Cancer by Sfakianakis Alexandros: 08/29/17

Τρίτη 29 Αυγούστου 2017

The use of ofatumumab in the treatment of B-cell malignancies

Future Oncology, Ahead of Print.

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MET-GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors

Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments. Experimental Design: We utilized biochemical approaches, cellular viability studies and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N=406) and patient-derived xenograft models of solid tumors (N=308). We evaluated response to crizotinib in a MET-amplified cohort of patient-derived xenografts models of lung cancer (N=6) and provide a case report of a lung cancer patient harboring a exon14 MET splice variant. Results: We found the interaction of MET with the adaptor protein GRB2 is necessary for oncogenic survival signaling by MET. MET:GRB2 complexes were identified only within MET¬¬-amplified patient-derived xenograft (PDX) models and patient specimens but exhibit substantial variability. Lack of MET:GRB2 complexes was associated with lack of response to MET TKI in cell lines and PDX models. Presence of MET:GRB2 complexes can further sub type tumors with exon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with exon14 MET lacking MET gene amplification. Conclusions: Proximity assays measuring MET:GRB2 signaling complexes provide novel insights into MET-mediated signaling and could complement current clinical genomics-based assay platforms.

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A panel of novel detection and prognostic methylated DNA markers in primary non-small cell lung cancer and serum DNA

Purpose: To establish a novel panel of cancer-specific methylated genes for cancer detection and prognostic stratification of early stage non-small cell lung cancer (NSCLC). Experimental Design: Identification of differentially methylated regions (DMRs) was performed with bumphunter on "The Cancer Genome Atlas (TCGA)" dataset, and clinical utility was assessed using quantitative methylation-specific PCR assay in multiple sets of primary NSCLC and body fluids that included serum, pleural effusion, and ascites samples. Results: A methylation panel of 6 genes (CDO1, HOXA9, AJAP1, PTGDR, UNCX, and MARCH11) was selected from TCGA dataset. Promoter methylation of the gene panel was detected in 92.2% (83/90) of the training cohort with a specificity of 72.0% (18/25) and in 93.0% (40/43) of an independent cohort of stage IA primary NSCLC. In serum samples from the later 43 stage IA subjects and population-matched 42 control subjects, the gene panel yielded a sensitivity of 72.1% (31/41) and specificity of 71.4% (30/42). Similar diagnostic accuracy was observed in pleural effusion and ascites samples. A prognostic risk category based on the methylation status of CDO1, HOXA9, PTGDR, and AJAP1 refined the risk stratification for outcomes as an independent prognostic factor for an early stage disease. Moreover, the paralogue group for HOXA9, predominantly overexpressed in subjects with HOXA9 methylation, showed poor outcomes. Conclusion: Promoter methylation of a panel of 6 genes has potential for use as a biomarker for early cancer detection and to predict prognosis at the time of diagnosis.

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Prognostic role of Epidermal growth factor receptor variant III (EGFRvIII) positivity in EGFR-amplified primary and recurrent glioblastomas

Purpose: Approximately 40% of all glioblastomas have amplified the epidermal growth factor receptor (EGFR) gene and about half of these tumors express the EGFRvIII variant. The prognostic role of EGFRvIII in EGFR-amplified glioblastoma patients and changes in EGFRvIII expression in recurrent versus primary glioblastomas remain controversial, but such data are highly relevant for EGFRvIII-targeted therapies. Experimental design: EGFR-amplified glioblastomas from 106 patients were assessed for EGFRvIII positivity. Changes in EGFR amplification and EGFRvIII status from primary to recurrent glioblastomas were evaluated in 40 patients with EGFR-amplified tumors and 33 patients with EGFR-non-amplified tumors. EGFR single nucleotide variants (SNVs) were assessed in 27 patients. Data were correlated with outcome and validated in 150 glioblastoma patients from The Cancer Genome Atlas (TCGA) consortium. Results: Sixty of 106 EGFR-amplified glioblastomas were EGFRvIII-positive (56.6%). EGFRvIII positivity was not associated with different progression-free or overall survival. EGFRvIII status was unchanged at recurrence in 35 of 40 patients with EGFR-amplified primary tumors (87.5%). Four patients lost and one patient gained EGFRvIII positivity at recurrence. None of 33 EGFR-non-amplified glioblastomas acquired EGFR amplification or EGFRvIII at recurrence. EGFR SNVs were frequent in EGFR-amplified tumors, but were not linked to survival. Conclusions: EGFRvIII and EGFR SNVs are not prognostic in EGFR-amplified glioblastoma patients. EGFR amplification is retained in recurrent glioblastomas. Most EGFRvIII-positive glioblastomas maintain EGFRvIII positivity at recurrence. However, EGFRvIII expression may change in a subset of patients at recurrence, thus repeated biopsy with reassessment of EGFRvIII status is recommended for recurrent glioblastoma patients to receive EGFRvIII-targeting agents.

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Macrophages facilitate resistance to anti-VEGF therapy by altered VEGFR expression

Purpose:VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized role of macrophages in such resistance. Macrophages were actively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophage-deficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current anti-angiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers.

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Low-dose cyclophosphamide induces anti-tumor T-cell responses which associate with survival in metastatic colorectal cancer

Purpose: Anti-cancer T-cell responses can control tumors, but immune-suppressive mechanisms in vivo prevent their function. The role of regulatory T-cells (Tregs) in metastatic colorectal cancer (mCRC) is unclear. We have previously shown depletion of Tregs enhances CRC-specific effector T-cell responses. Low dose cyclophosphamide (CPM) targets Tregs in animal models and some human studies, however the effect of CPM in mCRC is unknown. Experimental Design: Fifty-five mCRC patients were enrolled onto a phase I/II trial and randomized to receive two week-long courses of low-dose (50mg twice-a-day) CPM or not. The absolute number, phenotype and anti-tumor function of peripheral blood-derived lymphocyte subsets were monitored throughout treatment, along with 18-month follow-up. Results: Initially CPM reduced proliferation in all lymphocyte subsets, however, a rapid mobilization of effector T-cells overcame this decrease, leading to increased absolute T-cell numbers. In contrast, a reduction in proportional and absolute Treg, B-cell and NK-cell numbers occurred. The expansion and subsequent activation of effector T-cells was focused on tumor-specific T-cells, producing both granzyme B and IFN-gamma. CPM-treated patients demonstrating the most enhanced IFN-gamma+ tumor-specific T-cell responses exhibited a significant delay in tumor progression (HR=0.29, 95% CI 0.12-0.69, P=0.0047), compared to non-responders and no-treatment controls. Conclusions: CPM-induced Treg-depletion is mirrored by a striking boost to anti-tumor immunity. This study provides the first direct evidence of the benefit of naturally primed T-cells in mCRC patients. Our results also support the concept that non-mutated self-antigens can act as useful targets for immunotherapies.

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Non-Hodgkin and Hodgkin lymphomas select for overexpression of BCLW

Purpose: B-cell lymphomas must acquire resistance to apoptosis during their development. We recently discovered BCLW, an anti-apoptotic BCL2 family member thought only to contribute to spermatogenesis, was overexpressed in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. To gain insight into the contribution of BCLW to B-cell lymphomas and its potential to confer resistance to BCL2 inhibitors, we investigated the expression of BCLW and the other anti-apoptotic BCL2 family members in six different B-cell lymphomas. Experimental Design: We performed a large-scale gene expression analysis of data sets comprising approximately 2300 lymphoma patient samples, including non-Hodgkin and Hodgkin lymphomas as well as indolent and aggressive lymphomas. Data were validated experimentally with qRT-PCR and immunohistochemistry. Results: We report BCLW is significantly overexpressed in aggressive and indolent lymphomas, including DLBCL, Burkitt, follicular, mantle cell, marginal zone, and Hodgkin lymphomas. Notably, BCLW was preferentially overexpressed over that of BCL2 and negatively correlated with BCL2 in specific lymphomas. Unexpectedly, BCLW was overexpressed as frequently as BCL2 in follicular lymphoma. Evaluation of all five anti-apoptotic BCL2 family members in six types of B-cell lymphoma revealed that BCL2, BCLW, and BCLX were consistently overexpressed, whereas MCL1 and A1 were not. Additionally, individual lymphomas frequently overexpressed more than one anti-apoptotic BCL2 family member. Conclusions: Our comprehensive analysis indicates B-cell lymphomas commonly select for BCLW overexpression in combination with or instead of other anti-apoptotic BCL2 family members. Our results suggest BCLW is likely equally as important in lymphomagenesis as BCL2 and that targeting BCLW in lymphomas should be considered.

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Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies

Summary

Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC_0-inf) and maximum concentrations (C_max) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC_0-inf and C_max in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC_0-inf and C_max in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC_0-inf and C_max in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib.

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Influence of tumor response and treatment schedule on the distribution of tumor recurrence in esophageal cancer patients treated with neoadjuvant chemoradiotherapy

Background and Objectives

The impact of different neoadjuvant chemoradiotherapy (nCRT) schedules and pathologic complete response (pCR) on the distribution of recurrence is unclear in esophageal cancer (EC). We assessed the effect of pCR and nCRT schedule in EC.

Methods

Patients with T1N+/T2-4aN0-3/M0 EC treated in different centers, with either carboplatin/paclitaxel/41.4 Gy (CROSS: n = 134) or Cisplatin/5-fluorouracil/45-50.4 Gy (Cis/5FU: n = 88) followed by surgery were included. The effect of pCR on distribution and site-specific recurrence was determined for the CROSS group. After propensity score matching we compared the impact of both schedules (n = 63 each) on the recurrence pattern.

Results

Overall (P = 0.005) and disease-free survival (P = 0.002) were significantly longer after pCR (n = 24). The pattern of recurrence differed between pCR and non-pCR group (P = 0.001) for locoregional (0 vs 7; 6.4%), distant (5; 20.8% vs 36; 32.7%), and combined local and distant (0 vs 21; 19.1%), respectively. After pCR, less local and distant recurrences were seen (P = 0.008). With equal median time to recurrence, the distribution of metastases only differed for lung metastases (P = 0.029), with 15 (23.8%) in the CROSS group versus 6 (9.5%) following Cis/5FU.

Conclusions

Patients with pCR have less local and distant recurrence. The nCRT regime had a minor influence on the site-specific distribution of recurrence.

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The preoperative globulin-to-albumin ratio, a novel inflammation-based prognostic system, predicts survival after potentially curative liver resection for patients with hepatocellular carcinoma

Background and Objectives

Although the globulin-to-albumin ratio (GAR) is useful for prognostication of patients with various cancers, its relationship with hepatocellular carcinoma (HCC) remains unclear. The study aims to investigate the relationship between GAR and postoperative survival among patients with HCC undergoing potentially curative liver resection (LR).

Methods

We retrospectively reviewed 368 patients with newly diagnosed HCC who underwent initial and potentially curative LR. Univariate and multivariate analyses using the Cox proportional hazard model were performed to detect clinical characteristics that correlated with overall survival (OS). Kaplan-Meier analysis and log-rank test were used to compare OS and disease-free survival (DFS).

Results

The result of multivariate analysis using 25 clinical characteristics selected by univariate analysis revealed that the GAR (≥0.918/<0.918) was significantly associated with OS (hazard ratio [HR], 2.398; 95% confidence interval [CI], 1.012-5.683; P = 0.047), as well as platelet count (<14/≥14, ×10⁴/mm³) and portal vein invasion (presence/absence). Kaplan-Meier analysis and log-rank test demonstrated that the OS and DFS of patients with a high GAR (>0.918) were significantly worse than that of patients with a low GAR (≤0.918).

Conclusions

The GAR is a useful predictor of postoperative survival among patients with HCC undergoing potentially curative LR.

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Influence of tumor response and treatment schedule on the distribution of tumor recurrence in esophageal cancer patients treated with neoadjuvant chemoradiotherapy

Background and Objectives

Methods

Results

Conclusions

Patients with pCR have less local and distant recurrence. The nCRT regime had a minor influence on the site-specific distribution of recurrence.

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The preoperative globulin-to-albumin ratio, a novel inflammation-based prognostic system, predicts survival after potentially curative liver resection for patients with hepatocellular carcinoma

Background and Objectives

Methods

Results

Conclusions

The GAR is a useful predictor of postoperative survival among patients with HCC undergoing potentially curative LR.

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Treatment outcomes after reduction of the target volume of intensity-modulated radiotherapy following induction chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: A prospective, multi-center, randomized clinical trial

To investigate whether reducing the target volume of intensity-modulated radiotherapy (IMRT) after induction chemotherapy (IC) improves the quality of life (QOL) in locoregionally advanced nasopharyngeal carcinoma (NPC) without decreasing the local control and survival rate.

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The estimates of 5-year lung cancer prevalence in adult population in 2012

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IN THIS ISSUE

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Joint Symposium of Korean Cancer Association & UICC-ARO—Cross-boundary cancer studies: cancer and Universal Health Coverage (UHC) in Asia

Abstract

On 16 June 2016, the Korean Cancer Association (KCA) and Union for International Cancer Control-Asia Regional Office (UICC-ARO) organized a joint symposium as part of the official program of the 42nd Annual Meeting of the Korean Cancer Association to discuss the topic 'Cross-boundary Cancer Studies: Cancer and Universal Health Coverage (UHC) in Asia.' Universal Health Coverage is included in the Sustainable Development Goals adopted by the United Nations as part of the 2030 Agenda for Sustainable Development. The objectives of UHC are to ensure that all people can receive high-quality medical services, are protected from public health risks, and are prevented from falling into poverty due to medical costs or loss of income arising from illness. The participants discussed the growing cost of cancer in the Asian region and the challenges that this poses to the establishment and deployment of UHC in the countries of Asia, all of which face budgetary and other systemic constraints in controlling cancer in the region. Representatives from Korea, Japan and Indonesia reported on the status of UHC in their countries and the challenges that are being faced, many of which are common to other countries in Asia. In addition to country-specific presentations about the progress of and challenges facing UHC, there were also presentations from WHO Kobe Centre concerning advancing UHC in non-communicable diseases and prospects for further collaboration and research on UHC. A presentation from the University of Tokyo also highlighted the need to focus on multidisciplinary studies in an age of globalization and digitization.

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Sex differences in lung cancer survival: long-term trends using population-based cancer registry data in Osaka, Japan

Abstract

Objective

Several studies of sex differences in lung cancer survival have been reported. However, large-size population-based studies based on long-term observation are scarce. We investigated long-term trends in sex differences in lung cancer survival using population-based cancer registry data from Osaka, Japan.

Methods

We analyzed 79 330 cases from the Osaka Cancer Registry (OCR) diagnosed between 1975 and 2007. We calculated 5-year relative survival in the six periods (1975–1980, 1981–1986, 1987–1992, 1993–1997, 1998–2002 and 2003–2007). To estimate the trends in sex differences in lung cancer survival throughout the study period, we applied a multivariate excess hazard model to control for confounders.

Results

The proportion of adenocarcinoma (ADC) and 5-year relative relative survival have increased for both sexes. Sex differences in lung cancer survival have widened over the period, especially in ADC and since the late 1990s. The excess hazard ratio of death within 5 years for males was 1.19 (95% CI: 1.16–1.21), adjusting for period at diagnosis, histologic type, stage, age group and treatment.

Conclusion

We reported that females have better prognosis in lung cancer than males and the sex differences in lung cancer survival have become wider in Osaka, Japan. This can be partly explained by the sex differences in the proportions of histologic type and stage. Further studies considering other factors that influence sex differences in lung cancer survival are needed.

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Local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer

Abstract

Background

Radiotherapy is an effective treatment for the postoperative loco-regional recurrence of esophageal cancer; however, the optimal treatment field remains controversial. This study aims to evaluate the outcome of local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer.

Methods

We retrospectively investigated 35 patients treated for a postoperative loco-regional recurrence of esophageal cancer with local field radiotherapy between December 2008 and March 2016. The median irradiation dose was 60 Gy (range: 50–67.5 Gy). Thirty-one (88.6%) patients received concurrent chemotherapy.

Results

The median follow-up period was 18 months (range: 5–94 months). The 2-year overall survival was 55.7%, with a median survival time of 29.9 months. In the univariate analysis, the maximal diameter ≤20 mm (P = 0.0383), solitary lesion (P = 0.0352), and the complete remission after treatment (P = 0.00411) had a significantly better prognosis. A total of 27 of 35 patients (77.1%) had progressive disease (loco-regional failure [n = 9], distant metastasis [n = 7], and both loco-regional failure and distant metastasis [n = 11]). No patients had Grade 3 or greater mucositis.

Conclusion

Local field radiotherapy is a considerable treatment option for postoperative loco-regional recurrence of esophageal cancer.

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Leptomeningeal metastases of lung adenocarcinoma detected by 18 F-FDG PET/CT

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Retrospective analysis of definitive radiotherapy for neck node metastasis from unknown primary tumor: Japanese Radiation Oncology Study Group study

Abstract

Objective

To investigate the optimal treatment method and risk factor of neck node metastasis from unknown primary tumors (NUP) treated by radiotherapy.

Methods

Retrospective case study based on a multi-institutional survey was conducted by the Japanese Radiation Oncology Study Group. Patients pathologically diagnosed as having NUP from 1998 to 2007 were identified. Univariate and multivariate analyses of overall survival (OS), progression free survival (PFS), neck progression free survival (NPFS) and mucosal progression free survival (MPFS) were evaluated.

Results

In total, 130 patients with median age of 65 years were included. Nodal stages N1, N2a, N2b and N2c were observed for 10, 26, 43, 12 and 39 patients, respectively. All the patients received radiotherapy (RT) with neck dissection in 60 and with chemotherapy in 67 cases. The median doses to the metastatic nodes, prophylactic neck and prophylactic mucosal sites were 60.0, 50.4 and 50.4 Gy, respectively. The median follow-up period for surviving patients was 42 months. Among 12 patients, occult primary tumors in the neck region developed after radiotherapy. The 5-year OS, PFS, NPFS and MPFS were 58.1%, 42.4%, 47.3% and 54.9%, respectively. Univariate analysis showed that lower N stage (N1–2b), non-bulky node (<6 cm) and negative extracapsular extension (ECE) status were the factors associated with favorable OS, PFS, NPFS and MPFS. Radical surgery proved to be a favorable factor of OS, NPFS and MPFS. On multivariate analysis, lower N stage and negative ECE status were correlated with improved survival.

Conclusions

Lower nodal stage and negative ECE status showed a favorable impact on survival and disease control in patients with NUP treated by radiotherapy.

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Antitumor activity of iNGR-GRIM-19 in colorectal cancer

Abstract

Background

Gene associated with retinoid-interferon induced mortality-19 (GRIM-19) plays crucial roles in carcinogenesis.

Objective

To explore the antitumor activity of internalizing NGR (iNGR) gene associated with GRIM-19 in colorectal cancer.

Methods

Cells were incubated with fluorescein isothiocyanate-labeled fusion proteins followed by fluorescence microscopic analysis. Cell proliferation was determined by MTT assay. Cell cycle was analyzed by flow cytometric analysis. Cell migration and invasion capacity were evaluated by wound scratch and Transwell assays, respectively. Apoptosis was measured by Annexin V/PI staining and TUNEL assay. Gene expressions were determined by RT-PCR and Western blotting. Nude mice bearing colorectal cancer received vehicle, GRIM-19, or iNGR-GRIM-19 fusion protein injection, and the in vivo antitumor capacity of the fusion proteins was examined.

Results

iNGR-GRIM-19 was specifically taken up by human colorectal cancer Colo205 cells, but not corneal epithelial (HCEpic) cells, whereas GRIM-19 was not internalized by either cell type. Unlike GRIM-19, incubation with iNGR-GRIM-19 dose-dependently inhibited proliferation, induced G1 phase arrest, suppressed cell migration and invasion, and caused apoptosis in Colo205 cells. Additionally, injection of iNGR-GRIM-19 extended the lifespan of colorectal cancer-bearing nude mice and reduced in vivo tumor growth as compared with vehicle or GRIM-19 treatment. iNGR-GRIM-19 was localized only in the tumor mass, without affecting other tissues, such as liver or kidney. iNGR-GRIM-19 injection led to G1 phase arrest and induced cell apoptosis in xenografted colorectal cancer tissues.

Conclusions

iNGR-GRIM-19 has an efficient antitumor activity in vitro and in vivo, and might be a promising agent for the treatment of colorectal cancer.

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Adherence to oral chemotherapy medications among gastroenterological cancer patients visiting an outpatient clinic

Abstract

Objective

The purpose of this study was to investigate medication adherence to oral chemotherapy medications and determinants of medication non-adherence to them among gastroenterological cancer patients.

Methods

A cross-sectional study was conducted on 117 consecutive, consenting, eligible patients visiting an outpatient clinic of university hospital in Japan. Good medication adherence was defined as taking 100% of the prescribed dose. Medication adherence was measured via self-report. We hypothesized that there was a significant relationship between medication non-adherence and the five factors defined by the World Health Organization: patient-related, socioeconomic-related, condition-related, treatment-related, and healthcare-system/provider-related factors. Multiple logistic regression models were used to identify factors associated with oral chemotherapy medication non-adherence.

Results

The proportion of patients showing good medication adherence was 56.4%. The multiple logistic regression analysis revealed that the determinants of medication non-adherence to oral chemotherapy medications included having a history of patient-caused treatment interruptions due to worsening of symptoms (adjusted odds ratio [AOR] = 9.59, 95% confidence interval [CI] = 1.38–66.47), having diarrhea (AOR = 3.25, 95% CI = 1.13–9.34), experiencing pain (AOR = 0.17, 95% CI = 0.05–0.55), taking oral chemotherapy medication every 8 h (AOR = 5.52, 95% CI = 1.71–17.81), and diminished sense of priority for medication (AOR = 1.40, 95% CI = 1.21–1.63).

Conclusions

This study suggests that many patients with gastroenterological cancer were non-adherent to oral chemotherapy medications. It might be necessary to conduct periodic screening and connect patients at a high risk of medication non-adherence to appropriate support.

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A Phase II study of palonosetron, aprepitant, dexamethasone and olanzapine for the prevention of cisplatin-based chemotherapy-induced nausea and vomiting in patients with thoracic malignancy

Abstract

Background

The three-drug combination of a 5-hydroxytryptamine type 3 receptor antagonist, a neurokinin 1 receptor antagonist and dexamethasone is recommended for patients receiving highly emetogenic chemotherapy. However, standard antiemetic therapy is not completely effective in all patients.

Methods

We conducted an open-label, single-center, single-arm Phase II study to evaluate the efficacy of olanzapine in combination with standard antiemetic therapy in preventing chemotherapy-induced nausea and vomiting in patients with thoracic malignancy receiving their first cycle of cisplatin-based chemotherapy. Patients received 5 mg oral olanzapine on Days 1–5 in combination with standard antiemetic therapy. The primary endpoint was complete response (no vomiting and no use of rescue therapy) during the overall Phase (0–120 h post-chemotherapy).

Results

Twenty-three men and seven women were enrolled between May and October 2015. The median age was 64 years (range: 36–75 years). The most common chemotherapy regimen was 75 mg/m² cisplatin and 500 mg/m² pemetrexed, which was administered to 14 patients. Complete response rates in acute (0–24 h post-chemotherapy), delayed (24–120 h post-chemotherapy) and overall phases were 100%, 83% and 83% (90% confidence interval: 70–92%; 95% confidence interval: 66–93%), respectively. There were no Grade 3 or Grade 4 adverse events. Although four patients (13%) experienced Grade 1 somnolence, no patients discontinued olanzapine.

Conclusions

The addition of 5 mg oral olanzapine to standard antiemetic therapy demonstrates promising efficacy in preventing cisplatin-based chemotherapy-induced nausea and vomiting and an acceptable safety profile in patients with thoracic malignancy.

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Efficacy of early ureteral ligation on prevention of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma: a prospective single-arm multicenter clinical trial

Abstract

Objective

The rate of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma is high. Seeding upper urinary tract urothelial carcinoma cells onto the damaged bladder wall is considered to be one of the causes of intravesical recurrence after radical nephroureterectomy. We evaluated the utility of early ureteral ligation in preventing the intravesical recurrence.

Methods

This prospective single-arm clinical trial included patients who underwent radical nephroureterectomy for upper urinary tract urothelial carcinoma in the Tohoku Urological Evidence-Based Medicine Study Group between 2012 and 2013. Early ureteral ligation was defined as ligation of the ureter as quickly as possible after expanding the retroperitoneal space. A historical control was extracted from 454 patients who underwent radical nephroureterectomy in the same group, using propensity score-matched analysis. Intravesical recurrence-free survival rates were analyzed using Kaplan–Meier curves. Factors predicting intravesical recurrence were assessed using multivariate analyses.

Results

Seventy-four patients underwent early ureteral ligation. Seventeen (23%) patients had intravesical recurrence with a median follow-up period of 24 months. The 1- and 2-year intravesical recurrence-free survival rates in the early ureteral ligation group were 81% and 76%, and in the control group 75% and 63%, respectively (P = 0.160). In patients with renal pelvic cancer, the 1- and 2-year intravesical recurrence-free survival rates in the early ureteral ligation group were 89% and 86%, but in the control group 74% and 64%, respectively (P = 0.025). However, intravesical recurrence-free survival rates were similar in patients with ureteral cancer. Multivariate analyses of a subset of patients with renal pelvic cancer identified early ureteral ligation as an independent predictor of intravesical recurrence.

Conclusions

Early ureteral ligation decreases the rate of intravesical recurrence after radical nephroureterectomy in patients with renal pelvic cancer. Thus, early ureteral ligation might help in prevention of intravesical recurrence for renal pelvic cancer.

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The effect of predisposing atheroembolic risk factors on renal functional recovery between laparoscopy and open technique in patients with T1-stage renal cell carcinoma who underwent partial nephrectomy: a retrospective comparison study

Abstract

Objective

The present study aimed to determine the effect of an increasing number of predisposing atheroembolic risk factors on the development of chronic kidney disease (CKD) after partial nephrectomy (PN) in patients with T1-stage renal cell carcinoma (RCC).

Methods

The study included 147 patients with T1-stage RCC with a normal contralateral kidney and without preoperative CKD, who underwent open (OPN, N = 83, 56.5%) or laparoscopic PN (LPN, N = 64, 43.5%) between 2003 and 2014. Postoperative CKD was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m². The predictive factors for CKD between OPN and LPN were statistically assessed among various known clinicopathological factors associated with renal function in PN with a significance of two-sided P value <0.05.

Results

During a median follow-up of 42 months, the recurrence rate was 0.7% (n = 1), and the rate of postoperative CKD was 11.6% (n = 17). Significant differences in CKD-free survival were observed among patients with atheroembolic risks 5–7, 3–4 and 1–2 (P = 0.027). Regarding the predictive factors for the postoperative development of CKD between OPN and LPN, a predisposing atheroembolic risk ≥3 was significant among other clinicopathological factors in multivariate analysis (hazard ratio, 3.007, P = 0.031).

Conclusion

Patients with T1-staged RCC with ≥3 predisposing atheroembolic risk factors have a significantly higher risk of developing CKD after PN. Patients who underwent LPN had a lesser incidence of CKD development than patients who underwent OPN with ≥3 predisposing atheroembolic risk factors.

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Optimism, pessimism and self-efficacy in female cancer patients

Abstract

Objective

The aim of this examination was to study whether psychological resource variables (optimism and self-efficacy) decrease when cancer is present and to test the predictive power of these variables for anxiety, depression and quality of life (QoL).

Methods

The patient sample was comprised of 354 German women suffering from breast cancer or gynecological cancer. Participants filled in the resource assessment tools Life Orientation Test-Revised and the General Self-Efficacy Scale as well as the Hospital Anxiety and Depression Scale, the Patient Health Questionnaire-4 and the QoL instrument EORTC QLQ-C30 at two time points: (t1) during patients' hospital stay and (t2) 3 months later.

Results

The mean scores for optimism (total score: M = 16.2) and self-efficacy (M = 29.8) were even somewhat higher than the corresponding means of the general population. Optimism and self-efficacy were positively correlated with QoL (r between 0.15 and 0.17, P < 0.01) and negatively associated with anxiety and depression (r between −0.17 and −0.36, P < 0.01). However, only optimism was predictive of the t2 anxiety, depression and QoL scores when statistically taking into account the baseline levels of the outcome variables.

Conclusions

Having cancer does not generally reduce optimism and self-efficacy on the level of patients' mean scores. Cancer patients with a high level of habitual optimism will adapt to their disease better than pessimistic patients, even if the baseline levels of the outcome variables have been accounted for.

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Is preoperative spirometry a predictive marker for postoperative complications after colorectal cancer surgery?

Abstract

Background

Spirometry is a basic test that provides much information about pulmonary function; it is performed preoperatively in almost all patients undergoing colorectal cancer (CRC) surgery in our hospital. However, the value of spirometry as a preoperative test for CRC surgery remains unknown. The aim of this study was to determine whether spirometry is useful to predict postoperative complications (PCs) after CRC surgery.

Methods

The medical records of 1236 patients who had preoperative spirometry tests and underwent CRC surgery between 2005 and 2014 were reviewed. Preoperative spirometry results, such as forced vital capacity (FVC), one-second forced expiratory volume (FEV1), %VC (FVC/predicted VC) and FEV1/FVC (%FEV1), were analyzed with regard to PCs, including pneumonia.

Results

PCs were found in 383 (30.9%) patients, including 218 (56%) with surgical site infections, 67 (17%) with bowel obstruction, 62 (16%) with leakage and 20 (5.2%) with pneumonia. Of the spirometry results, %VC was correlated with PC according to logistic regression analysis (odds ratio, OR = 0.99, 95% confidence interval, CI = 0.98–0.99; P = 0.034). Multivariate analysis after adjusting for male sex, age, laparoscopic surgery, tumor location, operation time and blood loss showed that a lower %VC tends to be a risk factor for PC (OR = 0.99, 95% CI = 0.98–1.002; P = 0.159) and %VC was an independent risk factor for postoperative pneumonia in PCs (OR = 0.97, 95% CI = 0.94–0.99; P = 0.049).

Conclusions

In CRC surgery, %VC may be a predictor of postoperative complications, especially pneumonia.

http://ift.tt/2gntCcB

Severe esophagitis associated with cytomegalovirus during concurrent chemoradiotherapy for esophageal cancer

Abstract

Although radiation esophagitis is one of the most common adverse events that occurs during chemoradiotherapy (CRT) in patients with esophageal cancer, CRT-associated cytomegalovirus (CMV) esophagitis is rare. CMV esophagitis typically occurs in patients with an immunosuppressed status. Here we report a case of CMV esophagitis during CRT initially treated as radiation esophagitis. A 64-year-old man with mid-thoracic esophageal cancer was admitted to our hospital with clinical stage cT4bN1M1 (supraclavicular lymph node metastasis) Stage IV according to the UICC ver. 7 guidelines, and he was administered definitive concurrent CRT. From the 39th day of CRT onwards, he presented with a sustained fever and severe odynophagia that was resistant to antibiotic therapy. An esophagoscopy revealed severe esophagitis with a circumferential ulcer throughout the entire esophagus, and CMV esophagitis was clinically suspected because of positive result of CMV antigenemia. Subsequently, antiviral therapy for CMV provided dramatic relief of his symptoms. Later, CMV DNA was confirmed with a polymerase chain reaction in the biopsy specimen.The symptoms of CMV esophagitis resemble those of radiation esophagitis and can make the diagnosis difficult. Thus, CMV esophagitis associated CRT may be overlooked or masked by radiation esophagitis and can cause a delay in healing. Therefore, CMV esophagitis may be considered when severe intractable esophagitis is observed during CRT.

http://ift.tt/2iHlQuQ

Yokukansan for the treatment of preoperative anxiety and postoperative delirium in colorectal cancer patients: a retrospective study

Abstract

Background

Yokukansan (YKS), a Japanese traditional herbal medicine for neurosis and insomnia, is speculated to be useful for perioperative psychiatric symptoms in cancer patients, but there exists little empirical evidence. This study provides preliminary data about the efficacy, feasibility, and side effects of YKS for the treatment of preoperative anxiety and postoperative delirium in cancer patients.

Methods

We retrospectively reviewed the medical records of colorectal cancer patients who took YKS for preoperative anxiety, evaluating the following: (1) patient characteristics, (2) feasibility of taking YKS, (3) changes in preoperative anxiety based on the Clinical Global Impression (CGI) scale and Edmonton Symptom Assessment System-revised (ESAS-r-anxiety), (4) incidence of postoperative delirium and (5) YKS-related side effects.

Results

We reviewed 19 medical records. There was a significant difference between ESAS-r-anxiety scores (P = 0.028) before and after taking YKS, but no difference between CGI scores (P = 0.056). The incidence of postoperative delirium was 5.2% (95% CI = 0.0–14.5). One patient could not complete the course of YKS during the perioperative administration period, but there were no side effects of Grade 2 or worse according to the Common Terminology Criteria for Adverse Events v4.

Conclusions

Cancer patients could safely take YKS before surgery. There was a significant improvement in preoperative anxiety after taking YKS, and the incident rate of postoperative delirium was lower than in previous studies. These results suggest that YKS may be useful for perioperative psychiatric symptoms in cancer patients. Further well-designed studies are needed to substantiate our results.

http://ift.tt/2gptGZ9

Efficacy of radiotherapy for primary tumor in patients with unresectable pancreatic neuroendocrine tumors

Abstract

Background

Detailed information regarding the clinical efficacy of radiotherapy (RT) for primary tumor in patients with unresectable pancreatic neuroendocrine tumors (pNETs) is unknown. We therefore performed a retrospective study to evaluate the efficacy and safety of RT for primary pancreatic tumors in patients with pNETs.

Methods

We investigated 11 patients with pNETs who received RT to the primary site between January 1997 and June 2015. Seven patients had Grade 2 neuroendocrine tumors (NET-G2) and four had neuroendocrine carcinoma (NEC) according to the 2010 WHO histopathological classification.

Results

The tumor response and control rates were 27.2% and 100%, respectively (3: partial response, 8: stable disease). Among patients with NET-G2 tumors, the response rate was 28.5% (2/7 patients) and symptomatic improvement was noted in 33.3% of the patients (1/3 patients). The response rate for patients with NEC were 25% (1/4), one NEC patients with symptoms exhibited symptomatic improvement. The median overall survival and median progression-free survival were 35.9 months and 5.5 months, respectively. Grade 3 diarrhea as an acute toxicity and Grade 3 gastrointestinal hemorrhage as a late toxicity were observed.

Conclusions

RT to the primary cancer site in patients with pNETs was an effective modality for local disease control and the treated patients had good outcomes. If metastatic tumors are under control, RT to the primary site may be beneficial for patients with pNETs.

http://ift.tt/2iGmRmX

Effective chemomobilization with etoposide and cytarabine (EC regimen) in lymphoma patients: a single-center, retrospective, observational study

Abstract

Objective

Autologous stem cell transplantation is an important strategy for patients with relapsed or refractory lymphoma. Although various regimens for peripheral blood stem cell collection have been used, the optimal regimen has not yet been established. We aimed to evaluate the mobilization efficacy and safety of the regimen consisted of etoposide and cytarabine (EC regimen).

Methods

We retrospectively analyzed the clinical data of 46 lymphoma patients who received peripheral blood stem cell mobilization with the EC regimen [etoposide (100 mg/m²/day, days 1–4) and cytarabine (100 mg/m²/day, days 1–4)] at Toyohashi municipal hospital from 2004 to 2013.

Results

The median age of the patients was 55 years. The most common underlying diseases were diffuse large B-cell lymphoma (46%) and follicular lymphoma (26%). Three-quarters of patients were in their second complete or partial remission. The median total number of collected CD34⁺ cells was 10.6 × 10⁶ kg^–1. Forty-two patients (91%) yielded at least 2 × 10⁶ kg^–1 CD34⁺ cells within a median of 2 apheresis days, and 33 patients (72%) achieved it with only one apheresis. Successful mobilization was observed in five of six patients who failed to mobilize previously. Although febrile neutropenia occurred in 22 patients (48%), no fatal infection was observed.

Conclusion

The EC regimen was highly effective in lymphoma patients, including patients who mobilized poorly with other regimens.

http://ift.tt/2gptzwH

Postmarketing surveillance study of erlotinib plus gemcitabine for pancreatic cancer in Japan: POLARIS final analysis

Abstract

Objective

Erlotinib plus gemcitabine is approved in Japan for the treatment of metastatic pancreatic cancer. The POLARIS surveillance study investigated safety (focusing on interstitial lung disease [ILD]) and efficacy of erlotinib plus gemcitabine in Japanese pancreatic cancer patients.

Methods

Patients receiving erlotinib plus gemcitabine for pancreatic cancer in Japan between July 2011 and August 2012 were enrolled. ILD-like events were independently confirmed by a review committee. Overall survival (OS) and progression-free survival (PFS) were assessed, and risk factors for ILD occurrence were analyzed by multivariate Cox regression analysis.

Results

Safety data were available for 843 patients and efficacy data for 841. Adverse drug reactions were reported in 83.5% of patients, no new safety signals were identified. ILD events were confirmed by the review committee in 52 patients (6.2%), with two fatal cases (0.2%). Median time from initial erlotinib treatment to ILD events was 70.5 days. Of the 52 patients with ILD events, 86.5% improved or fully recovered from ILD (median time 24 days). Multivariate analysis identified previous or concurrent lung disease (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.0–4.5; P = 0.0365) and ≥3 organs with metastases (HR, 4.2; 95% CI, 2.2–8.2; P < 0.0001) as potential ILD risk factors. Accumulated OS rate at 28 weeks was 68.2%, and median PFS was 92 days (95% CI, 86–101).

Conclusions

Erlotinib plus gemcitabine has an acceptable safety and efficacy profile in pancreatic cancer; however, patients should be assessed for previous/concurrent lung disease and metastatic burden, before and during treatment.

http://ift.tt/2iHldkY

Cardiovascular toxic effects of targeted cancer therapy

Abstract

Over the past decade, there has been a major shift in chemotherapy from non-specific cytotoxic drugs to molecular targeted drug therapies. As more molecular targeted therapies are developed, new types of cardiovascular toxicities induced by targeted therapies are a growing problem. Cardiotoxicity induced by the human epidermal growth factor receptor-2 inhibitor trastuzumab manifests as decreased left ventricular ejection fraction. In contrast to anthracycline treatment, most cardiac events occur during trastuzumab treatment, but are reversed quickly when treatment is interrupted and cardiac intervention is established. Vascular endothelial growth factor pathway inhibitors decrease vascular tone, leading to hypertension. After drug initiation, the early detection and aggressive pharmacological management of hypertension are necessary to avoid severe complications. Cardiovascular safety is an emerging challenge in patients treated with newer generations of BCR-ABL inhibitors. Although rare, dasatinib-induced pulmonary hypertension is potentially fatal. Vascular events including cardiac and cerebral ischemic events and peripheral arterial occlusive disease have emerged as a new type of toxicity in patients treated with ponatinib and nilotinib. Thus, a wide variety of cardiovascular toxicities have been observed in patients treated with targeted drugs and have become a critically important topic of discussion for the practicing oncologist and cardiologists. Awareness of the potential side effects, recognition of signs and symptoms, and the establishment of therapeutic strategies are all crucial to providing quality patient care.

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Inferior vena cava atresia predisposing to acute lower extremity deep vein thrombosis in children: A descriptive dual-center study

Abstract

Purpose

Thrombosis in the healthy pediatric population is a rare occurrence. Little is known about the optimal treatment or outcomes of children with unprovoked acute lower extremity (LE) deep vein thrombosis (DVT) associated with atresia of the inferior vena cava (IVC).

Methods

We retrospectively analyzed the records of patients with acute LE DVT subsequently found to have IVC atresia who presented to two tertiary pediatric institutions between 2008 and 2016. Data were reviewed for thrombophilia risk factors, treatment, and outcomes.

Results

Eighteen patients, aged 13–18 years (median: 16 years), presenting with acute LE DVT were found to have IVC atresia. Three patients also presented with pulmonary embolism. Fourteen patients underwent site-directed thrombolysis in addition to anticoagulation. Five patients (28%) had confirmed or suspected recurrent thrombosis. Thirteen patients (72%) had no identified provocation for DVT. Ten patients (56%) had post-thrombotic syndrome, and 17 of 18 patients remain on indefinite anticoagulation.

Conclusion

This study suggests that IVC atresia is a risk factor for LE DVT and pulmonary embolism in otherwise healthy children and highlights the importance of dedicated imaging of the IVC in young patients with unprovoked LE DVT. Indefinite anticoagulation may be considered in pediatric patients presenting with unprovoked thrombosis secondary to an atretic IVC.

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Mutational status of NRAS, KRAS, and PTPN11 genes is associated with genetic/cytogenetic features in children with B-precursor acute lymphoblastic leukemia

Abstract

Background

We aimed to investigate the frequencies and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor acute lymphoblastic leukemia (ALL), the largest cohort in Asians.

Procedure

Between 1995 and 2012, marrow samples at diagnosis from 535 children were studied for NRAS, KRAS, and PTPN11 mutations. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 346).

Results

The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.8% (57/530), 10.2% (54/530), and 3.0% (16/526), respectively. NRAS mutations were associated with a higher frequency of hyperdiploidy (P = 0.01) and lower frequency of ETV6-RUNX1 (P < 0.01), whereas KRAS mutations were associated with younger age (P < 0.01), a higher frequency of KMT2A rearranged (P < 0.01) but no significant difference if infants with ALL were excluded, and inferior event-free survival (66.6% vs. 80.5%, P = 0.04). None of patients with TCF3-PBX1 had KRAS mutation (P = 0.02).

Conclusions

Our study showed that the frequency of KRAS mutations in Taiwan was significantly higher than that reported in Caucasians. The occurrence of RAS pathway mutations was associated with recurrent genetic/cytogenetic abnormalities in pediatric B-precursor ALL.

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Clinical outcomes and toxicity following palliative radiotherapy for childhood cancers

Abstract

Background

Few reports of palliative radiotherapy (RT) for pedialltric malignancies have been published. We described clinical indications, outcomes, and toxicities for children who received palliative RT.

Procedure

Pediatric patients (age ≤18 years) treated with palliative RT for incurable cancer from January 1 2008 to February 26, 2014 were included. Diagnosis, details of RT, treatment response, toxicity, and survival were retrospectively reviewed.

Results

Forty-six patients received 76 RT courses. Fifteen patients (33%) had ≥2 courses. Median age at palliative RT was 10.3 years; 54% were male. The most common diagnoses were neuroblastoma (20%) and diffuse intrinsic pontine glioma (17%). The most common indications for RT were oligometastatic disease in asymptomatic patients (39%) and pain (25%). The most common treatment sites were brain (32%) and bone (29%). Median RT dose was 30 Gy. Median number of RT fractions was 12. Sixty-five treatment courses (86%) were delivered with fraction sizes ≥2.5 Gy. Twenty-seven treatment courses (36%) were given under general anesthesia. Median follow-up was 3.9 months. Grade 1–2 RT-related toxicity occurred in 21% of treatment courses and 4–8% up to 12 months after RT. Two patients had Grade 3 toxicity during RT (esophagitis). Of symptomatic patients, 91%, 73%, 58%, and 43% had improved or stable symptoms during RT and 0–3, 3–6, and 6–12 months afterwards, respectively. Median survival after palliative RT was 4.2 months. Four of 21 surviving patients (19%) had hospice care at last follow-up.

Conclusions

Palliative RT was well tolerated in children with incurable malignancies, with most cases associated with acceptable toxicity, and improved or stable symptoms.

http://ift.tt/2wGzXX9

Central nervous system disease in pediatric acute myeloid leukemia

http://ift.tt/2wm327x

Clinical benefit of antiangiogenic therapy in advanced and metastatic chondrosarcoma

Abstract

Chondrosarcoma is the most common bone sarcoma in adults. Conventional chondrosarcoma, the commonest histological subtype, is largely resistant to anthracycline-based chemotherapy. There have been anecdotal reports of durable clinical benefit with antiangiogenic agents in this disease. A retrospective search of patients treated at three sarcoma referral centers was performed to identify patients with advanced chondrosarcoma treated with antiangiogenic agents. The aim of this study was to evaluate the efficacy and safety of antiangiogenic agents in advanced chondrosarcoma. Ten patients were identified; seven with conventional, one each with clear cell, extraskeletal mesenchymal chondrosarcoma and extraskeletal myxoid chondrosarcoma. The median progression-free survival for patients with conventional and clear cell sarcoma was 22.6 months. Median overall survival has not been met. Antiangiogenic therapy was well tolerated in this series of patients. Our retrospective data suggest that antiangiogenic therapy can provide prolonged clinical benefit in advanced chondrosarcoma patients. Further prospective trials are required to precisely define the role of this class of agent in advanced chondrosarcoma.

http://ift.tt/2wfQiAW

Metabolic liver function in humans measured by 2- 18 F-fluoro-2-deoxy-D-galactose PET/CT–reproducibility and clinical potential

Abstract

Background

PET/CT with the radioactively labelled galactose analogue 2-¹⁸F-fluoro-2-deoxy-D-galactose (¹⁸F-FDGal) can be used to quantify the hepatic metabolic function and visualise regional metabolic heterogeneity. We determined the day-to-day variation in humans with and without liver disease. Furthermore, we examined whether the standardised uptake value (SUV) of ¹⁸F-FDGal from static scans can substitute the hepatic systemic clearance of ¹⁸F-FDGal (K _met, mL blood/min/mL liver tissue/) quantified from dynamic scans as measure of metabolic function.

Four patients with cirrhosis and six healthy subjects underwent two ¹⁸F-FDGal PET/CT scans within a median interval of 15 days for determination of day-to-day variation. The correlation between K _met and SUV was examined using scan data and measured arterial blood concentrations of ¹⁸F-FDGal (blood samples) from 14 subjects from previous studies. Regional and whole-liver values of K _met and SUV along with total metabolic liver volume and total metabolic liver function (total SUV, average SUV multiplied by total metabolic liver volume) were calculated.

Results

No significant day-to-day differences were found for K _met or SUV. SUV had higher intraclass correlation coefficients than K _met (0.92–0.97 vs. 0.49–0.78). The relationship between K _met and SUV was linear. Total metabolic liver volume had non-significant day-to-day variation (median difference 50 mL liver tissue; P = 0.6). Mean total SUV in healthy subjects was 23,840 (95% CI, 21,609; 26,070), significantly higher than in the patients (P < 0.001).

Conclusions

The reproducibility of ¹⁸F-FDGal PET/CT was good and SUV can substitute K _met for quantification of hepatic metabolic function. Total SUV of ¹⁸F-FDGal is a promising tool for quantification of metabolic liver function in pre-treatment evaluation of individual patients.

http://ift.tt/2vppFuo

Tumoral LINE-1 hypomethylation is associated with poor survival of patients with intrahepatic cholangiocarcinoma

Abstract

Background

DNA methylation changes occurring in cancer cells are featured with both promoter CpG island hypermethylation and diffuse genomic hypomethylation. Long interspersed element-1 (LINE-1) is repeated in an interspersed manner with an estimated 500,000 copies per genome. LINE-1 has its CpG sites of the 5′ untranslated region methylated heavily in normal cells and undergoes demethylation in association with cancerization. However, little information is available regarding LINE-1 hypomethylation and its prognostic implication in intrahepatic cholangiocarcinomas.

Methods

A total of 172 cases of intrahepatic cholangiocarcinomas were analyzed for their methylation levels at four CpG sites of LINE-1 using bisulfite pyrosequencing. We examined the relation between tumoral LINE-1 methylation level and clinicopathological features, including survival.

Results

Tumor differentiation, lymphatic invasion, and T stage were associated with a low average methylation level of LINE-1 at the four CpG sites; LINE-1 methylation level tended to be lower in high-grade differentiation, lymphatic emboli, and higher T stage. LINE-1 hypomethylation was significantly linked with lower cancer-specific survival in patients with intrahepatic cholangiocarcinoma and was found to be an independent prognostic parameter.

Conclusions

Our findings suggest that tumoral LINE-1 hypomethylation could be a molecular biomarker heralding poor prognosis of patients with intrahepatic cholangiocarcinoma. Our findings need to be validated in further study.

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Prognosis and treatment of FOLFOX therapy related interstitial pneumonia: a plea for multimodal immune modulating therapy in the respiratory insufficient patient

Abstract

Background

The FOLFOX regimen, i.e., folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), is a drug cocktail that is used to treat gastric and colorectal cancers. Despite the concomitant improvements in response rate, duration of response and patient survival, reports of serious toxic pulmonary side effects have progressively emerged.

Case presentation

We describe a patient who was treated with FOLFOX as an adjuvant to a rectosigmoidal resection of a rectosigmoidal carcinoma and who developed respiratory insufficiency requiring mechanical ventilation. Computed tomography (CT) imaging and open lung biopsy findings were compatible with interstitial pneumonia (IP). She received multimodal combination treatment (acetylcysteine, corticosteroids, immune globulins and cyclophosphamide) and survived.

We performed a systematic literature search and reviewed all 45 reported cases of FOLFOX-related lung toxicity and/or pulmonary fibrosis for their clinical characteristics and their outcomes related to therapy.

Conclusions

We found that for the 45 cases with available data, the median age was 70 years, and the male–female ratio was 3.5: 1. In the patients exhibiting only mild respiratory symptoms, discontinuation of the culprit drug (oxaliplatin) resulted in a 100% regression of the symptoms. However the prognosis of the respiratory insufficient patient proved to be grim: death occurred in 76.9% of the cases despite conventional treatment with corticosteroids. We therefore urge oncologists and critical care specialists not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroids and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents whenever life-threatening respiratory symptoms in oxaliplatin-treated patients do not subside; all the more so considering the fact that our analysis showed that every patient who survived intubation and mechanical ventilation experienced a full clinical recovery.

http://ift.tt/2wQokgN

Cancer incidence in eastern Morocco: cancer patterns and incidence trends, 2005–2012

Abstract

Background

Cancer is one of the major health problems worldwide. In this article, we present for the first time the cancer incidence trends, the distribution and the socioeconomic profile of incident cancer cases in Eastern Morocco over a period of eight years.

Methods

Retrospective descriptive study of patients diagnosed with cancer at the Hassan II Regional Oncology Center (ROC) since it was created in October 2005 until December 2012. During the study period, the ROC was the only hospital specialized in cancer care in Eastern Morocco.

Results

A total of 7872 incident cases of cancer were registered in Eastern Morocco. Among these incident cases 5220 cases were women and 2652 were men, with a female to male ratio of 1.97. The mean age at diagnosis was 58 years for males and 52 for females and 94% of the patients aged over 30 years. For both sexes combined and for all cancer sites, breast cancer was the commonest followed by cervix uteri, colon-rectum, lung, nasopharynx, and stomach cancers. The most common cancer in women was breast cancer, followed respectively by cervix uteri cancer, colon-rectum cancer, ovary cancer, and stomach cancer. In men, the lung cancer ranked first, followed respectively by colon-rectum cancer, nasopharynx cancer, prostate cancer, and stomach cancer. For most cancers, crude incidence rates (CR) have increased significantly. The CR for all cancers combined has increased from 56.6 to 80.3 per 100,000 females and from 32.3 to 42.6 per 100,000 males during the study period. Patients profile analysis showed that 79% of cancer patients were from urban areas, 83% were unemployed and 85% had no health insurance.

Conclusions

The distribution of cancers in Eastern Morocco is different from those observed in other regions of Morocco. Unlike most countries, women were much more affected with cancer than men in Eastern Morocco. More importantly, the rates of many cancers are rising. Therefore, our data justify the need to develop effective programs for cancer control and prevention in Eastern Morocco. A better access to cancer care should be a priority of the health policies, given that the majority of cancer patients in Eastern Morocco are unemployed, and do not have medical care coverage.

http://ift.tt/2xKm47e

Population-based colorectal cancer screening programmes using a faecal immunochemical test: should faecal haemoglobin cut-offs differ by age and sex?

Abstract

Background

The Basque Colorectal Cancer Screening Programme has both high participation rate and high compliance rate of colonoscopy after a positive faecal occult blood test (FIT). Although, colorectal cancer (CRC) screening with biannual (FIT) has shown to reduce CRC mortality, the ultimate effectiveness of the screening programmes depends on the accuracy of FIT and post-FIT colonoscopy, and thus, harms related to false results might not be underestimated. Current CRC screening programmes use a single faecal haemoglobin concentration (f-Hb) cut-off for colonoscopy referral for both sexes and all ages. We aimed to determine optimum f-Hb cut-offs by sex and age without compromising neoplasia detection and interval cancer proportion.

Methods

Prospective cohort study using a single-sample faecal immunochemical test (FIT) on 444,582 invited average-risk subjects aged 50–69 years. A result was considered positive at ≥20 μg Hb/g faeces. Outcome measures were analysed by sex and age for a wide range of f-Hb cut-offs.

Results

We analysed 17,387 positive participants in the programme who underwent colonoscopy. Participation rate was 66.5%. Men had a positivity rate for f-Hb of 8.3% and women 4.8% (p < 0.0001). The detection rate for advanced neoplasia (cancer plus advanced adenoma) was 44.0‰ for men and 15.9‰ for women (p < 0.0001). The number of colonoscopies required decreased in both sexes and all age groups through increasing the f-Hb cut-off. However, the loss in CRC detection increased by up to 28.1% in men and 22.9% in women. CRC missed were generally at early stages (Stage I-II: from 70.2% in men to 66.3% in women).

Conclusions

This study provides detailed outcomes in men and women of different ages at a range of f-Hb cut-offs. We found differences in positivity rates, neoplasia detection rate, number needed to screen, and interval cancers in men and women and in younger and older groups. However, there are factors other than sex and age to consider when consideration is given to setting the f-Hb cut-off.

http://ift.tt/2wQbEXi

Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis

Abstract

Background

Circular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported.

Methods

CircRNA deep sequencing was performed by using 10 pathologically diagnosed glioblastoma samples and their paired adjacent normal brain tissues. Northern blotting, Sanger sequencing, antibody, and liquid chromatograph Tandem Mass Spectrometer were used to confirm the existence of circ-FBXW7 and its encoded protein in in two cell lines. Lentivirus-transfected stable U251 and U373 cells were used to assess the biological functions of the novel protein invitro and invivo (five mice per group). Clinical implications of circ-FBXW7 were assessed in 38 pathologically diagnosed glioblastoma samples and their paired periphery normal brain tissues by using quantitative polymerase chain reaction (two-sided log-rank test).

Results

Circ-FBXW7 is abundantly expressed in the normal human brain (reads per kilobase per million mapped reads [RPKM] = 9.31). The spanning junction open reading frame in circ-FBXW7 driven by internal ribosome entry site encodes a novel 21-kDa protein, which we termed FBXW7-185aa. Upregulation of FBXW7-185aa in cancer cells inhibited proliferation and cell cycle acceleration, while knockdown of FBXW7-185aa promoted malignant phenotypes invitro and invivo. FBXW7-185aa reduced the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization. Moreover, circ-FBXW7 and FBXW7-185aa levels were reduced in glioblastoma clinical samples compared with their paired tumor-adjacent tissues (P < .001). Circ-FBXW7 expression positively associated with glioblastoma patient overall survival (P = .03).

Conclusions

Endogenous circRNA encodes a functional protein in human cells, and circ-FBXW7 and FBXW7-185aa have potential prognostic implications in brain cancer.

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Phospholipid Phosphatase 4 promotes proliferation and tumorigenesis, and activates Ca 2+ -permeable Cationic Channel in lung carcinoma cells

Abstract

Background

Phospholipid phosphatase 4 (PPAPDC1A or PLPP4) has been demonstrated to be involved in the malignant process of many cancers. The purpose of this study was to investigate the clinical significance and biological roles of PLPP4 in lung carcinoma.

Methods

PLPP4 expression was examined in 8 paired lung carcinoma tissues by real-time PCR and in 265 lung carcinoma tissues by immunohistochemistry (IHC). Statistical analysis was performed to evaluate the clinical correlation between PLPP4 expression and clinicopathological features and survival in lung carcinoma patients. In vitro and in vivo assays were performed to assess the biological roles of PLPP4 in lung carcinoma. Fluorescence-activated cell sorting, Western blotting and luciferase assays were used to identify the underlying pathway through which PLPP4 silencing mediates biological roles in lung carcinoma.

Results

PLPP4 is differentially elevated in lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SQC) tissues. Statistical analysis demonstrated that high expression of PLPP4 significantly and positively correlated with clinicopathological features, including pathological grade, T category and stage, and poor overall and progression-free survival in lung carcinoma patients. Silencing PLPP4 inhibits proliferation and cell cycle progression in vitro and tumorigenesis in vivo in lung carcinoma cells. Our results further reveal that PLPP4 silencing inhibits Ca²⁺-permeable cationic channel, suggesting that downregulation of PLPP4 inhibits proliferation and tumorigenesis in lung carcinoma cells via reducing the influx of intracellular Ca²⁺.

Conclusion

Our results indicate that PLPP4 may hold promise as a novel marker for the diagnosis of lung carcinoma and as a potential therapeutic target to facilitate the development of novel treatment for lung carcinoma.

http://ift.tt/2wm4x5Q

Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts

Abstract

Purpose

The present review aimed to assess the role of exosomal miRNAs in cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancer cells. The roles of exosomal miRNAs and miRNA dysregulation in CAF formation and activation were summarized.

Methods

All relevant publications were retrieved from the PubMed database, with key words such as CAFs, CAF, stromal fibroblasts, cancer-associated fibroblasts, miRNA, exosomal, exosome, and similar terms.

Results

Recent studies have revealed that CAFs, NFs, and cancer cells can secrete exosomal miRNAs to affect each other. Dysregulation of miRNAs and exosomal miRNAs influence the formation and activation of CAFs. Furthermore, miRNA dysregulation in CAFs is considered to be associated with a secretory phenotype change, tumor invasion, tumor migration and metastasis, drug resistance, and poor prognosis.

Conclusions

Finding of exosomal miRNA secretion provides novel insights into communication among CAFs, NFs, and cancer cells. MicroRNA dysregulation is also involved in the whole processes of CAF formation and function. Dysregulation of miRNAs in CAFs can affect the secretory phenotype of the latter cells.

http://ift.tt/2wGG3ql

The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness

Abstract

Background

The Ghrelin-system is a complex, pleiotropic family composed of several peptides, including native-ghrelin and its In1-ghrelin splicing variant, and receptors (GHSR 1a/b), which are dysregulated in various endocrine-related tumors, where they associate to pathophysiological features, but the presence, functional role, and mechanisms of actions of In1-ghrelin splicing variant in prostate-cancer (PCa), is completely unexplored. Herein, we aimed to determine the presence of key ghrelin-system components (native-ghrelin, In1-ghrelin, GHSR1a/1b) and their potential pathophysiological role in prostate cancer (PCa).

Methods

In1-ghrelin and native-ghrelin expression was evaluated by qPCR in prostate tissues from patients with high PCa-risk (n = 52; fresh-tumoral biopsies), and healthy-prostates (n = 12; from cystoprostatectomies) and correlated with clinical parameters using Spearman-test. In addition, In1-ghrelin and native-ghrelin was measured in plasma from an additional cohort of PCa-patients with different risk levels (n = 30) and control-healthy patients (n = 20). In vivo functional (proliferation/migration) and mechanistic (gene expression/signaling-pathways) assays were performed in PCa-cell lines in response to In1-ghrelin and native-ghrelin treatment, overexpression and/or silencing. Finally, tumor progression was monitored in nude-mice injected with PCa-cells overexpressing In1-ghrelin, native-ghrelin and empty vector (control).

Results

In1-ghrelin, but not native-ghrelin, was overexpressed in high-risk PCa-samples compared to normal-prostate (NP), and this expression correlated with that of PSA. Conversely, GHSR1a/1b expression was virtually absent. Remarkably, plasmatic In1-ghrelin, but not native-ghrelin, levels were also higher in PCa-patients compared to healthy-controls. Furthermore, In1-ghrelin treatment/overexpression, and to a much lesser extent native-ghrelin, increased aggressiveness features (cell-proliferation, migration and PSA secretion) of NP and PCa cells. Consistently, nude-mice injected with PC-3-cells stably-transfected with In1-ghrelin, but not native-ghrelin, presented larger tumors. These effects were likely mediated by ERK1/2-signaling activation and involved altered expression of key oncogenes/tumor suppressor genes. Finally, In1-ghrelin silencing reduced cell-proliferation and PSA secretion from PCa cells.

Conclusions

Altogether, our results indicate that In1-ghrelin levels (in tissue) and circulating levels (in plasma) are increased in PCa where it can regulate key pathophysiological processes, thus suggesting that In1-ghrelin may represent a novel biomarker and a new therapeutic target in PCa.

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Total glycosides of Paeony shows Neuroprotective effects against Semen Strychni -induced neurotoxicity by recovering secretion of hormones and improving brain energy metabolism

Abstract

In this study, we investigated the protective effect of total glycosides of paeony against Semen Strychni-induced neurotoxicity and discussed some probably mechanisms. Levels of estrone, estradiol, estriol and growth hormone in male rats' serum were determined by ELISA, levels of ATP and substances associated with energy metabolism in rats' brain were determined by HPLC and levels of progesterone was determined by a UPLC-MS/MS method. The results showed that neurotoxicity induced by Semen Strychni could cause a significant decrease (p < 0.05, compare to the blank group) in secretion of estrogens and GH and disorder brain energy metabolism at the same time. While, rats with total glycosides of paeony pre-protection (orally administrated with total glycosides of paeony for 15 days before administrating Semen Strychni extract) showed a much better condition in the secretion of hormones and brain energy metabolism, and showed no significant changes in most of those associated substances when comparing to the blank group. Our study indicated that total glycosides of paeony have neuroprotective effects on Semen Strychni-induced neurotoxicity. It could recover the disordered hormone secretion and improve the brain energy metabolism. Total glycosides of paeony is potential to be further used in clinic to protect against neurotoxicity induced by other reasons.

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Temporal influence of endocrine therapy with tamoxifen and chemotherapy on nutritional risk and obesity in breast cancer patients

Abstract

Background

The effect of endocrine therapy with tamoxifen (TMX) on weight gain has been reported in the literature, but the outcomes are still controversial. Moreover, previous treatment options, such as chemotherapy (CT), also include body changes. The focus of this study was to verify the temporal influence of endocrine therapy with TMX on nutritional risk and obesity and its association with CT in breast cancer patients.

Methods

In this cross-sectional study, 84 breast cancer surviving women were evaluated during endocrine therapy with TMX. Anthropometric, biochemical and body composition parameters were measured. A generalized estimating equation (GEE) was used to examine the association between CT and groups of women using TMX categorized by the duration of the treatment (group 1, women using TMX for the first 3 years; group 2, women using TMX between 3 and 4 years and group 3, women using TMX for more than 4 years).

Results

The interaction of CT with duration of TMX use showed a significant effect on Body Mass Index (BMI), waist circumference (WC) and body fat percentage (BFP) (GEE p-value = 0.002, 0.000, 0.000, respectively). Women from group 1 who underwent CT presented higher values of body variables compared to those women from group 2 who also underwent CT (BMI = 29.14 ± 0.93, 26.76 ± 0.85 kg/m²; WC = 94.45 ± 1.96, 91.07 ± 2.44 cm; BFP = 36.36 ± 1.50, 33.43 ± 1.66%, respectively). On the other hand, women from group 1 who did not undergo CT presented lower values of body variables compared to those women from group 2 who also did not undergo CT (BMI = 25.29 ± 0.46, 28.40 ± 0.95 kg/m²; WC = 85.84 ± 0.90, 97.75 ± 0.88 cm; BFP = 30.32 ± 0.43; 42.95 ± 1.03%, respectively).

Conclusions

Women on endocrine therapy with TMX are mostly overweighed and obese, most evidently in women who received CT, and who were at the beginning of treatment. Women that did not undergo CT, despite presenting lower values of body variables in the first 3 years, still deserve special attention because significantly higher values were observed in women between 3 and 4 years of therapy.

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Distinct preoperative clinical features predict four histopathological subtypes of high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum

Abstract

Background

The Cancer Genome Atlas Research Network reported that high-grade serous carcinoma (HGSC) can be classified based on gene expression profiles into four subtypes, termed "immunoreactive," "differentiated," "proliferative," and "mesenchymal." We previously established a novel histopathological classification of HGSC, corresponding to the gene expression subtypes: immune reactive (IR), papillo-glandular (PG), solid and proliferative (SP), and mesenchymal transition (MT). The purpose of this study is to identify distinct clinical findings among the four pathological subtypes of HGSC, as well as to predict pathological subtype based on preoperative images.

Methods

We retrospectively assessed 65 HGSC cases (IR: 17, PG: 7, SP: 14, MT: 27) and analyzed preoperative images.

Results

All IR cases originated from either the ovary or fallopian tube (P = 0.0269). Significantly more IR cases were diagnosed at earlier stages (P = 0.0013), and IR cases displayed lower levels of ascites (P = 0.0014), fewer peritoneal lesions (P = 0.0080), a sporadic pattern of peritoneal lesions (P = 0.0016), a lower incidence of omental cake (P = 0.0416), and fewer distant metastases (P = 0.0146) compared with the other subtypes. MT cases were more likely to be of peritoneal origin (P = 0.0202), presented at advanced stages with higher levels of ascites (P = 0.0008, 0.0052, respectively), and more frequently had a diffuse pattern of peritoneal lesions (P = 0.0059), omental cake (P = 0.0179), and distant metastasis (P = 0.0053). A decision tree analysis estimated the histopathological subtypes based on preoperative images, with a sensitivity of 67.3%.

Conclusions

Pathological subtypes of HGSC have distinct clinical behaviors, and preoperative images enable better prediction of pathological subtype. These findings may lead to individualized treatment plans if the effect of treatment based on the HGSC subtype is elucidated.

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Prognostic significance of E-cadherin and N-cadherin expression in Gliomas

Abstract

Background

Epithelial-mesenchymal transition (EMT), principally involving an E-cadherin to N-cadherin shift, linked to tumor invasion or metastasis, and therapeutic resistance in various human cancer. A growing body of recent evidence has supported the hypothesis that EMT play a crucial role in the invasive phenotype of gliomas. To evaluate the prognostic connotation of EMT traits in glioma, expression of E-cadherin and N-cadherin was explored in a large series of glioma patients in relation to patient survival rate.

Methods

Expressions of E- and N-cadherin were examined using immunohistochemical analysis in 92 glioma cases diagnosed at our hospital. These markers expressions were also explored in 21 cases of fresh frozen glioma samples and in glioma cell lines by Western blot analysis.

Results

Expression of E-cadherin was observed in eight cases (8.7%) with weak staining intensity in the majority of the immunoreactive cases (7/8). Expression of N-cadherin was identified in 81 cases (88.0%) with high expression in 64 cases (69.5%). Fresh frozen tissue samples and glioma cell lines showed similar results by Western blot analysis. There was no significant difference in either overall survival (OS) or progression-free survival (PFS) according to E-cadherin expression (P > 0.05). Although the OS rates were not affected by N-cadherin expression levels (P = 0.138), PFS increased in the low N-cadherin expression group with marginal significance (P = 0.058). The survival gains based on N-cadherin expression levels were significantly augmented in a larger series of publicly available REMBRANDT data (P < 0.001).

Conclusions

E- and N-cadherin, as representative EMT markers, have limited prognostic value in glioma. Nonetheless, the EMT process in gliomas may be compounded by enhanced N-cadherin expression supported by unfavorable prognostic outcomes.

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Presence of immune cells, low tumor proliferation and wild type BRAF mutation status is associated with a favourable clinical outcome in stage III cutaneous melanoma

Abstract

Background

The variable prognosis in stage III cutaneous melanoma is partially due to unknown prognostic factors. Improved prognostic tools are required to define patients with an increased risk of developing metastatic disease who might benefit from adjuvant therapies. The aim was to examine if cellular immune markers in association with tumor proliferation rate and BRAF mutation status have an impact on prognosis in stage III melanoma.

Methods

We have used two sets of case series with stage III disease: 23 patients with short survival (≤ 13 months) and 19 patients with long survival (≥ 60 months). Lymph node metastases were analyzed for Ki67, CD8 and FOXP3 protein expression using immunohistochemistry. BRAF mutation status was analyzed in a previous study on the same samples.

Results

Low tumor proliferation rate was significantly associated with a better prognosis (p = 0.013). Presence of FOXP3+ T cells was not correlated to adverse clinical outcome. A highly significant trend for a longer survival was found in the presence of an increasing number of markers; CD8+ and FOXP3+ T cells, low tumor proliferation and BRAF wildtype status (p = 0.003). Presence of at least three of these four markers was found to be an independent favorable prognostic factor (OR 19.4, 95% CI 1.9-197, p = 0.012), when adjusting for ulceration and number of lymph node metastases. Proliferation alone remained significant in multivariate analyses (OR 26.1, 95% CI 2.0-344, p = 0.013) but with a wider confidence interval. This panel still remained independent when also adjusting for a previously identified prognostic glycolytic-pigment panel.

Conclusions

We have demonstrated that presence of immune cells in association with tumor proliferation and BRAF mutation status may further contribute to identify stage III melanoma patients with high risk of relapse.

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Rare triad of periampullary carcinoid, duodenal gastrointestinal stromal tumor and plexiform neurofibroma at hepatic hilum in neurofibromatosis type 1: a case report

Abstract

Background

Neurofibromatosis type 1 is a relatively common inherited disorder. Patients with neurofibromatosis type 1 are at high risk of developing neurogenic, neuroendocrine and mesenchymal intra-abdominal tumors. Although coexistence of multiple tumors of different types is frequent in neurofibromatosis type 1, simultaneous occurrence of abdominal tumors of three types in very rare.

Case presentation

A 66-year-old lady with neurofibromatosis type 1 presented with painless progressive jaundice for six months. Laboratory investigations revealed iron deficiency anemia and conjugated hyperbilirubinemia. Tumor markers were normal. Abdominal computed tomography showed a 3 × 2 cm heterogenous mass in the periampullary region with mild dilation of the common bile duct and another 2 × 1.7 cm mass in the fourth portion of the duodenum. Endoscopic biopsy confirmed the diagnosis of periampullary carcinoid. At surgery, multiple small nodules were detected at the hepatic hilum. Frozen section suggested them to be neurofibromas. Patient underwent pancreatoduodenectomy and had uneventful recovery with no recurrence at two months. Microscopic examination of the resected specimen confirmed presence of three tumors: periampullary well differentiated neuroendocrine tumor, gastrointestinal stromal tumor of the fourth part of duodenum and plexiform neurofibroma at the hepatic hilum.

Conclusion

Patients of neurofibromatosis type 1 with abdominal symptoms should be treated with high index of clinical suspicion and thoroughly evaluated to rule out multiple tumors.

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Adherence and feasibility of 2 treatment schedules of S-1 as adjuvant chemotherapy for patients with completely resected advanced lung cancer: a multicenter randomized controlled trial

Abstract

Background

We conducted a multicenter randomized study of adjuvant S-1 administration schedules for surgically treated pathological stage IB-IIIA non-small cell lung cancer patients.

Methods

Patients receiving curative surgical resection were centrally randomized to arm A (4 weeks of oral S-1 and a 2-week rest over 12 months) or arm B (2 weeks of S-1 and a 1-week rest over 12 months). The primary endpoints were completion of the scheduled adjuvant chemotherapy over 12 months, and the secondary endpoints were relative total administration dose, toxicity, and 3-year disease-free survival.

Results

From April 2005 to January 2012, 80 patients were enrolled, of whom 78 patients were eligible and assessable. The planned S-1 administration over 12 months was accomplished to 28 patients in 38 arm A patients (73.7%) and to 18 patients in 40 arm B patients (45.0%, p = 0.01). The average relative dose intensity was 77.2% for arm A and 58.4% for arm B (p = 0.01). Drug-related grade 3 adverse events were recorded for 11% of arm A and 5% of arm B (p = 0.43). Grade 1–3 elevation of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine transaminase were more frequently recorded in arm A than in arm B. The 3-year disease-free survival rate was 79.0% for arm A and 79.3% for arm B (p = 0.94).

Conclusions

The superiority of feasibility of the shorter schedule was not recognized in the present study. The conventional schedule showed higher completion rates over 12 months (p = 0.01) and relative dose intensity of S-1 (p = 0.01). Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1–3 elevation of bilirubin.

Trial registration

This randomized multicenter study was retrospectively registered with the UMIN-CTR (UMIN000016086, registration date December 30, 2014).

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Differences in elongation of very long chain fatty acids and fatty acid metabolism between triple-negative and hormone receptor-positive breast cancer

Abstract

Background

Triple-negative breast cancer (TN) is more aggressive than other subtypes of breast cancer and has a lower survival rate. Furthermore, detailed biological information about the disease is lacking. This study investigated characteristics of metabolic pathways in TN.

Methods

We performed the metabolome analysis of 74 breast cancer tissues and the corresponding normal breast tissues using LC/MS. Furthermore, we classified the breast cancer tissues into ER-positive, PgR-positive, HER2-negative breast cancer (EP+H-) and TN, and then the differences in their metabolic pathways were investigated. The RT-PCR and immunostaining were carried out to examine the expression of ELOVL1, 2, 3, 4, 5, 6, and 7.

Results

We identified 142 of hydrophilic metabolites and 278 of hydrophobic lipid metabolites in breast tissues. We found the differences between breast cancer and normal breast tissues in choline metabolism, glutamine metabolism, lipid metabolism, and so on. Most characteristic of comparison between EP+H- and TN were differences in fatty acid metabolism was which were related to the elongation of very long chain fatty acids were detected between TN and EP+H-. Real-time RT-PCR showed that the mRNA expression levels of ELOVL1, 5, and 6 were significantly upregulated by 8.5-, 4.6- and 7.0-fold, respectively, in the TN tumors compared with their levels in the corresponding normal breast tissue samples. Similarly, the mRNA expression levels of ELOVL1, 5, and 6 were also significantly higher in the EP+H- tissues than in the corresponding normal breast tissues (by 4.9-, 3.4-, and 2.1-fold, respectively). The mRNA expression level of ELOVL6 was 2.6-fold higher in the TN tumors than in the EP+H- tumors. During immunostaining, the TN and EP+H- tumors demonstrated stronger ELOVL1 and 6 staining than the corresponding normal breast tissues, but ELOVL5 was not stained strongly in the TN or EP+H- tumors. Furthermore, the TN tumors exhibited stronger ELOVL1 and 6 staining than the EP+H- tumors.

Conclusions

Marked differences in fatty acid metabolism pathways, including those related to ELOVL1 and 6, were detected between TN and EP+H-, and it was suggested that ELOVL1 and 6-related fatty acid metabolism pathways may be targets for therapies against TN.

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Prostate cancer-specific survival among warfarin users in the Finnish Randomized Study of Screening for Prostate Cancer

Abstract

Background

Venous thromboembolic events (VTE) are common in cancer patients and associated with higher mortality. In vivo thrombosis and anticoagulation might be involved in tumor growth and progression. We studied the association of warfarin and other anticoagulant use as antithrombotic medication and prostate cancer (PCa) death in men with the disease.

Methods

The study included 6,537 men diagnosed with PCa during 1995-2009. Information on anticoagulant use was obtained from a national reimbursement registry. Cox regression with adjustment for age, PCa risk group, primary therapy and use of other medication was performed to compare risk of PCa death between warfarin users with 1) men using other types of anticoagulants and 2) non-users of anticoagulants. Medication use was analyzed as a time-dependent variable to minimize immortal time bias.

Results

In total, 728 men died from PCa during a median follow-up of 9 years. Compared to anticoagulant non-users, post-diagnostic use of warfarin was associated with an increased risk of PCa death (overall HR 1.47, 95% CI 1.13-1.93). However, this was limited to low-dose, low-intensity use. Otherwise, the risk was similar to anticoagulant non-users. Additionally, we found no risk difference between warfarin and other types of anticoagulants. Pre-diagnostic use of warfarin was not associated with the risk of PCa death.

Conclusions

We found no reduction in risk of PCa death associated with warfarin use. Conversely, the risk was increased in short-term use, which is probably explained by a higher risk of thrombotic events prompting warfarin use in patients with terminal PCa.

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Propensity score matching analysis of a phase II study on simultaneous modulated accelerated radiation therapy using helical tomotherapy for nasopharyngeal carcinomas

Abstract

Background

Using propensity score matching method (PSM) to evaluate the feasibility and clinical outcomes of simultaneous modulated accelerated radiation therapy (SMART) using helical tomotherapy (HT) in patients with nasopharyngeal carcinoma (NPC).

Methods

Between August 2007 and January 2016, 381 newly diagnosed NPC patients using HT were enrolled in pre-PSM cohort, including 161 cases in a prospective phase II study (P67.5 study, with a prescription dose of 67.5Gy in 30 fractions to the primary tumour and positive lymph nodes) and 220 cases in a retrospective study (P70 study, with a prescription dose of 70Gy in 33 fractions to the primary tumour and positive lymph nodes). Acute and late toxicities were assessed according to the established RTOG/EORTC criteria and Common Terminology Criteria for Adverse Events (CTCAE) V 3.0. Survival rate were assessed with Kaplan-Meier method, log-rank test and Cox regression.

Results

After matching, 148 sub-pairs of 296 patients were generated in post-PSM cohort. The incidence of grade 3–4 leukopenia, thrombocytopenia and anemia in the P67.5 group was significantly higher than in the P70 study, but no significant different was found in other acute toxicities or late toxicities between the two groups. The median follow-up was 33 months in the P67.5 and P70 group, ranging 12–54 months and 6–58 months, respectively. No significant differences in 3-year local-regional recurrence free survival (LRRFS), distant metastasis-free survival (DMFS), disease free survival (DFS) and overall survival (OS) were observed between the 2 groups. Univariate analysis showed that age, T stage, clinical stage were the main factors effecting survival. Cox proportional hazards model showed that 67.5Gy/30F pattern seemed superior in 3-year OS (HR = 0.476, 95% CI: 0.236-0.957).

Conclusions

Through increasing fraction dose and shortening treatment time, the P67.5 study achieved excellent short-term outcomes and potential clinical benefits, with acceptable acute and late toxicities.

Trial registration

The trial was registered at Chinese Clinical Trial Registry on 5 July 2014 with a registration code of ChiCTRONC-14,004,895.

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Comparative evaluation of 18 F-FLT and 18 F-FDG for detecting cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis

Abstract

Background

¹⁸F-FDG PET has been used in sarcoidosis for diagnosis and determination of the extent of the disease. However, assessing inflammatory lesions in cardiac sarcoidosis using ¹⁸F-FDG can be challenging because it accumulates physiologically in normal myocardium. Another radiotracer, 3′-deoxy-3′-¹⁸F-fluorothymidine (¹⁸F-FLT), has been investigated as a promising PET tracer for evaluating tumor proliferative activity. In contrast to ¹⁸F-FDG, ¹⁸F-FLT uptake in the normal myocardium is low. The purpose of this retrospective study was to compare the uptake of ¹⁸F-FLT and ¹⁸F-FDG in the evaluation of cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis.

Data for 20 patients with newly diagnosed sarcoidosis were examined. ¹⁸F-FLT and ¹⁸F-FDG PET/CT studies had been performed at 1 h after each radiotracer injection. The patients had fasted for at least 18 h before ¹⁸F-FDG PET/CT but were given no special dietary instructions regarding the period before ¹⁸F-FLT PET/CT. Uptake of ¹⁸F-FLT and ¹⁸F-FDG was examined visually and semiquantitatively using maximal standardized uptake value (SUVmax).

Results

Two patients had cardiac sarcoidosis, 7 had extra-cardiac thoracic sarcoidosis, and 11 had both cardiac and extra-cardiac thoracic sarcoidosis. On visual analysis for diagnosis of cardiac sarcoidosis, 4/20 ¹⁸F-FDG scans were rated as inconclusive because the ¹⁸F-FDG pattern was diffuse, whereas no FLT scans were rated as inconclusive. The sensitivity of ¹⁸F-FDG PET/CT for detection of cardiac sarcoidosis was 85%; specificity, 100%; and accuracy, 90%. The corresponding values for ¹⁸F-FLT PET/CT were 92, 100, and 95%, respectively. Using semiquantitative analysis of cardiac sarcoidosis, the mean ¹⁸F-FDG SUVmax was significantly higher than the mean ¹⁸F-FLT SUVmax (P < 0.005). Both ¹⁸F-FDG and ¹⁸F-FLT PET/CT studies detected all 24 extra-cardiac lesions. Using semiquantitative analysis of extra-cardiac sarcoidosis, the mean ¹⁸F-FDG SUVmax was significantly higher than the mean ¹⁸F-FLT SUVmax (P < 0.001).

Conclusions

The results of this preliminary study suggest that ¹⁸F-FLT PET/CT can detect cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis as well as ¹⁸F-FDG PET/CT, although uptake of ¹⁸F-FLT in lesions was significantly lower than that of ¹⁸F-FDG. However, ¹⁸F-FLT PET/CT may be easier to perform since it requires neither prolonged fasting nor a special diet prior to imaging.

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Fluorine-18 fluorodeoxyglucose positron emission tomography for cardiac sarcoidosis—is it time to consider a new radiotracer?

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Implantation of a Multifocal Toric Intraocular Lens after Radial Keratotomy and Cross-Linking with Hyperopia and Astigmatism Residues: A Case Report

Radial keratotomy is a refractive surgical technique, widely used in the 80s and early 90s to correct myopia and astigmatism, but now overcome by more recent laser techniques. Important consequences, often in patients with more than 45 years of age, are progressive hyperopic shift and/or an increase in corneal astigmatism, whose main cause seems to be an increase in the curvature radius of the central portion of the cornea. This seems to be due to radial keratotomy incisions – with the consequent need for cross-linking – intraocular pressure, and corneal biomechanical parameters. The authors propose phacoemulsification with a customized multifocal toric intraocular lens implantation to correct the induced shift and hyperopic astigmatism. A decent postoperative visual acuity was observed with good patient satisfaction. A specific protocol must be applied to optimize the correct diagnosis, presurgical evaluation and postsurgical outcomes that are to be maintained over time, without regressions.
Case Rep Ophthalmol 2017;8:440–445

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