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib induced frequent responses in patients with primary central nervous system lymphoma but was associated with significant toxicity, including pulmonary and cerebral aspergillosis infections.

Teaser

In this issue of Cancer Cell, Lionakis et al. demonstrate that the combination of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib induced frequent responses in patients with primary central nervous system lymphoma but was associated with significant toxicity, including pulmonary and cerebral aspergillosis infections.


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Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma

Publication date: Available online 25 May 2017
Source:Cancer Cell
Author(s): Michail S. Lionakis, Kieron Dunleavy, Mark Roschewski, Brigitte C. Widemann, John A. Butman, Roland Schmitz, Yandan Yang, Diane E. Cole, Christopher Melani, Christine S. Higham, Jigar V. Desai, Michele Ceribelli, Lu Chen, Craig J. Thomas, Richard F. Little, Juan Gea-Banacloche, Sucharita Bhaumik, Maryalice Stetler-Stevenson, Stefania Pittaluga, Elaine S. Jaffe, John Heiss, Nicole Lucas, Seth M. Steinberg, Louis M. Staudt, Wyndham H. Wilson
Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy.

Teaser

Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor signaling. In a phase 1b study, Lionakis et al. observe promising therapeutic effects of the BTK inhibitor ibrutinib in PCNSL but also increased aspergillosis, which they show is linked to BTK-dependent fungal immunity in a mouse model.


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