Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma

Abstract

Background

Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CCRT-AC) is currently recommended as the standard treatment for locally advanced nasopharyngeal carcinoma (LA-NPC). Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (NAC-CCRT) is an alternative strategy for decreasing tumor size and controlling micrometastases before main treatment. The aim of this study was to investigate and compare survival outcomes between LA-NPC patients treated with CCRT-AC and those treated with NAC-CCRT.

Methods

This retrospective cohort study included consecutive histologically confirmed LA-NPC patients that were treated with NAC-CCRT or CCRT-AC at Siriraj Hospital during the March 2010 to October 2014 study period. CCRT in both protocols consisted of 3-week cycles of cisplatin 100 mg/m² with concurrent radiotherapy. Either NAC or AC consisted of 3-week cycles of cisplatin on day 1 and fluorouracil/leucovorin on days 1–4 for a maximum three cycles. The primary endpoint was 5-year overall survival (OS). Flexible parametric survival analysis was used, because the proportional hazards assumption of Cox regression was violated.

Results

Of the 266 LA-NPC patients that received treatment during the study period, 79 received NAC-CCRT and 187 received CCRT-AC. Median follow-up was 37 months. Significantly more patients with advanced clinical stage (stage IVA-IVB) received NAC-CCRT (86% in NAC-CCRT vs. 29% in CCRT-AC; p < 0.001). Compared to CCRT-AC in crude analysis, 3-year and 5-year OS of NAC-CCRT were 72% vs. 86% and 62% vs. 75% respectively (p = 0.059). Interestingly, the 3-year and 5-year post-estimation adjusted OS was 84% and 74% for NAC-CCRT and 81% and 70% for CCRT-AC, respectively (HR: 0.83, 95% confidence interval (CI): 0.45–1.56; p = 0.571). Also, adjusted analysis of distant-metastasis survival, NAC-CCRT showed HR was 0.79 (95% CI:0.37–1.72, p = 0.557). Conversely, adjusted analysis of locoregional relapse (LLR)-free survival revealed NAC-CCRT to have a significantly higher risk of LRR (HR: 2.18, 95% CI: 0.98–4.87; p = 0.057).

Conclusions

The results suggested that prognosis in the NAC-CCRT treated patients was not superior to that of the CCRT-AC treated individuals. In patients that receive neoadjuvant chemotherapy, locoregional relapse should be of concern. High-risk distant metastasis patients (N3 stage) that could achieve survival advantage from NAC-CCRT is an interesting and important topic for further study.

https://ift.tt/2ITeFbW

Detection of circulating tumor cells in patients with pituitary tumors

Abstract

Background

Circulating tumor cells (CTCs) are tumor cells that have shed from a primary tumor and circulate in the peripheral blood. Recent experimental and clinical studies show that CTCs can be detected in early-stage disease.

Case presentation

We report three cases of pituitary adenoma (PA) in which tumor cells with particles were detected in the interstitial vascular compartment by transmission electron microscopy. Tumors were completely resected. Immunohistochemical analysis showed a β-catenin score of 10.5 ± 1.5 in the three cases with CTCs compared with 2.4 ± 0.5 in 24 control adenomas. The Ki-67 labeling index was 2.1 ± 0.7 in CTCs vs. 0.2 ± 0.3 in control cases (p = 0.043), and the p53 score was 4.33 ± 1.3 vs. 0.31 ± 0.17 (p = 0.000). The E-cadherin score did not differ significantly between the two groups.

Conclusions

CTCs can be detected in benign tumors such as PAs and not only in late-stage malignant tumors with apparent distant metastases. The present findings suggest that pituitary carcinomas develop from adenomas.

https://ift.tt/2ITeAoE

To fast, or not to fast before chemotherapy, that is the question

Abstract

Fasting in disease prevention and treatment has recently become a popular topic, particularly in the context of oncology. Unfortunately, the growing attention paid by the media has created a background of speculations and ambiguous messages.

The attitude towards the role of fasting in cancer patients should be very cautious, as the risk of malnutrition/sarcopenia and disinformation may be associated with this approach.

Whether the results obtained by fasting in the cellular and animal models can be transferred to cancer patients is still to be ascertained. At the moment, more preclinical studies are required to determine in which cancers, at which stage, and in what combinations fasting, fasting-mimicking diets or caloric restriction mimetics may prove effective.

So, despite the "rumors" of marketing and media, nowadays fasting and calorie restriction around CT represent only a promising intuition, which requires proper efforts and time to be validated by evidence-based clinical data.

https://ift.tt/2IVo7eZ

Shorter survival in adolescent and young adult patients, compared to adult patients, with stage IV colorectal cancer in Japan

Abstract

Background

The incidence of colorectal cancer in adolescent and young adult patients is increasing. However, survival and clinical features of young patients, especially those with stage IV disease, relative to adult patients remain unclear.

Methods

This retrospective single-institution cohort study was conducted at a tertiary care cancer center. Subjects were 861 consecutive patients who were diagnosed with stage IV colorectal cancer at the age of 15 to 74 years and who were referred to the division of surgery or gastrointestinal oncology at the National Cancer Center Hospital from 1999 to 2013. Overall survival (OS) was investigated and clinicopathological variables were analyzed for prognostic significance.

Results

Of these, 66 (8%) were adolescent and young adult patients and 795 (92%) were adult patients. Median survival time was 13.6 months in adolescent and young adult patients and 22.4 months in adult patients, and 5-year OS rates were 17.3% and 20.3%, respectively, indicating significant worse prognosis of adolescent and young adult patients (p = 0.042). However, age itself was not an independent factor associated with prognosis by multivariate analysis. When compared with adult patients, adolescent and young adult patients consisted of higher proportion of the patients who did not undergo resection of primary tumor, which was an independent factor associated with poor prognosis in multivariate analysis. In patients who did not undergo resection (n = 349), OS of adolescent and young adult patients were significantly worse (p = 0.033).

Conclusions

Prognoses were worse in adolescent and young adult patients with stage IV colorectal cancer compared to adult patients in Japan, due to a higher proportion of patients who did not undergo resection with more advanced and severe disease, but not due to age itself.

https://ift.tt/2ITeu0g

Outcomes of Pemetrexed-based chemotherapies in HER2 -mutant lung cancers

Abstract

Background

HER2 mutation has been found to be an oncogenic driver gene in non-small cell lung cancers(NSCLC) and HER2-directed therapies have shown promising results in this unique population, while little is known about its association with outcomes of chemotherapy. The aim of this study was to investigate the efficacy of first line chemotherapy in patients with advanced HER2-mutant lung adenocarcinomas.

Methods

Patients with advanced NSCLC(N = 1714) initially underwent testing for EGFR, KRAS, BRAF mutations and ALK, ROS1 rearrangements, and negative cases were then assessed for HER2 mutations using the method of amplification refractory mutation system(ARMS). The efficacy of first line pemetrexed-based chemotherapy was investigated in patients with HER2-mutant and those with EGFR-mutant, ALK/ROS1-rearranged and KRAS-mutant advanced adenocarcinomas.

Results

HER2 mutations were detected in 29 of 572(5.1%) specimens from a selected population of EGFR/KRAS/BRAF/ALK/ROS1 negative patients. All of them are adenocarcinomas. Among patients with HER2-mutant lung cancers, 25 received pemetrexed-based first line chemotherapy. The objective response rate(ORR) was 36.0%. Their median progression free survival(PFS) was 5.1 months, which was similar with that of KRAS-mutant group (n = 40,5.0 months, p = 0.971), numerically shorter than that of EGFR-mutant group(n = 74, 6.5 months, p = 0.247) and statistically significantly shorter than that of ALK/ROS1-rearranged group (n = 39,9.2 months, p = 0.004). Furthermore, HER2 variants subgroup analysis showed that PFS was inferior in A775_G776insYVMA group compared with other variants (4.2 vs 7.2 months, p = 0.085).

Conclusions

Patients with advanced HER2-mutant lung adenocarcinomas showed an inferior outcome of first line pemetrexed-based chemotherapy compared to those with ALK/ROS1 rearrangements, which strengthen the need for effective HER2-targeted drugs in clinical practice.

https://ift.tt/2GfzOLR

Knockdown delta-5-desaturase in breast cancer cells that overexpress COX-2 results in inhibition of growth, migration and invasion via a dihomo-γ-linolenic acid peroxidation dependent mechanism

Abstract

Background

Cyclooxygenase-2 (COX-2), the inducible COX form, is a bi-functional membrane-bound enzyme that typically metabolizes arachidonic acid (downstream ω-6 fatty acid) to form 2-series of prostaglandins known to be involved in cancer development. Overexpression of COX-2 has been found in a majority of breast carcinomas, and has also been associated with increased severity and the development of the metastasis. Our lab recently demonstrated that COX-2 can also metabolize dihomo-γ-linolenic acid (DGLA, a precursor of ω-6 arachidonic acid) to produce an anti-cancer byproduct, 8-hydroxyoctanoic acid (8-HOA) that can inhibit growth and migration of colon and pancreatic cancer cells. We thus tested whether our strategy of knocking down delta-5-desaturase (D5D, the key enzyme that converts DGLA to arachidonic acid) in breast cancer cells overexpressing COX-2 can also be used to promote 8-HOA formation, thereby suppressing cancer growth, migration, and invasion.

Methods

SiRNA and shRNA transfection were used to knock down D5D expression in MDA-MB 231 and 4 T1 cells (human and mouse breast cancer cell lines expressing high COX-2, respectively). Colony formation assay, FITC Annexin V/PI double staining, wound healing and transwell assay were used to assess the effect of our strategy on inhibition of cancer growth, migration, and invasion. GC/MS was used to measure endogenous 8-HOA, and western blotting was performed to evaluate the altered key protein expressions upon the treatments.

Results

We demonstrated that D5D knockdown licenses DGLA to inhibit growth of breast cancer cells via promoting formation of 8-HOA that can inhibit histone deacetylase and activate cell apoptotic proteins, such as procaspase 9 and PARP. Our strategy can also significantly inhibit cancer migration and invasion, associated with altered expression of MMP-2/− 9, E-cadherin, vimentin and snail. In addition, D5D knockdown and DGLA supplementation greatly enhanced the efficacy of 5-fluorouracil on breast cancer growth and migration.

Conclusions

Consistent to our previous studies on colon and pancreatic cancer, here we demonstrate again that the high level of COX-2 in breast cancer cells can be capitalized on inhibiting cancer growth and migration. The outcome of this translational research could guide us to develop new anti-cancer strategy and/or to improve current chemotherapy for breast cancer treatment.

https://ift.tt/2IXXeHo

Shorter survival in adolescent and young adult patients, compared to adult patients, with stage IV colorectal cancer in Japan

Abstract

Background

The incidence of colorectal cancer in adolescent and young adult patients is increasing. However, survival and clinical features of young patients, especially those with stage IV disease, relative to adult patients remain unclear.

Methods

This retrospective single-institution cohort study was conducted at a tertiary care cancer center. Subjects were 861 consecutive patients who were diagnosed with stage IV colorectal cancer at the age of 15 to 74 years and who were referred to the division of surgery or gastrointestinal oncology at the National Cancer Center Hospital from 1999 to 2013. Overall survival (OS) was investigated and clinicopathological variables were analyzed for prognostic significance.

Results

Of these, 66 (8%) were adolescent and young adult patients and 795 (92%) were adult patients. Median survival time was 13.6 months in adolescent and young adult patients and 22.4 months in adult patients, and 5-year OS rates were 17.3% and 20.3%, respectively, indicating significant worse prognosis of adolescent and young adult patients (p = 0.042). However, age itself was not an independent factor associated with prognosis by multivariate analysis. When compared with adult patients, adolescent and young adult patients consisted of higher proportion of the patients who did not undergo resection of primary tumor, which was an independent factor associated with poor prognosis in multivariate analysis. In patients who did not undergo resection (n = 349), OS of adolescent and young adult patients were significantly worse (p = 0.033).

Conclusions

Prognoses were worse in adolescent and young adult patients with stage IV colorectal cancer compared to adult patients in Japan, due to a higher proportion of patients who did not undergo resection with more advanced and severe disease, but not due to age itself.

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Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma

Abstract

Background

Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CCRT-AC) is currently recommended as the standard treatment for locally advanced nasopharyngeal carcinoma (LA-NPC). Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (NAC-CCRT) is an alternative strategy for decreasing tumor size and controlling micrometastases before main treatment. The aim of this study was to investigate and compare survival outcomes between LA-NPC patients treated with CCRT-AC and those treated with NAC-CCRT.

Methods

This retrospective cohort study included consecutive histologically confirmed LA-NPC patients that were treated with NAC-CCRT or CCRT-AC at Siriraj Hospital during the March 2010 to October 2014 study period. CCRT in both protocols consisted of 3-week cycles of cisplatin 100 mg/m² with concurrent radiotherapy. Either NAC or AC consisted of 3-week cycles of cisplatin on day 1 and fluorouracil/leucovorin on days 1–4 for a maximum three cycles. The primary endpoint was 5-year overall survival (OS). Flexible parametric survival analysis was used, because the proportional hazards assumption of Cox regression was violated.

Results

Of the 266 LA-NPC patients that received treatment during the study period, 79 received NAC-CCRT and 187 received CCRT-AC. Median follow-up was 37 months. Significantly more patients with advanced clinical stage (stage IVA-IVB) received NAC-CCRT (86% in NAC-CCRT vs. 29% in CCRT-AC; p < 0.001). Compared to CCRT-AC in crude analysis, 3-year and 5-year OS of NAC-CCRT were 72% vs. 86% and 62% vs. 75% respectively (p = 0.059). Interestingly, the 3-year and 5-year post-estimation adjusted OS was 84% and 74% for NAC-CCRT and 81% and 70% for CCRT-AC, respectively (HR: 0.83, 95% confidence interval (CI): 0.45–1.56; p = 0.571). Also, adjusted analysis of distant-metastasis survival, NAC-CCRT showed HR was 0.79 (95% CI:0.37–1.72, p = 0.557). Conversely, adjusted analysis of locoregional relapse (LLR)-free survival revealed NAC-CCRT to have a significantly higher risk of LRR (HR: 2.18, 95% CI: 0.98–4.87; p = 0.057).

Conclusions

The results suggested that prognosis in the NAC-CCRT treated patients was not superior to that of the CCRT-AC treated individuals. In patients that receive neoadjuvant chemotherapy, locoregional relapse should be of concern. High-risk distant metastasis patients (N3 stage) that could achieve survival advantage from NAC-CCRT is an interesting and important topic for further study.

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Erlotinib treatment after platinum-based therapy in elderly patients with non-small-cell lung cancer in routine clinical practice – results from the ElderTac study

Abstract

Background

In this prospective non-interventional study, the effectiveness and tolerability of erlotinib in elderly patients with non-small-cell lung cancer (NSCLC) after ≥1 platinum-based chemotherapy were assessed.

Methods

A total of 385 patients ≥65 years of age with advanced NSCLC receiving erlotinib were observed over 12 months. The primary endpoint was the 1-year overall survival (OS) rate.

Results

Patients were predominantly Caucasian (99.2%), a mean of 73 years old; 24.7% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Most common tumor histologies were adenocarcinoma (64.9%) and squamous cell carcinoma (22.3%). Of 119 patients tested, 15.1% had an activating epidermal growth factor receptor gene (EGFR) mutation. The 1-year OS rate was 31% (95% CI 25–36) with a median OS of 7.1 months (95% CI 6.0–7.9). OS was significantly better in females than males (p = 0.0258) and in patients with an EGFR mutation compared to EGFR wild-type patients (p = 0.0004). OS was not affected by age (p = 0.3436) and ECOG PS (p = 0.5364). Patients with squamous NSCLC tended to live longer than patients with non-squamous EGFR wild-type tumors (median OS: 8.6 vs 5.5 months). Cough and dyspnea improved during the observation period. The erlotinib safety profile was comparable to that in previous studies with rash (45.2%) and diarrhea (22.6%) being the most frequently reported adverse events.

Conclusions

Erlotinib represents a suitable palliative treatment option in further therapy lines for elderly patients with advanced NSCLC. The results obtained under real-life conditions add to our understanding of the benefits and risks of erlotinib in routine clinical practice.

Trial registration

BfArM (https://www.bfarm.de; ML23023); ClinicalTrials.gov (NCT01535729; 20 Feb 2012).

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Detection of circulating tumor cells in patients with pituitary tumors

Abstract

Background

Circulating tumor cells (CTCs) are tumor cells that have shed from a primary tumor and circulate in the peripheral blood. Recent experimental and clinical studies show that CTCs can be detected in early-stage disease.

Case presentation

We report three cases of pituitary adenoma (PA) in which tumor cells with particles were detected in the interstitial vascular compartment by transmission electron microscopy. Tumors were completely resected. Immunohistochemical analysis showed a β-catenin score of 10.5 ± 1.5 in the three cases with CTCs compared with 2.4 ± 0.5 in 24 control adenomas. The Ki-67 labeling index was 2.1 ± 0.7 in CTCs vs. 0.2 ± 0.3 in control cases (p = 0.043), and the p53 score was 4.33 ± 1.3 vs. 0.31 ± 0.17 (p = 0.000). The E-cadherin score did not differ significantly between the two groups.

Conclusions

CTCs can be detected in benign tumors such as PAs and not only in late-stage malignant tumors with apparent distant metastases. The present findings suggest that pituitary carcinomas develop from adenomas.

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Development of primary human pancreatic cancer organoids, matched stromal and immune cells and 3D tumor microenvironment models

Abstract

Background

Patient-derived tumor models are the new standard for pre-clinical drug testing and biomarker discovery. However, the emerging technology of primary pancreatic cancer organoids has not yet been broadly implemented in research, and complex organotypic models using organoids in co-culture with stromal and immune cellular components of the tumor have yet to be established. In this study, our objective was to develop and characterize pancreatic cancer organoids and multi-cell type organotypic co-culture models to demonstrate their applicability to the study of pancreatic cancer.

Methods

We employed organoid culture methods and flow cytometric, cytologic, immunofluorescent and immunohistochemical methods to develop and characterize patient-derived pancreatic cancer organoids and multi-cell type organotypic co-culture models of the tumor microenvironment.

Results

We describe the culture and characterization of human pancreatic cancer organoids from resection, ascites and rapid autopsy sources and the derivation of adherent tumor cell monocultures and tumor-associated fibroblasts from these sources. Primary human organoids displayed tumor-like cellular morphology, tissue architecture and polarity in contrast to cell line spheroids, which formed homogenous, non-lumen forming spheres. Importantly, we demonstrate the construction of complex organotypic models of tumor, stromal and immune components of the tumor microenvironment. Activation of myofibroblast-like cancer associated fibroblasts and tumor-dependent lymphocyte infiltration were observed in these models.

Conclusions

These studies provide the first report of novel and disease-relevant 3D in-vitro models representing pancreatic tumor, stromal and immune components using primary organoid co-cultures representative of the tumor-microenvironment. These models promise to facilitate the study of tumor-stroma and tumor-immune interaction and may be valuable for the assessment of immunotherapeutics such as checkpoint inhibitors in the context of T-cell infiltration.

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The prognostic significance of topoisomerase II alpha protein in early stage luminal breast cancer

Abstract

Background

Topoisomerase II alpha (TOP2A) protein has been shown to be a proliferation marker associated with tumor grade and Ki67 index. The prognostic effect of TOP2A seems different among different subtypes of breast cancer. The current study evaluated the prognostic impact of TOP2A protein on luminal breast cancer.

Method

Altogether 434 stage I-II luminal breast cancer patients who underwent curative surgery in Sun Yat-Sen University Cancer Center between 2007 and 2009 were enrolled. TOP2A protein expression was assessed by immunohistochemistry. Clinical and pathological data were retrospectively collected.

Result

With a cut-off value of 30%, 127 (29.3%) patients were classified as TOP2A overexpression. TOP2A overexpression was associated with a higher tumor grade and Ki67 index. Patients with TOP2A high expression showed a significantly higher rate of distant metastasis and shorter distant metastasis free survival (DMFS) compared with patients with low TOP2A expression. The prognostic influence of TOP2A expression was more significant in years 5–8 after diagnosis, and more pronounced in stage II patients, luminal B disease, and patients treated with adjuvant endocrine therapy alone. Multivariate survival analysis revealed TOP2A overexpression was an independent fact for worse DMFS.

Conclusion

TOP2A protein showed a time dependent influence on prognosis in stage I-II luminal breast cancer, suggesting it might be a potential predictor of late recurrence for this group of patients.

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Outcomes of Pemetrexed-based chemotherapies in HER2 -mutant lung cancers

Abstract

Background

HER2 mutation has been found to be an oncogenic driver gene in non-small cell lung cancers(NSCLC) and HER2-directed therapies have shown promising results in this unique population, while little is known about its association with outcomes of chemotherapy. The aim of this study was to investigate the efficacy of first line chemotherapy in patients with advanced HER2-mutant lung adenocarcinomas.

Methods

Patients with advanced NSCLC(N = 1714) initially underwent testing for EGFR, KRAS, BRAF mutations and ALK, ROS1 rearrangements, and negative cases were then assessed for HER2 mutations using the method of amplification refractory mutation system(ARMS). The efficacy of first line pemetrexed-based chemotherapy was investigated in patients with HER2-mutant and those with EGFR-mutant, ALK/ROS1-rearranged and KRAS-mutant advanced adenocarcinomas.

Results

HER2 mutations were detected in 29 of 572(5.1%) specimens from a selected population of EGFR/KRAS/BRAF/ALK/ROS1 negative patients. All of them are adenocarcinomas. Among patients with HER2-mutant lung cancers, 25 received pemetrexed-based first line chemotherapy. The objective response rate(ORR) was 36.0%. Their median progression free survival(PFS) was 5.1 months, which was similar with that of KRAS-mutant group (n = 40,5.0 months, p = 0.971), numerically shorter than that of EGFR-mutant group(n = 74, 6.5 months, p = 0.247) and statistically significantly shorter than that of ALK/ROS1-rearranged group (n = 39,9.2 months, p = 0.004). Furthermore, HER2 variants subgroup analysis showed that PFS was inferior in A775_G776insYVMA group compared with other variants (4.2 vs 7.2 months, p = 0.085).

Conclusions

Patients with advanced HER2-mutant lung adenocarcinomas showed an inferior outcome of first line pemetrexed-based chemotherapy compared to those with ALK/ROS1 rearrangements, which strengthen the need for effective HER2-targeted drugs in clinical practice.

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Knockdown delta-5-desaturase in breast cancer cells that overexpress COX-2 results in inhibition of growth, migration and invasion via a dihomo-γ-linolenic acid peroxidation dependent mechanism

Abstract

Background

Cyclooxygenase-2 (COX-2), the inducible COX form, is a bi-functional membrane-bound enzyme that typically metabolizes arachidonic acid (downstream ω-6 fatty acid) to form 2-series of prostaglandins known to be involved in cancer development. Overexpression of COX-2 has been found in a majority of breast carcinomas, and has also been associated with increased severity and the development of the metastasis. Our lab recently demonstrated that COX-2 can also metabolize dihomo-γ-linolenic acid (DGLA, a precursor of ω-6 arachidonic acid) to produce an anti-cancer byproduct, 8-hydroxyoctanoic acid (8-HOA) that can inhibit growth and migration of colon and pancreatic cancer cells. We thus tested whether our strategy of knocking down delta-5-desaturase (D5D, the key enzyme that converts DGLA to arachidonic acid) in breast cancer cells overexpressing COX-2 can also be used to promote 8-HOA formation, thereby suppressing cancer growth, migration, and invasion.

Methods

SiRNA and shRNA transfection were used to knock down D5D expression in MDA-MB 231 and 4 T1 cells (human and mouse breast cancer cell lines expressing high COX-2, respectively). Colony formation assay, FITC Annexin V/PI double staining, wound healing and transwell assay were used to assess the effect of our strategy on inhibition of cancer growth, migration, and invasion. GC/MS was used to measure endogenous 8-HOA, and western blotting was performed to evaluate the altered key protein expressions upon the treatments.

Results

We demonstrated that D5D knockdown licenses DGLA to inhibit growth of breast cancer cells via promoting formation of 8-HOA that can inhibit histone deacetylase and activate cell apoptotic proteins, such as procaspase 9 and PARP. Our strategy can also significantly inhibit cancer migration and invasion, associated with altered expression of MMP-2/− 9, E-cadherin, vimentin and snail. In addition, D5D knockdown and DGLA supplementation greatly enhanced the efficacy of 5-fluorouracil on breast cancer growth and migration.

Conclusions

Consistent to our previous studies on colon and pancreatic cancer, here we demonstrate again that the high level of COX-2 in breast cancer cells can be capitalized on inhibiting cancer growth and migration. The outcome of this translational research could guide us to develop new anti-cancer strategy and/or to improve current chemotherapy for breast cancer treatment.

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A phase I/Ib study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer

Abstract

Background

We conducted a phase I/Ib, open-label, single-arm trial to assess the safety, tolerability and optimal scheduling regimen of OTSGC-A24 cancer vaccine in patients with advanced gastric cancer.

Methods

Patients with advanced gastric cancer with HLA-A*24:02 haplotype were included in this study. OTSGC-A24 was administered at 1 mg in 3-weekly (3w), 2-weekly (2w), and weekly (1w) cohorts to evaluate the safety, immunological response and schedule. Based on the highest specific cytotoxic T lymphocyte (CTL) induction rate at 4 weeks, using the ELISPOT test, cohorts were expanded to define the optimal dosing schedule for OTSGC-A24.

Results

In this study, 24 advanced gastric cancer patients with HLA-A*24:02 haplotype were enrolled and treated in 3 cohorts (3w cohort: 3; 2w cohort: 11 and 1w cohort: 10 patients). The most common adverse events were decreased appetite (29%), diarrhea (21%), myalgia (25%). The most common treatment-related adverse event was injection site erythema (25%). No dose-limiting toxicities were observed in any cohort and OTSGC-A24 was well tolerated. Positive CTL responses after vaccination were observed in 15 patients (75%) at 4 weeks: 3w cohort (33%), 2w cohort (88%), 1w cohort (78%). At 12 weeks, 18 patients had responded (90%); 3w cohort (100%), 2w cohort (100%), 1w cohort (78%). The best radiological was stable disease (40%). Median progression free survival was 1.7 months (95% CI: 1.4 to 3.5) and median overall survival was 5.7 months (95% CI 3.8 to 8.6).

Conclusions

OTSGC-A24 combined peptide cancer vaccine was well tolerated. Significant responses in CTL were observed and the recommended phase 2 dose is 1 mg OTSGC-A24 sub-cutaneous, every 2 weeks. Although no radiological response was observed, a respectable overall survival was achieved, consistent with other immunotherapy agents being investigated in gastric cancer.

Trial registration

ClinicalTrials.gov Identifier: NCT01227772, Date registered: 21 Oct 2010.

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miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect

https://ift.tt/2IWbmAS

Bioinformatic analysis of prognostic value of ZW10 interacting protein in lung cancer

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Biomarker expression in rectal cancer tissue before and after neoadjuvant therapy

https://ift.tt/2IUGznX

CalliSpheres drug-eluting beads versus lipiodol transarterial chemoembolization in the treatment of hepatocellular carcinoma: a short-term efficacy and safety study

Abstract

Background

The present study aimed to evaluate the short-term efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) with CalliSpheres Beads loaded with doxorubicin (DOX) in the treatment of Chinese patients with hepatocellular carcinoma (HCC) compared to conventional TACE (cTACE).

Methods

A total of 54 patients with HCC treated by TACE from June 2016 to February 2017 were retrospectively analyzed. These included 24 cases in the DEB-TACE group and 30 cases in the cTACE group. The clinical efficacy, tumor recurrence rate, and complications were compared between the two groups. Furthermore, liver function tests and alpha-feto protein levels were compared between the two groups before and at 1 week and 1 month after interventional treatment.

Results

There were no significant differences in baseline characteristics (p > 0.05). Tumor response rates and disease control rates in the DEB-TACE group were significantly higher than those in the cTACE group at 3 and 6 months after treatment (p < 0.05). Recurrence rates at 6 months were significantly higher for cTACE compared to DEB-TACE (43.3 vs. 16.7%; p = 0.036). At 1 month, the AFP level in the DEB-TACE group was significantly lower than that in the cTACE group (p = 0.008). At the end of follow-up, four cases in the DEB-TACE group and two cases in the cTACE group were treated with salvage surgery after downstaging the disease. Liver function of both groups improved at 1 month. However, alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels in the DEB-TACE group were better than those in the cTACE group (p < 0.05). The incidence of DOX-related complications in the DEB-TACE group was significantly lower than in the cTACE group (p < 0.05).

Conclusion

The short-term efficacy of DEB-TACE is better, and the complication rates are lower compared to cTACE in the treatment of Chinese patients with HCC. However, long-term clinical efficacy and survival benefit should be analyzed in future studies.

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Mesh-reinforced pancreaticojejunostomy versus conventional pancreaticojejunostomy after pancreaticoduodenectomy: a retrospective study of 126 patients

Abstract

Background

Pancreatic fistula is a major cause of morbidity and mortality after pancreaticoduodenectomy. The aim of this study is to compare the safety and efficacy of a newly developed technique, namely mesh-reinforced pancreaticojejunostomy, in comparison with the conventional use of pancreaticojejunostomy after undergoing a pancreaticoduodenectomy.

Methods

Data was collected from regarding 126 consecutive patients, who underwent the mesh-reinforced pancreaticojejunostomy or conventional pancreaticojejunostomy, after standard pancreaticoduodenectomy by one group of surgeons, between the time period of 2005 and 2016. This data was collected retrospectively. Surgical parameters and perioperative outcomes were compared between these two groups.

Results

A total of 65 patients received mesh-reinforced pancreaticojejunostomy and 61 underwent conventional pancreaticojejunostomy. There were no substantial differences in surgical parameters, mortality, biliary leakage, delayed gastric emptying, gastrojejunostomy leakage, intra-abdominal fluid collection, postpancreatectomy hemorrhage, reoperation, and the total hospital costs between the two groups. Pancreatic fistula rate (15 versus 34%; p = 0.013), overall surgical morbidity (25 versus 43%; p = 0.032), and length of hospital stay (18 ± 9 versus 23 ± 12 days; p = 0.016) were significantly reduced after mesh-reinforced pancreaticojejunostomy. Multivariate analysis of the postoperative pancreatic fistula revealed that the independent factors that were highly associated with pancreatic fistula were a soft pancreatic texture and the type of conventional pancreaticojejunostomy.

Conclusions

This retrospective single-center study showed that mesh-reinforced pancreaticojejunostomy appears to be a safe technique for pancreaticojejunostomy. It may reduce pancreatic fistula rate and surgical complications after pancreaticoduodenectomy.

Trial registration

This research is waivered from trial registration because it is a retrospective analysis of medical records.

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Treatment of intraoperatively detected peritoneal carcinomatosis of colorectal origin with cytoreductive surgery and intraperitoneal chemotherapy

Abstract

Background

Diagnosis of peritoneal carcinomatosis (PC) may be missed by preoperative imaging. We are presenting our experience with incidentally detected PC of colorectal origin treated with cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) at the same operation.

Methods

Between January 2010 and September 2016, 19 patients underwent CRS and IPC due to incidentally detected PC of colorectal origin. Data were analyzed from a prospectively collected database.

Results

The median age was 59 (29–78). In three patients, PC was diagnosed during emergency surgery. The primary tumor was located in the rectum (three patients; one with recurrent disease), left colon (9 patients), and right colon (7 patients). All patients underwent CRS and IPC, and one patient operated laparoscopically. Median peritoneal cancer index (PCI) was 5 (range, 3–14), and complete cytoreduction (CC-0) was achieved in 14 patients. After CRS, 8 patients received early postoperative intraperitoneal chemotherapy (EPIC), 7 patients received hyperthermic intraperitoneal chemotherapy (HIPEC), and 4 patients received both HIPEC and EPIC. The median hospital stay was 9 (6–29) days. Postoperative complications occurred in 6 patients. There was no postoperative mortality. Median follow-up was 40.2 (12–94) months. Five-year overall survival was 63.2%. Estimated mean survival time is longer in patients who underwent complete cytoreduction compared to patients having CC-1 or CC-2 cytoreduction (87.7 vs. 20.3 months; p < 0.001).

Conclusion

Cytoreductive surgery and IPC can be performed safely in patients with intraoperatively detected incidental PC of colorectal origin.

from Cancer via ola Kala on Inoreader https://ift.tt/2GsS9IC
via IFTTT

Thomas L. Slovis (1941-2018)

from Cancer via ola Kala on Inoreader https://ift.tt/2ulMHCF
via IFTTT

Mesh-reinforced pancreaticojejunostomy versus conventional pancreaticojejunostomy after pancreaticoduodenectomy: a retrospective study of 126 patients

Abstract

Background

Pancreatic fistula is a major cause of morbidity and mortality after pancreaticoduodenectomy. The aim of this study is to compare the safety and efficacy of a newly developed technique, namely mesh-reinforced pancreaticojejunostomy, in comparison with the conventional use of pancreaticojejunostomy after undergoing a pancreaticoduodenectomy.

Methods

Data was collected from regarding 126 consecutive patients, who underwent the mesh-reinforced pancreaticojejunostomy or conventional pancreaticojejunostomy, after standard pancreaticoduodenectomy by one group of surgeons, between the time period of 2005 and 2016. This data was collected retrospectively. Surgical parameters and perioperative outcomes were compared between these two groups.

Results

A total of 65 patients received mesh-reinforced pancreaticojejunostomy and 61 underwent conventional pancreaticojejunostomy. There were no substantial differences in surgical parameters, mortality, biliary leakage, delayed gastric emptying, gastrojejunostomy leakage, intra-abdominal fluid collection, postpancreatectomy hemorrhage, reoperation, and the total hospital costs between the two groups. Pancreatic fistula rate (15 versus 34%; p = 0.013), overall surgical morbidity (25 versus 43%; p = 0.032), and length of hospital stay (18 ± 9 versus 23 ± 12 days; p = 0.016) were significantly reduced after mesh-reinforced pancreaticojejunostomy. Multivariate analysis of the postoperative pancreatic fistula revealed that the independent factors that were highly associated with pancreatic fistula were a soft pancreatic texture and the type of conventional pancreaticojejunostomy.

Conclusions

This retrospective single-center study showed that mesh-reinforced pancreaticojejunostomy appears to be a safe technique for pancreaticojejunostomy. It may reduce pancreatic fistula rate and surgical complications after pancreaticoduodenectomy.

Trial registration

This research is waivered from trial registration because it is a retrospective analysis of medical records.

https://ift.tt/2E1gksw

FOLFIRI plus panitumumab in the treatment of wild-type KRAS and wild-type NRAS metastatic colorectal cancer

Abstract

Background

The aim of this study was to investigate the efficacy and safety of first-line panitumumab plus folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) in patients with wild-type KRAS and wild-type NRAS metastatic colorectal cancer (mCRC).

Methods

Patients with wild-type KRAS and wild-type NRAS mCRC presenting to the medical oncology department of the Okmeydani Training and Research Hospital in Istanbul, Turkey, between April 2014 and January 2018 were enrolled in this study.

Results

A total of 64 patients (35 males and 29 females) with a median age of 59 (35–81) years old were enrolled. The median follow-up was 18.9 months, and the median progression-free survival was 13 months. The median overall survival (OS) was 26 months in the patients with wild-type KRAS and wild-type NRAS mCRC. It was 90.4% for the 6-month OS, 79.5% for the 1-year OS, 53.7% for the 2-year OS and 31.1% for the 3-year OS. The median OS of the patients who underwent metastasectomies was 40 [95% confidence interval (CI) = 19.9–60.1] months, and the median OS of the patients without metastasectomies was 22 (95% CI = 17.7–26.4) months. There was a statistically significant difference between these (P = 0.007).

Conclusion

The first-line FOLFIRI plus panitumumab was associated with favourable efficacy in the patients with wild-type KRAS and wild-type NRAS mCRC, and it was well tolerated. The removal of the metastases that became resectable after chemotherapy further prolonged the patients' survival.

Trial registration

Retrospectively registered: 33886

https://ift.tt/2DXty9i

CalliSpheres drug-eluting beads versus lipiodol transarterial chemoembolization in the treatment of hepatocellular carcinoma: a short-term efficacy and safety study

Abstract

Background

The present study aimed to evaluate the short-term efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) with CalliSpheres Beads loaded with doxorubicin (DOX) in the treatment of Chinese patients with hepatocellular carcinoma (HCC) compared to conventional TACE (cTACE).

Methods

A total of 54 patients with HCC treated by TACE from June 2016 to February 2017 were retrospectively analyzed. These included 24 cases in the DEB-TACE group and 30 cases in the cTACE group. The clinical efficacy, tumor recurrence rate, and complications were compared between the two groups. Furthermore, liver function tests and alpha-feto protein levels were compared between the two groups before and at 1 week and 1 month after interventional treatment.

Results

There were no significant differences in baseline characteristics (p > 0.05). Tumor response rates and disease control rates in the DEB-TACE group were significantly higher than those in the cTACE group at 3 and 6 months after treatment (p < 0.05). Recurrence rates at 6 months were significantly higher for cTACE compared to DEB-TACE (43.3 vs. 16.7%; p = 0.036). At 1 month, the AFP level in the DEB-TACE group was significantly lower than that in the cTACE group (p = 0.008). At the end of follow-up, four cases in the DEB-TACE group and two cases in the cTACE group were treated with salvage surgery after downstaging the disease. Liver function of both groups improved at 1 month. However, alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels in the DEB-TACE group were better than those in the cTACE group (p < 0.05). The incidence of DOX-related complications in the DEB-TACE group was significantly lower than in the cTACE group (p < 0.05).

Conclusion

The short-term efficacy of DEB-TACE is better, and the complication rates are lower compared to cTACE in the treatment of Chinese patients with HCC. However, long-term clinical efficacy and survival benefit should be analyzed in future studies.

https://ift.tt/2GsSo6u

Treatment of intraoperatively detected peritoneal carcinomatosis of colorectal origin with cytoreductive surgery and intraperitoneal chemotherapy

Abstract

Background

Diagnosis of peritoneal carcinomatosis (PC) may be missed by preoperative imaging. We are presenting our experience with incidentally detected PC of colorectal origin treated with cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) at the same operation.

Methods

Between January 2010 and September 2016, 19 patients underwent CRS and IPC due to incidentally detected PC of colorectal origin. Data were analyzed from a prospectively collected database.

Results

The median age was 59 (29–78). In three patients, PC was diagnosed during emergency surgery. The primary tumor was located in the rectum (three patients; one with recurrent disease), left colon (9 patients), and right colon (7 patients). All patients underwent CRS and IPC, and one patient operated laparoscopically. Median peritoneal cancer index (PCI) was 5 (range, 3–14), and complete cytoreduction (CC-0) was achieved in 14 patients. After CRS, 8 patients received early postoperative intraperitoneal chemotherapy (EPIC), 7 patients received hyperthermic intraperitoneal chemotherapy (HIPEC), and 4 patients received both HIPEC and EPIC. The median hospital stay was 9 (6–29) days. Postoperative complications occurred in 6 patients. There was no postoperative mortality. Median follow-up was 40.2 (12–94) months. Five-year overall survival was 63.2%. Estimated mean survival time is longer in patients who underwent complete cytoreduction compared to patients having CC-1 or CC-2 cytoreduction (87.7 vs. 20.3 months; p < 0.001).

Conclusion

Cytoreductive surgery and IPC can be performed safely in patients with intraoperatively detected incidental PC of colorectal origin.

https://ift.tt/2GsS9IC

Thomas L. Slovis (1941-2018)

https://ift.tt/2ulMHCF

Mental disorders around cancer diagnosis and increased hospital admission rate - a nationwide cohort study of Swedish cancer patients

Abstract

Background

Whether the emotional distress around cancer diagnosis is associated with the long-term outcomes and care utilization is unknown. We aimed to examine the association of mental disorders around cancer diagnosis with the hospital admission rates of cancer patients thereafter.

Methods

We conducted a nationwide cohort study including 218,508 cancer patients diagnosed in Sweden during 2004–2009 and followed them from 90 days after cancer through 2010. We used a clinical diagnosis of stress-related mental disorders from 90 days before to 90 days after cancer diagnosis as the exposure. We studied first all hospital admissions and then separately three common admissions, including external injuries, infections, and cardiovascular diseases. The Cox model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs).

Results

Four thousand one hundred five patients received a diagnosis of stress-related mental disorders around the cancer diagnosis, and experienced a 35% increased rate of any hospital admission during follow-up (HR: 1.35, 95%CI: 1.28–1.41) as well as hospital admissions for external injuries (HR: 1.89, 95%CI: 1.67–2.14), infections (HR: 1.28, 95%CI: 1.08–1.52), and cardiovascular diseases (HR: 1.16, 95%CI: 1.03–1.30). Similar association was noted for most common cancer types.

Conclusions

These data suggest that cancer patients diagnosed with a stress-related mental disorder immediately before or after cancer diagnosis are subsequently at increased risk of hospital admissions for major comorbidities of cancer.

from Cancer via ola Kala on Inoreader https://ift.tt/2uocuKg
via IFTTT

Anti-EGFR targeted therapy delivered before versus during radiotherapy in locoregionally advanced nasopharyngeal carcinoma: a big-data, intelligence platform-based analysis

Abstract

Background

Little is known about the prognostic difference of anti-EGFR therapy, cetuximab (CTX) or nimotuzumab (NTZ), concurrently with induction chemotherapy (IC, investigational arm) or RT (control arm) for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). We conducted this retrospective study to address this.

Methods

We identified 296 patients with newly diagnosed LA-NPC at Sun Yat-Sen University Cancer Center between January 2012 and May 2015. Patients were treated by IC with CCRT or RT and CTX/NTZ was delivered during IC or radiotherapy. Survival outcomes and toxicities between different arms were compared.

Results

In total, there were 149 patients in the investigational arm and 147 in control arm. The 3-year disease-free survival, overall survival, distant metastasis-free survival and locoregional relapse-free survival rates for investigational arm vs. control arm were 84.3% vs. 74.3% (P = 0.027), 94.0% vs. 92.1% (P = 0.673), 88.0% vs. 81.8% (P = 0.147) and 93.3% vs. 88.0% (P = 0.093). Multivariate analysis revealed patients in the control arm achieved significantly worse disease-free survival (HR, 1.497; 95% CI, 1.016–2.206; P = 0.026) compared with those in the investigational arm; however, no significant difference was identified for other endpoints. Patients in the investigational arm experienced more grade 3–4 skin reaction (15.4% vs. 2.0%, P <  0.001) and mucositis (10.1% vs. 3.4%, P = 0.022) during induction phase, but less skin reaction (5.4% vs. 25.9%, P <  0.001) and mucositis (24.8% vs. 36.7%, P = 0.026) during RT.

Conclusions

Our findings suggested that CTX/NTZ concurrently with IC may be a more effective and promising strategy for patients with LA-NPC receiving intensity-modulated radiotherapy.

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via IFTTT

Frequency of HPV in oral cavity squamous cell carcinoma

Abstract

Background

The prevalence of high-risk human papillomavirus (HPV) DNA in cases of oral cavity squamous cell carcinoma (SCC) varies widely. The aim of this study is to investigate the frequency of high-risk HPV DNA in a large Brazilian cohort of patients with oral cavity SCC.

Methods

Biopsy and resected frozen and formalin-fixed paraffin-embedded specimens of oral cavity SCC were available from 101 patients who were recruited at two Brazilian centres. Stringent measures with respect to case selection and prevention of sample contamination were adopted to ensure reliability of the data. Nested PCR using MY09/MY11 and GP5⁺/GP6⁺ as well as PGMY09/11 L1 consensus primers were performed to investigate the presence of HPV DNA in the tumours. HPV-positive cases were subjected to direct sequencing. Shapiro–Wilk and Student t test were used to evaluate data normality and to compare the means, respectively. Qualitative variables were analysed by logistic regression.

Results

Our results demonstrate that the frequency of high-risk HPV types in oral cavity SCC is very low and is less than 4%. All HPV-positive cases were HPV16. In addition, our results do not show a significant association between the tumour clinical features and the risk factors (tobacco, alcohol and HPV) for oral cavity SCC.

Conclusion

In the current study, we observed an overlapping pattern of risk factors that are related to tumour development. This, along with a low frequency of high-risk HPV DNA, supports the findings that HPV is not involved in the genesis of oral cavity SCC in Brazilian population.

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via IFTTT

GDF15 predict platinum response during first-line chemotherapy and can act as a complementary diagnostic serum biomarker with CA125 in epithelial ovarian cancer

Abstract

Background

Growth differentiation factor 15 (GDF15) has attracted much interest as a novel biomarker for epithelial ovarian carcinoma (EOC). Research focus has been directed at GDF15 as a diagnostic detection, while the prognostic determination of GDF15 in EOC patients remains to be clearly elucidated. The present study aimed to investigate GDF15 level relative to clinicopathological characters, chemoresponse, and clinical outcome of EOC patients.

Methods

Serum from 122 patients with primary diagnosed EOC were analyzed for GDF15 and serum cancer antigen 125 (CA125). All cases were treated with debulking surgery and first-line chemotherapy, and samples were obtained just before debulking surgical treatment and first-line chemotherapy. Subsequently, clinical characteristics, responses to chemotherapy and progression-free survival (PFS) were recorded.

Results

Increasing levels of serum GDF15 was significantly associated with FIGO stage and lymphonodus metastasis. GDF15 and CA125 detection are complementary in the diagnosis of EOC and can be simultaneously profiled. The chemo-resistant EOC patients (median, 1225.0 pg/mL) showed significantly higher GDF15 than chemo-sensitive patients (median, 824.2 pg/mL; P = 0.013). Highly expressed GDF15 was an independent negative prognostic indicator in the PFS (P = 0.026) of the 122 EOC cases in the multivariate analysis. Additionally, patients with high level of serum CA125 significantly associated with suboptimal (P = 0.043) debulking surgery.

Conclusions

Our results provide valuable evidence that GDF15 is related with first-line chemo-resistance, with highly expressed GDF15 being a strong and an independent indicator of shorter PFS in EOC patients.

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via IFTTT

Depletion of nuclear import protein karyopherin alpha 7 (KPNA7) induces mitotic defects and deformation of nuclei in cancer cells

Abstract

Background

Nucleocytoplasmic transport is a tightly regulated process carried out by specific transport machinery, the defects of which may lead to a number of diseases including cancer. Karyopherin alpha 7 (KPNA7), the newest member of the karyopherin alpha nuclear importer family, is expressed at a high level during embryogenesis, reduced to very low or absent levels in most adult tissues but re-expressed in cancer cells.

Methods

We used siRNA-based knock-down of KPNA7 in cancer cell lines, followed by functional assays (proliferation and cell cycle) and immunofluorescent stainings to determine the role of KPNA7 in regulation of cancer cell growth, proper mitosis and nuclear morphology.

Results

In the present study, we show that the silencing of KPNA7 results in a dramatic reduction in pancreatic and breast cancer cell growth, irrespective of the endogenous KPNA7 expression level. This growth inhibition is accompanied by a decrease in the fraction of S-phase cells as well as aberrant number of centrosomes and severe distortion of the mitotic spindles. In addition, KPNA7 depletion leads to reorganization of lamin A/C and B1, the main nuclear lamina proteins, and drastic alterations in nuclear morphology with lobulated and elongated nuclei.

Conclusions

Taken together, our data provide new important evidence on the contribution of KPNA7 to the regulation of cancer cell growth and the maintenance of nuclear envelope environment, and thus deepens our understanding on the impact of nuclear transfer proteins in cancer pathogenesis.

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Nomograms predict long-term survival for patients with periampullary adenocarcinoma after pancreatoduodenectomy

Abstract

Background

The prognosis of patients with periampullary adenocarcinoma after pancreatoduodenectomy is diverse and not yet clearly illustrated. The aim of this study was to develop a nomogram to predict individual risk of overall survival (OS) and progression-free survival (PFS) in patients with periampullary adenocarcinoma after pancreatoduodenectomy.

Methods

A total of 205 patients with periampullary adenocarcinoma after pancreatoduodenectomy were retrospectively included. OS and PFS were evaluated by the Kaplan-Meier method. Two nomograms for predicting OS and PFS were established, and the predictive accuracy was measured by the concordance index (Cindex) and calibration plots.

Results

Lymph node ratio (LNR), carbohydrate antigen 19–9 (CA19–9) and anatomical location were incorporated into the nomogram for OS prediction and LNR, CA19–9; anatomical location and tumor differentiation were incorporated into the nomogram for PFS prediction. All calibration plots for the probability of OS and PFS fit well. The Cindexes of the nomograms for OS and PFS prediction were 0.678 and 0.68, respectively. The OS and PFS survival times were stratified significantly using the nomogram-predicted survival probabilities.

Conclusions

The present nomograms for OS and PFS prediction can provide valuable information for tailored decision-making for patients with periampullary adenocarcinoma after pancreatoduodenectomy.

https://ift.tt/2uocDgM

Anti-EGFR targeted therapy delivered before versus during radiotherapy in locoregionally advanced nasopharyngeal carcinoma: a big-data, intelligence platform-based analysis

Abstract

Background

Little is known about the prognostic difference of anti-EGFR therapy, cetuximab (CTX) or nimotuzumab (NTZ), concurrently with induction chemotherapy (IC, investigational arm) or RT (control arm) for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). We conducted this retrospective study to address this.

Methods

We identified 296 patients with newly diagnosed LA-NPC at Sun Yat-Sen University Cancer Center between January 2012 and May 2015. Patients were treated by IC with CCRT or RT and CTX/NTZ was delivered during IC or radiotherapy. Survival outcomes and toxicities between different arms were compared.

Results

In total, there were 149 patients in the investigational arm and 147 in control arm. The 3-year disease-free survival, overall survival, distant metastasis-free survival and locoregional relapse-free survival rates for investigational arm vs. control arm were 84.3% vs. 74.3% (P = 0.027), 94.0% vs. 92.1% (P = 0.673), 88.0% vs. 81.8% (P = 0.147) and 93.3% vs. 88.0% (P = 0.093). Multivariate analysis revealed patients in the control arm achieved significantly worse disease-free survival (HR, 1.497; 95% CI, 1.016–2.206; P = 0.026) compared with those in the investigational arm; however, no significant difference was identified for other endpoints. Patients in the investigational arm experienced more grade 3–4 skin reaction (15.4% vs. 2.0%, P <  0.001) and mucositis (10.1% vs. 3.4%, P = 0.022) during induction phase, but less skin reaction (5.4% vs. 25.9%, P <  0.001) and mucositis (24.8% vs. 36.7%, P = 0.026) during RT.

Conclusions

Our findings suggested that CTX/NTZ concurrently with IC may be a more effective and promising strategy for patients with LA-NPC receiving intensity-modulated radiotherapy.

https://ift.tt/2GrqYOr

Mental disorders around cancer diagnosis and increased hospital admission rate - a nationwide cohort study of Swedish cancer patients

Abstract

Background

Whether the emotional distress around cancer diagnosis is associated with the long-term outcomes and care utilization is unknown. We aimed to examine the association of mental disorders around cancer diagnosis with the hospital admission rates of cancer patients thereafter.

Methods

We conducted a nationwide cohort study including 218,508 cancer patients diagnosed in Sweden during 2004–2009 and followed them from 90 days after cancer through 2010. We used a clinical diagnosis of stress-related mental disorders from 90 days before to 90 days after cancer diagnosis as the exposure. We studied first all hospital admissions and then separately three common admissions, including external injuries, infections, and cardiovascular diseases. The Cox model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs).

Results

Four thousand one hundred five patients received a diagnosis of stress-related mental disorders around the cancer diagnosis, and experienced a 35% increased rate of any hospital admission during follow-up (HR: 1.35, 95%CI: 1.28–1.41) as well as hospital admissions for external injuries (HR: 1.89, 95%CI: 1.67–2.14), infections (HR: 1.28, 95%CI: 1.08–1.52), and cardiovascular diseases (HR: 1.16, 95%CI: 1.03–1.30). Similar association was noted for most common cancer types.

Conclusions

These data suggest that cancer patients diagnosed with a stress-related mental disorder immediately before or after cancer diagnosis are subsequently at increased risk of hospital admissions for major comorbidities of cancer.

https://ift.tt/2uocuKg

Frequency of HPV in oral cavity squamous cell carcinoma

Abstract

Background

The prevalence of high-risk human papillomavirus (HPV) DNA in cases of oral cavity squamous cell carcinoma (SCC) varies widely. The aim of this study is to investigate the frequency of high-risk HPV DNA in a large Brazilian cohort of patients with oral cavity SCC.

Methods

Biopsy and resected frozen and formalin-fixed paraffin-embedded specimens of oral cavity SCC were available from 101 patients who were recruited at two Brazilian centres. Stringent measures with respect to case selection and prevention of sample contamination were adopted to ensure reliability of the data. Nested PCR using MY09/MY11 and GP5⁺/GP6⁺ as well as PGMY09/11 L1 consensus primers were performed to investigate the presence of HPV DNA in the tumours. HPV-positive cases were subjected to direct sequencing. Shapiro–Wilk and Student t test were used to evaluate data normality and to compare the means, respectively. Qualitative variables were analysed by logistic regression.

Results

Our results demonstrate that the frequency of high-risk HPV types in oral cavity SCC is very low and is less than 4%. All HPV-positive cases were HPV16. In addition, our results do not show a significant association between the tumour clinical features and the risk factors (tobacco, alcohol and HPV) for oral cavity SCC.

Conclusion

In the current study, we observed an overlapping pattern of risk factors that are related to tumour development. This, along with a low frequency of high-risk HPV DNA, supports the findings that HPV is not involved in the genesis of oral cavity SCC in Brazilian population.

https://ift.tt/2GwazYY

GDF15 predict platinum response during first-line chemotherapy and can act as a complementary diagnostic serum biomarker with CA125 in epithelial ovarian cancer

Abstract

Background

Growth differentiation factor 15 (GDF15) has attracted much interest as a novel biomarker for epithelial ovarian carcinoma (EOC). Research focus has been directed at GDF15 as a diagnostic detection, while the prognostic determination of GDF15 in EOC patients remains to be clearly elucidated. The present study aimed to investigate GDF15 level relative to clinicopathological characters, chemoresponse, and clinical outcome of EOC patients.

Methods

Serum from 122 patients with primary diagnosed EOC were analyzed for GDF15 and serum cancer antigen 125 (CA125). All cases were treated with debulking surgery and first-line chemotherapy, and samples were obtained just before debulking surgical treatment and first-line chemotherapy. Subsequently, clinical characteristics, responses to chemotherapy and progression-free survival (PFS) were recorded.

Results

Increasing levels of serum GDF15 was significantly associated with FIGO stage and lymphonodus metastasis. GDF15 and CA125 detection are complementary in the diagnosis of EOC and can be simultaneously profiled. The chemo-resistant EOC patients (median, 1225.0 pg/mL) showed significantly higher GDF15 than chemo-sensitive patients (median, 824.2 pg/mL; P = 0.013). Highly expressed GDF15 was an independent negative prognostic indicator in the PFS (P = 0.026) of the 122 EOC cases in the multivariate analysis. Additionally, patients with high level of serum CA125 significantly associated with suboptimal (P = 0.043) debulking surgery.

Conclusions

Our results provide valuable evidence that GDF15 is related with first-line chemo-resistance, with highly expressed GDF15 being a strong and an independent indicator of shorter PFS in EOC patients.

https://ift.tt/2uoBBN6

Depletion of nuclear import protein karyopherin alpha 7 (KPNA7) induces mitotic defects and deformation of nuclei in cancer cells

Abstract

Background

Nucleocytoplasmic transport is a tightly regulated process carried out by specific transport machinery, the defects of which may lead to a number of diseases including cancer. Karyopherin alpha 7 (KPNA7), the newest member of the karyopherin alpha nuclear importer family, is expressed at a high level during embryogenesis, reduced to very low or absent levels in most adult tissues but re-expressed in cancer cells.

Methods

We used siRNA-based knock-down of KPNA7 in cancer cell lines, followed by functional assays (proliferation and cell cycle) and immunofluorescent stainings to determine the role of KPNA7 in regulation of cancer cell growth, proper mitosis and nuclear morphology.

Results

In the present study, we show that the silencing of KPNA7 results in a dramatic reduction in pancreatic and breast cancer cell growth, irrespective of the endogenous KPNA7 expression level. This growth inhibition is accompanied by a decrease in the fraction of S-phase cells as well as aberrant number of centrosomes and severe distortion of the mitotic spindles. In addition, KPNA7 depletion leads to reorganization of lamin A/C and B1, the main nuclear lamina proteins, and drastic alterations in nuclear morphology with lobulated and elongated nuclei.

Conclusions

Taken together, our data provide new important evidence on the contribution of KPNA7 to the regulation of cancer cell growth and the maintenance of nuclear envelope environment, and thus deepens our understanding on the impact of nuclear transfer proteins in cancer pathogenesis.

https://ift.tt/2GtWM5k

Is double-approach surgery and tenodesis without a gastrocnemius flap better for dealing with proximal fibular osteosarcoma?

Abstract

Background

Resection of proximal fibular osteosarcoma involving the posteromedial aspect of the fibula is challenging. Reconstruction using a gastrocnemius flap may result in significant lateral instability and abnormal knee movement. Furthermore, postoperative gait may be disturbed by foot drop resulting from scarification of the common peroneal nerve.

Methods

Between January 2011 and December 2013, five patients with proximal fibular osteosarcoma were treated via the double-approach procedure using en bloc resection without a gastrocnemius flap. Simultaneously, all patients received one-stage tenodesis of the anterior tibial and toe extensor tendons. Clinical outcomes, including local tumor recurrence, complications, and functional outcomes, were evaluated.

Results

The mean follow-up duration was 47.2 months (range 42–52 months). No patients experienced local recurrence. The patients' Enneking functional scores were excellent (80%) or good (20%) at the final follow-up.

Conclusions

In patients with proximal fibular osteosarcoma, the double-approach procedure allows easier and safer en bloc tumor resection with vessel and nerve protection. One-stage tenodesis without a gastrocnemius flap is associated with good functional outcomes.

https://ift.tt/2um2wsK

Is double-approach surgery and tenodesis without a gastrocnemius flap better for dealing with proximal fibular osteosarcoma?

Abstract

Background

Resection of proximal fibular osteosarcoma involving the posteromedial aspect of the fibula is challenging. Reconstruction using a gastrocnemius flap may result in significant lateral instability and abnormal knee movement. Furthermore, postoperative gait may be disturbed by foot drop resulting from scarification of the common peroneal nerve.

Methods

Between January 2011 and December 2013, five patients with proximal fibular osteosarcoma were treated via the double-approach procedure using en bloc resection without a gastrocnemius flap. Simultaneously, all patients received one-stage tenodesis of the anterior tibial and toe extensor tendons. Clinical outcomes, including local tumor recurrence, complications, and functional outcomes, were evaluated.

Results

The mean follow-up duration was 47.2 months (range 42–52 months). No patients experienced local recurrence. The patients' Enneking functional scores were excellent (80%) or good (20%) at the final follow-up.

Conclusions

In patients with proximal fibular osteosarcoma, the double-approach procedure allows easier and safer en bloc tumor resection with vessel and nerve protection. One-stage tenodesis without a gastrocnemius flap is associated with good functional outcomes.

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via IFTTT

Treatment of B-cell precursor acute lymphoblastic leukemia with the Galectin-1 inhibitor PTX008

Abstract

Background

Drug resistance of B-cell precursor acute lymphoblastic leukemia (BP-ALL) cells is conferred by both intrinsic and extrinsic factors, which could be targeted to promote chemo-sensitization. Our previous studies showed that Galectin-3, a lectin that clusters galactose-modified glycoproteins and that has both an intracellular and extracellular location, protects different subtypes of BP-ALL cells against chemotherapy. Galectin-1 is related to Galectin-3 and its expression was previously reported to be restricted to the MLL subtype of BP-ALL.

Methods and results

Here, we report that Galectin-1 is expressed at different levels in and on different subclasses of BP-ALLs. Bone marrow plasma also contains high levels of Galectin-1. PTX008 is an allosteric inhibitor which inhibits Galectin-1 but not Galectin-3-mediated agglutination. The compound reduces migration of BP-ALL cells to CXCL12 and OP9 stromal cells and inhibits fibronectin-mediated adhesion. It also affects cell cycle progression of BCP-ALL cells. PTX008 is cytostatic for BP-ALL cells even when these are co-cultured with protective stroma, and can sensitize ALL cells to vincristine chemotherapy in vitro and in mice.

Conclusions

PTX008 inhibits multiple functions that contribute to BP-ALL survival. The effects of Galectin-1 inhibition on both BP-ALL cell proliferation and migration suggest both the leukemia cells as well as the microenvironment that protects these cells may be targeted.

https://ift.tt/2IV4Gmx

Treatment of B-cell precursor acute lymphoblastic leukemia with the Galectin-1 inhibitor PTX008

Abstract

Background

Drug resistance of B-cell precursor acute lymphoblastic leukemia (BP-ALL) cells is conferred by both intrinsic and extrinsic factors, which could be targeted to promote chemo-sensitization. Our previous studies showed that Galectin-3, a lectin that clusters galactose-modified glycoproteins and that has both an intracellular and extracellular location, protects different subtypes of BP-ALL cells against chemotherapy. Galectin-1 is related to Galectin-3 and its expression was previously reported to be restricted to the MLL subtype of BP-ALL.

Methods and results

Here, we report that Galectin-1 is expressed at different levels in and on different subclasses of BP-ALLs. Bone marrow plasma also contains high levels of Galectin-1. PTX008 is an allosteric inhibitor which inhibits Galectin-1 but not Galectin-3-mediated agglutination. The compound reduces migration of BP-ALL cells to CXCL12 and OP9 stromal cells and inhibits fibronectin-mediated adhesion. It also affects cell cycle progression of BCP-ALL cells. PTX008 is cytostatic for BP-ALL cells even when these are co-cultured with protective stroma, and can sensitize ALL cells to vincristine chemotherapy in vitro and in mice.

Conclusions

PTX008 inhibits multiple functions that contribute to BP-ALL survival. The effects of Galectin-1 inhibition on both BP-ALL cell proliferation and migration suggest both the leukemia cells as well as the microenvironment that protects these cells may be targeted.

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Approach to oligometastatic disease in head and neck cancer, on behalf of the GORTEC

Future Oncology, Ahead of Print.


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Treatment of hepatocellular carcinoma: a cost analysis of yttrium-90 transarterial radioembolization versus sorafenib

Future Oncology, Ahead of Print.


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Approach to oligometastatic disease in head and neck cancer, on behalf of the GORTEC

Future Oncology, Ahead of Print.


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Treatment of hepatocellular carcinoma: a cost analysis of yttrium-90 transarterial radioembolization versus sorafenib

Future Oncology, Ahead of Print.


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Approach to oligometastatic disease in head and neck cancer, on behalf of the GORTEC

Future Oncology, Ahead of Print.


https://ift.tt/2DXTRw7

Treatment of hepatocellular carcinoma: a cost analysis of yttrium-90 transarterial radioembolization versus sorafenib

Future Oncology, Ahead of Print.


https://ift.tt/2GcUfgA

Ramucirumab as Second-Line Therapy in Metastatic Gastric Cancer: Real-World Data from the RAMoss Study

Abstract

Background

Ramucirumab—alone or combined with paclitaxel—represents one of the main options for patients failing first-line treatment for advanced gastric cancer.

Objective

The RAMoss study aimed to evaluate the safety and efficacy profile of ramucirumab in the "real-life setting".

Patients and Methods

Patients from 25 Italian hospitals started therapy consisting of ramucirumab 8 mg/kg i.v. d1,15q28 with or without paclitaxel 80 mg/m² i.v. d1,8,15q28. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Results

One hundred sixty-seven patients with disease progression on first-line therapy received ramucirumab as monotherapy (10%) or combined with paclitaxel (90%). Median treatment duration was 4 months (1–17 months). Global incidence of grade (G) 3–4 toxicity was 9.6%, and for neutropenia 5.4%; treatment was discontinued due to toxicity in 3% of patients. The most frequent adverse events (AE) were G1–2 fatigue (27.5%), G1–2 neuropathy (26.3%), and G1–2 neutropenia (14.9%). ORR was 20.2%. Stable disease was observed in 39.2% of patients, with a disease control rate of 59.4%. With a median follow-up of 11 months, median PFS was 4.3 months (95% confidence interval [CI] 4.1–4.7), whereas median OS was 8.0 months (95% CI: 7.09–8.9). In a multivariate analysis, ECOG performance status <1 or ≥1 (HR 1.13, 95% CI 1.0–1.27, p = 0.04) and the presence versus absence of peritoneal metastases (HR 1.57, 95% CI 1.63–2.39, p = 0.03) were independent poor prognostic factors.

Conclusions

These "real-life" efficacy data on ramucirumab treatment are in line with previous randomized trials. Ramucirumab is well tolerated in daily clinical practice.

https://ift.tt/2pGMyDW

Carcinoembryonic antigen as a marker of radioresistance in colorectal cancer: a potential role of macrophages

Abstract

Background

We sought to identify the carcinoembryonic antigen (CEA) as a marker of radioresistance in rectal cancer.

Methods

From July 1997 to January 2008, 104 patients with stage II or III rectal cancer who were treated with post-operative radiotherapy (PORT) were included in this study. The doses of radiotherapy ranged from 45 to 54.6 Gy. The CEA levels were measured before surgery. We analyzed the actuarial rates of overall survival (OS), distant metastasis (DM), and local recurrence (LR) using Kaplan-Meier curves. Multivariate analyses were performed with Cox regression models. We used THP-1 monocyte cell lines for macrophage differentiation (M0, M1 or M2). The RNA extracted from the macrophages was analyzed via a genomic method in the core laboratory. The radiosensitivities of CEA-rich LS1034 cells were compared between cells with and without the conditioned media from CEA-stimulated macrophages.

Results

Preoperative CEA levels ≥10 ng/mL were independent predictive factors for OS (p = 0.005), DM (p = 0.026), and LR (p = 0.004). The OS rates among the patients with pretreatment CEA levels < 10 ng/mL and ≥10 ng/mL were 64.5% and 35.9% (p = 0.004), respectively. The corresponding rates of DM were 40.6% and 73.1% (p = 0.024). The corresponding rates of LR were 6.6% and 33.9% (p = 0.002). In the M0 macrophages, exogenous CEA elicited a dose-response relationship with M2 differentiation. In the CEA-stimulated M0 cells, some mRNAs were upregulated by as much as 5-fold, including MMP12, GDF15, and JAG1. In the CEA-stimulated M2 cells, a 4-fold up-regulation of GADD45G mRNA was noted. The conditioned media from the CEA-stimulated M2 cells elicited an increase in the numbers of LS180, SW620, and LS1034 cells after irradiation. CEA caused the M2 differentiation of the macrophages.

Conclusion

Pretreatment CEA levels ≥10 ng/mL are a significant risk factor for OS, DM, and LR following PORT for rectal cancer. CEA causes radioresistance in the presence of M2 macrophages. More comprehensive examinations prior to surgery and intensive adjuvant therapy are suggested for patients with CEA levels ≥10 ng/mL. Further studies of these mechanisms are needed.

https://ift.tt/2unOiHR

Carcinoembryonic antigen as a marker of radioresistance in colorectal cancer: a potential role of macrophages

Abstract

Background

We sought to identify the carcinoembryonic antigen (CEA) as a marker of radioresistance in rectal cancer.

Methods

From July 1997 to January 2008, 104 patients with stage II or III rectal cancer who were treated with post-operative radiotherapy (PORT) were included in this study. The doses of radiotherapy ranged from 45 to 54.6 Gy. The CEA levels were measured before surgery. We analyzed the actuarial rates of overall survival (OS), distant metastasis (DM), and local recurrence (LR) using Kaplan-Meier curves. Multivariate analyses were performed with Cox regression models. We used THP-1 monocyte cell lines for macrophage differentiation (M0, M1 or M2). The RNA extracted from the macrophages was analyzed via a genomic method in the core laboratory. The radiosensitivities of CEA-rich LS1034 cells were compared between cells with and without the conditioned media from CEA-stimulated macrophages.

Results

Preoperative CEA levels ≥10 ng/mL were independent predictive factors for OS (p = 0.005), DM (p = 0.026), and LR (p = 0.004). The OS rates among the patients with pretreatment CEA levels < 10 ng/mL and ≥10 ng/mL were 64.5% and 35.9% (p = 0.004), respectively. The corresponding rates of DM were 40.6% and 73.1% (p = 0.024). The corresponding rates of LR were 6.6% and 33.9% (p = 0.002). In the M0 macrophages, exogenous CEA elicited a dose-response relationship with M2 differentiation. In the CEA-stimulated M0 cells, some mRNAs were upregulated by as much as 5-fold, including MMP12, GDF15, and JAG1. In the CEA-stimulated M2 cells, a 4-fold up-regulation of GADD45G mRNA was noted. The conditioned media from the CEA-stimulated M2 cells elicited an increase in the numbers of LS180, SW620, and LS1034 cells after irradiation. CEA caused the M2 differentiation of the macrophages.

Conclusion

Pretreatment CEA levels ≥10 ng/mL are a significant risk factor for OS, DM, and LR following PORT for rectal cancer. CEA causes radioresistance in the presence of M2 macrophages. More comprehensive examinations prior to surgery and intensive adjuvant therapy are suggested for patients with CEA levels ≥10 ng/mL. Further studies of these mechanisms are needed.

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Knockdown of IFI27 inhibits cell proliferation and invasion in oral squamous cell carcinoma

Abstract

Background

The development of oral squamous cell carcinoma (OSCC) involves genetic mutations, epigenetic gene expression modification, and other processes. It has been reported that IFI27 is upregulated in OSCC, but its function is unknown. The aim of this study was to investigate the role of IFI27 on OSCC cell proliferation and invasion.

Methods

The protein level of IFI27 in OSCC tissues and adjacent tissues was detected by immunohistochemistry. In the OSCC cell model, we designed the IFI27 siRNA to downregulate the expression of IFI27; gene and protein of IFI27 in those models were then detected by Q-PCR and Western blot. MTT assay was used to detect the effect of -IFI27 knockdown on cell proliferation; Annexin V-PI staining flow cytometry was used to detect the effect of IFI27 downregulation on apoptosis of cancer cells. The effect of IFI27 downregulation on oral cancer cell invasion was detected using Transwell assay.

Results

IFI27 was highly expressed in OSCC tissues by immunohistochemical assay. In the OSCC cell model, IFI27 siRNA could downregulate the mRNA and protein expression level of IFI27. As showed in MTT assay, Annexin V-PI assay, and Transwell assay, through the downregulation of IFI27, TSCCA and TCA8113 cell proliferation were inhibited, OSCC cell apoptosis was promoted, and its migration and invasion were inhibited.

Conclusion

IFI27 is involved in the development and progression of OSCC. Its high expression promotes cell proliferation and invasion and reduces apoptosis. These findings may provide new biomarkers and therapeutic targets for OSCC diagnosis and clinical treatment.

https://ift.tt/2I8cBM1

Knockdown of IFI27 inhibits cell proliferation and invasion in oral squamous cell carcinoma

Abstract

Background

The development of oral squamous cell carcinoma (OSCC) involves genetic mutations, epigenetic gene expression modification, and other processes. It has been reported that IFI27 is upregulated in OSCC, but its function is unknown. The aim of this study was to investigate the role of IFI27 on OSCC cell proliferation and invasion.

Methods

The protein level of IFI27 in OSCC tissues and adjacent tissues was detected by immunohistochemistry. In the OSCC cell model, we designed the IFI27 siRNA to downregulate the expression of IFI27; gene and protein of IFI27 in those models were then detected by Q-PCR and Western blot. MTT assay was used to detect the effect of -IFI27 knockdown on cell proliferation; Annexin V-PI staining flow cytometry was used to detect the effect of IFI27 downregulation on apoptosis of cancer cells. The effect of IFI27 downregulation on oral cancer cell invasion was detected using Transwell assay.

Results

IFI27 was highly expressed in OSCC tissues by immunohistochemical assay. In the OSCC cell model, IFI27 siRNA could downregulate the mRNA and protein expression level of IFI27. As showed in MTT assay, Annexin V-PI assay, and Transwell assay, through the downregulation of IFI27, TSCCA and TCA8113 cell proliferation were inhibited, OSCC cell apoptosis was promoted, and its migration and invasion were inhibited.

Conclusion

IFI27 is involved in the development and progression of OSCC. Its high expression promotes cell proliferation and invasion and reduces apoptosis. These findings may provide new biomarkers and therapeutic targets for OSCC diagnosis and clinical treatment.

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Biomarker discovery from we to me: Is learning from each patient a new approach?

The immune response is a dynamic multistep process, with a complex system regulation. Identification of predictive biomarkers is therefore challenging. Deep investigation of an exceptional responder to pembrolizumab in ovarian cancer identifies new mechanism of response and highlights the power of individualized medicine strategy.

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Data Analysis Strategies in Medical Imaging

Radiographic imaging continues to be one of the most effective and clinically useful tools within oncology. Sophistication of artificial intelligence (AI) has allowed for detailed quantification of radiographic characteristics of tissues using predefined engineered algorithms or deep learning methods. Precedents in radiology as well as a wealth of research studies hint at the clinical relevance of these characteristics. However, there are critical challenges associated with the analysis of medical imaging data. While some of these challenges are specific to the imaging field, many others like reproducibility and batch effects are generic and have already been addressed in other quantitative fields such as genomics. Here, we identify these pitfalls and provide recommendations for analysis strategies of medical imaging data including data normalization, development of robust models, and rigorous statistical analyses. Adhering to these recommendations will not only improve analysis quality, but will also enhance precision medicine by allowing better integration of imaging data with other biomedical data sources.

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The long neglected player: modeling tumor uptake to guide optimal dosing

Pharmacokinetic modeling is widely used to support decision making in translational medicine and patient care, traditionally using circulating drug exposure. The development of mechanistic computational models that integrate drug concentrations at the site of action making use of existing knowledge opens a new paradigm in optimal dosing.

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ER+ breast cancers resistant to prolonged neoadjuvant letrozole exhibit an E2F4 transcriptional program sensitive to CDK4/6 inhibitors

Purpose:This study aimed to identify biomarkers of resistance to endocrine therapy in ER+ breast cancers (BC) treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA-sequencing in 68 ER+ BC from patients treated with preoperative letrozole (median 7 months). Results:Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC>1, FDR<0.03) in letrozole-resistant tumors with transcription binding data showed significant overlap with 20 E2F4-regulated genes (p=2.56E-15). In patients treated with the CDK4/6 inhibitor palbociclib before surgery, treatment significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors, including 18 of the 20 E2F4 target genes. In long term estrogen-deprived ER+ BC cells, palbociclib also downregulated all 20 E2F4-target genes and P-RB levels, whereas the ER downregulator fulvestrant or paclitaxel only partially suppressed expression of this set of genes and had no effect on P-RB. Finally, an E2F4 activation signature was strongly associated with resistance to aromatase inhibitors in the ACOSOG Z1031B neoadjuvant trial and with an increased risk of relapse in adjuvant treated ER+ tumors in METABRIC. Conclusions: In tumors resistant to prolonged neoadjuvant letrozole, we identified a gene expression signature of E2F4 target activation. CDK4/6 inhibition suppressed E2F4 target gene expression in estrogen-deprived ER+ BC cells and in patients' ER+ tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER+ breast cancer who fail to respond to preoperative estrogen deprivation.

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Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth [Research Articles]

Genetic alterations that potentiate PI3K signalling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report PIK3CA mutation/amplification correlates with poor prostate cancer patient survival. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate Pik3ca in mouse prostate epithelium. We show Pik3caH1047R mutation causes p110α-dependent invasive prostate carcinoma in-vivo. Furthermore, we report PIK3CA mutation and PTEN loss co-exist in prostate cancer patients, and can cooperate in-vivo to accelerate disease progression via AKT-mTORC1/2 hyperactivation. Contrasting single mutants that slowly acquire castration-resistant prostate cancer (CRPC), concomitant Pik3ca mutation and Pten loss caused de-novo CRPC. Thus, Pik3ca mutation and Pten deletion are not functionally redundant. Our findings indicate that PIK3CA mutation is an attractive prognostic indicator for prostate cancer that may cooperate with PTEN loss to facilitate CRPC in patients.

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Making Better CARs for Kids [News in Brief]

Prior chemotherapy may impair ability to manufacture effective therapies, prompting shift in clinical practice.

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Height and overall cancer risk and mortality: evidence from a Mendelian randomisation study on 310,000 UK Biobank participants

Height and overall cancer risk and mortality: evidence from a Mendelian randomisation study on 310,000 UK Biobank participants

Height and overall cancer risk and mortality: evidence from a Mendelian randomisation study on 310,000 UK Biobank participants, Published online: 27 March 2018; doi:10.1038/s41416-018-0063-4

Height and overall cancer risk and mortality: evidence from a Mendelian randomisation study on 310,000 UK Biobank participants

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Biomarker discovery from we to me: Is learning from each patient a new approach?

The immune response is a dynamic multistep process, with a complex system regulation. Identification of predictive biomarkers is therefore challenging. Deep investigation of an exceptional responder to pembrolizumab in ovarian cancer identifies new mechanism of response and highlights the power of individualized medicine strategy.

https://ift.tt/2uoekec

Higher Absolute Lymphocyte Counts Predict Lower Mortality from Early-Stage Triple-Negative Breast Cancer

Background: Tumor-infiltrating lymphocytes (TILs) in pre-treatment biopsies are associated with improved survival in triple-negative breast cancer (TNBC). We investigated whether higher peripheral lymphocyte counts are associated with lower breast cancer-specific mortality (BCM) and overall mortality (OM) in TNBC. Methods: Data on treatments and diagnostic tests from electronic medical records of two healthcare systems were linked with demographic, clinical, pathologic, and mortality data from the California Cancer Registry. Multivariable regression models adjusted for age, race/ethnicity, socioeconomic status, cancer stage, grade, neoadjuvant/adjuvant chemotherapy use, radiotherapy use, and germline BRCA1/2 mutations were used to evaluate associations between absolute lymphocyte count (ALC), BCM and OM. For a subgroup with TILs data available, we explored the relationship between TILs and peripheral lymphocyte counts. Results: 1,463 Stage I-III TNBC patients were diagnosed from 2000-2014; 1113 (76%) received neoadjuvant/adjuvant chemotherapy within one year of diagnosis. Of 759 patients with available ALC data, 481 (63.4%) were ever lymphopenic (minimum ALC <1.0 K/μL). On multivariable analysis, higher minimum ALC, but not absolute neutrophil count, predicted lower OM (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.16-0.35) and BCM (HR: 0.19, CI: 0.11-0.34). Five-year probability of BCM was 15% for patients who were ever lymphopenic versus 4% for those who were not. An exploratory analysis (N=70) showed a significant association between TILs and higher peripheral lymphocyte counts during neoadjuvant chemotherapy. Conclusion: Higher peripheral lymphocyte counts predicted lower mortality from early-stage, potentially curable TNBC, suggesting that immune function may enhance the effectiveness of early TNBC treatment.

https://ift.tt/2IVoDtx

Data Analysis Strategies in Medical Imaging

Radiographic imaging continues to be one of the most effective and clinically useful tools within oncology. Sophistication of artificial intelligence (AI) has allowed for detailed quantification of radiographic characteristics of tissues using predefined engineered algorithms or deep learning methods. Precedents in radiology as well as a wealth of research studies hint at the clinical relevance of these characteristics. However, there are critical challenges associated with the analysis of medical imaging data. While some of these challenges are specific to the imaging field, many others like reproducibility and batch effects are generic and have already been addressed in other quantitative fields such as genomics. Here, we identify these pitfalls and provide recommendations for analysis strategies of medical imaging data including data normalization, development of robust models, and rigorous statistical analyses. Adhering to these recommendations will not only improve analysis quality, but will also enhance precision medicine by allowing better integration of imaging data with other biomedical data sources.

https://ift.tt/2uisQUU

The long neglected player: modeling tumor uptake to guide optimal dosing

Pharmacokinetic modeling is widely used to support decision making in translational medicine and patient care, traditionally using circulating drug exposure. The development of mechanistic computational models that integrate drug concentrations at the site of action making use of existing knowledge opens a new paradigm in optimal dosing.

https://ift.tt/2IVo82D

ER+ breast cancers resistant to prolonged neoadjuvant letrozole exhibit an E2F4 transcriptional program sensitive to CDK4/6 inhibitors

Purpose:This study aimed to identify biomarkers of resistance to endocrine therapy in ER+ breast cancers (BC) treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA-sequencing in 68 ER+ BC from patients treated with preoperative letrozole (median 7 months). Results:Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC>1, FDR<0.03) in letrozole-resistant tumors with transcription binding data showed significant overlap with 20 E2F4-regulated genes (p=2.56E-15). In patients treated with the CDK4/6 inhibitor palbociclib before surgery, treatment significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors, including 18 of the 20 E2F4 target genes. In long term estrogen-deprived ER+ BC cells, palbociclib also downregulated all 20 E2F4-target genes and P-RB levels, whereas the ER downregulator fulvestrant or paclitaxel only partially suppressed expression of this set of genes and had no effect on P-RB. Finally, an E2F4 activation signature was strongly associated with resistance to aromatase inhibitors in the ACOSOG Z1031B neoadjuvant trial and with an increased risk of relapse in adjuvant treated ER+ tumors in METABRIC. Conclusions: In tumors resistant to prolonged neoadjuvant letrozole, we identified a gene expression signature of E2F4 target activation. CDK4/6 inhibition suppressed E2F4 target gene expression in estrogen-deprived ER+ BC cells and in patients' ER+ tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER+ breast cancer who fail to respond to preoperative estrogen deprivation.

https://ift.tt/2umvd99

Height and overall cancer risk and mortality: evidence from a Mendelian randomisation study on 310,000 UK Biobank participants

Height and overall cancer risk and mortality: evidence from a Mendelian randomisation study on 310,000 UK Biobank participants

Height and overall cancer risk and mortality: evidence from a Mendelian randomisation study on 310,000 UK Biobank participants, Published online: 27 March 2018; doi:10.1038/s41416-018-0063-4

Height and overall cancer risk and mortality: evidence from a Mendelian randomisation study on 310,000 UK Biobank participants

https://ift.tt/2ukiiVh

MiR-144 suppresses proliferation, invasion, and migration of breast cancer cells through inhibiting CEP55

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Effects of miR-144 on the sensitivity of human anaplastic thyroid carcinoma cells to cisplatin by autophagy regulation

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MiR-144 suppresses proliferation, invasion, and migration of breast cancer cells through inhibiting CEP55

.


https://ift.tt/2Gdd4vO

Effects of miR-144 on the sensitivity of human anaplastic thyroid carcinoma cells to cisplatin by autophagy regulation

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Clinical outcome after high-precision radiotherapy for skull base meningiomas: Pooled data from three large German centers for radiation oncology

To evaluate outcome in patients with base of skull meningiomas treated with modern high precision radiation therapy (RT) techniques.

https://ift.tt/2GeW1K3

Why validation of prognostic models matters?

Prognostic models are powerful tools for treatment personalisation. However, not all proposed models work well when validated using new data, despite impressive results being reported initially. Here, we will use a hands-on approach to highlight important aspects of prognostic modelling, as well as to demonstrate methods to generate generalisable models.

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Personalized automated treatment planning for breast plus locoregional lymph nodes using Hybrid RapidArc

Publication date: Available online 26 March 2018
Source:Practical Radiation Oncology
Author(s): Mariët J van Duren-Koopman, Jim P Tol, Max Dahele, Ewa Bucko, Philip Meijnen, Ben J Slotman, Wilko FAR Verbakel
PurposeBreast cancer patients who require locoregional lymph node (LLN) irradiation can be treated using a hybrid RapidArc technique combining two tangential and three RapidArc fields. Since the creation of hybrid RapidArc plans is complex and labor-intensive, we developed an automated treatment planning workflow using the scripting application programming interface of the Eclipse treatment planning system.Methods and Materials¹⁵ patients (⁵ right and¹⁰ left-sided) previously treated with breast+LLN radiotherapy were replanned using the script. The automated workflow included: i) optimal placement of the tangential fields based on the planning target volume (PTV) and organ-at-risk (OAR) contours, followed by optimization of field weights and beam energy, ii) positioning of the RapidArc fields, iii) subsequent RapidArc optimization using the RapidPlan knowledge-based planning solution.ResultsAverage total planning times were 163±97 and 33±⁵ minutes for the manual and automated plans, respectively, with approximately 130 and⁵ minutes of user interaction. Dosimetrically, both sets of plans were very similar, with comparable PTV dose homogeneity values and OAR mean dose differences of ≤.¹9Gy. In¹⁴/¹⁵ patients, the physician judged that the automated plan was either preferred (n=⁴) or equal (n=¹⁰) to the manual plan.ConclusionsThe complex hybrid RapidArc planning process for patients requiring breast+LLN irradiation was automated by optimizing the tangential field setup and integrating RapidPlan. The quality of the automated and manual plans was comparable while automated planning times were substantially shorter. The principles described here could be used to automate other planning workflows.



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