Brachytherapy in Head and Neck Cancers: “Are We Doing It or Are We Done with It”

Abstract

We performed an e-Survey and reviewed the literature on the prevalence of use of brachytherapy in head and neck cancers in order to understand the patterns of care and probable application of this modality. A five-point questionnaire was prepared and sent to 300 oncologists through a web-based survey engine. This was done in preparation for my lecture on "Ongoing Research and Potential Research Avenues" in IBSCON held in Chennai in August 2016. SPSS software was used for the statistical analysis. Of a total of 300 emails that were sent out for the survey, 120 replies were received, which is 40%. Among the results of various questions, (i) 65% of the oncologists felt that there were > 300 ongoing studies in brachytherapy and out of them only 10–20 were on head and neck brachytherapy; (ii) 58% of the responders felt that external beam radiotherapy (EBRT) advances followed by lack of training and experience are the reasons for declining role of brachytherapy; (iii) among the responders, numbers of head and neck brachytherapy performed stand third after gynecological and breast brachytherapy. This survey shows that brachytherapy in head and neck cancers is an essential tool, but seldom practiced. If no path-breaking event happens, we may be dealing with it as a dying art.

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Brachytherapy in Head and Neck Cancers: “Are We Doing It or Are We Done with It”

Abstract

We performed an e-Survey and reviewed the literature on the prevalence of use of brachytherapy in head and neck cancers in order to understand the patterns of care and probable application of this modality. A five-point questionnaire was prepared and sent to 300 oncologists through a web-based survey engine. This was done in preparation for my lecture on "Ongoing Research and Potential Research Avenues" in IBSCON held in Chennai in August 2016. SPSS software was used for the statistical analysis. Of a total of 300 emails that were sent out for the survey, 120 replies were received, which is 40%. Among the results of various questions, (i) 65% of the oncologists felt that there were > 300 ongoing studies in brachytherapy and out of them only 10–20 were on head and neck brachytherapy; (ii) 58% of the responders felt that external beam radiotherapy (EBRT) advances followed by lack of training and experience are the reasons for declining role of brachytherapy; (iii) among the responders, numbers of head and neck brachytherapy performed stand third after gynecological and breast brachytherapy. This survey shows that brachytherapy in head and neck cancers is an essential tool, but seldom practiced. If no path-breaking event happens, we may be dealing with it as a dying art.

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Quantitative Proteomics Identify the Possible Tumor Suppressive Role of Protease-Activated Receptor-4 in Esophageal Squamous Cell Carcinoma Cells

Abstract

Exposure to carcinogens of tobacco smoke may result in methylation of protease-activated receptors-4 (PAR4) gene and further induces the loss of PAR4 expression, which is considered to be involved in carcinogenesis of esophageal squamous cell carcinoma (ESCC). Here we employed a TMT-based quantitative proteomic approach to identify PAR4-regulated changes of proteomic profiles in ESCC cells and to identify potentially therapeutic value. A total of 33 proteins were found significantly changed with 15 up-regulated and 18 down-regulated in PAR4-activating peptide (PAR4-AP) treated ESCC cells compared with controls. Bioinformatics analysis showed that key higher expressed proteins included those associated with apoptosis and tumor suppressor (e.g. CASP9), and lower expressed proteins included those associated with anti-apoptosis, autophagy and promoting cell proliferation (e.g. CHMP1B, PURA, PARG and HIST1H2AH). Western blot verified changes in five representative proteins including CASP9, CHMP1B, PURA, PARG and HIST1H2AH. Immunohistochemistry analysis showed that CHMP1B, PURA, PARG and HIST1H2AH expression in ESCC tissues were significantly higher than those in adjacent nontumorous tissues. Our findings will be helpful in further investigations into the functions and molecular mechanisms of PAR4 in ESCC.

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Quantitative Proteomics Identify the Possible Tumor Suppressive Role of Protease-Activated Receptor-4 in Esophageal Squamous Cell Carcinoma Cells

Abstract

Exposure to carcinogens of tobacco smoke may result in methylation of protease-activated receptors-4 (PAR4) gene and further induces the loss of PAR4 expression, which is considered to be involved in carcinogenesis of esophageal squamous cell carcinoma (ESCC). Here we employed a TMT-based quantitative proteomic approach to identify PAR4-regulated changes of proteomic profiles in ESCC cells and to identify potentially therapeutic value. A total of 33 proteins were found significantly changed with 15 up-regulated and 18 down-regulated in PAR4-activating peptide (PAR4-AP) treated ESCC cells compared with controls. Bioinformatics analysis showed that key higher expressed proteins included those associated with apoptosis and tumor suppressor (e.g. CASP9), and lower expressed proteins included those associated with anti-apoptosis, autophagy and promoting cell proliferation (e.g. CHMP1B, PURA, PARG and HIST1H2AH). Western blot verified changes in five representative proteins including CASP9, CHMP1B, PURA, PARG and HIST1H2AH. Immunohistochemistry analysis showed that CHMP1B, PURA, PARG and HIST1H2AH expression in ESCC tissues were significantly higher than those in adjacent nontumorous tissues. Our findings will be helpful in further investigations into the functions and molecular mechanisms of PAR4 in ESCC.

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Combined Diagnosis of Systemic Lupus Erythematosus and Tuberculosis in an Irish Adolescent Female

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology, which can affect any organ system. Tuberculosis (TB) is a common infection in SLE because of immune dysregulation associated with the latter. We report a case of an adolescent female who presented with a year's history of polyarticular arthralgia and fever. Physical examination revealed a large left effusion that needed drainage. Investigations revealed a combined diagnosis of SLE and TB. Management comprised quadruple anti-TB therapy and SLE treatment. She made a steady recovery and has maintained a stable state from the lupus perspective.

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Effects of posaconazole (a strong CYP3A4 inhibitor), two new tablet formulations, and food on the pharmacokinetics of idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors

Abstract

Purpose

Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. To optimize its dosing conditions, a number of clinical pharmacology characteristics were examined in this multi-center trial in patients with advanced solid tumors.

Method

This was an open-label, single-dose, crossover clinical pharmacology study investigating the effects of strong CYP3A4 inhibition with posaconazole (Part 1), two new oral formulations (Part 2), as well as high-energy/high-fat and low-energy/low-fat meals (Part 3) on the relative bioavailability of idasanutlin. After completing Part 1, 2, or 3, patients could have participated in an optional treatment with idasanutlin. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) of MIC-1 elevation (Part 1 only), and safety/tolerability.

Results

The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease (7%) in C_max and a modest increase (31%) in AUC for idasanutlin, a marked reduction in C_max (~ 60%) and AUC0 (~ 50%) for M4 metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. C_max and AUC were both 45% higher for the SDP formulation. While the low-fat meal caused a less than 20% increase in all PK exposure parameters with the 90% CI values just outside the upper end of the equivalence criteria (80–125%), the high-fat meal reached bioequivalence with dosing under fasting.

Conclusion

In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally affected idasanutlin PK and PD without clinical significance. The SDP formulation improved rBA/exposures by ~ 50% without major food effect.

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Long-term results of S-1 plus cisplatin with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer

Abstract

Purpose

The purpose of this phase I/II study was to evaluate the feasibility and efficacy of S-1 plus cisplatin at the recommended schedule with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC).

Methods

Eligible patients with LA-NSCLC were treated with cisplatin intravenously at a dose of 60 mg/m² on day 8 plus oral S-1 at a dosage of 40 mg/m² twice per day for two different treatment schedules for up to 4 cycles. Patients also concurrently received 60 Gy of thoracic radiation in 30 fractions. The primary endpoint of the phase II study was the proportion of patients who survived for more than 2 years.

Results

Between August 2005 and October 2010, a total of 45 patients were enrolled in this phase I/II study; their long-term survival was then followed for a median period of 5.8 years. Nineteen of the 39 patients in the phase II study survived for more than 2 years and met the primary endpoint of the study. The median overall survival period was 24.9 months [95% confidence interval (CI) 17.4–74.5 months], and the 2- and 5-year overall survival rates were 51.0 and 43.0%, respectively. The response rate was 85%, and the median progression-free survival period was 13.8 months (95% CI 9.5–27.1 months). Hematological toxicity was mild. Grade 3 febrile neutropenia and pneumonitis was observed in 5 and 5%, respectively.

Conclusion

Our study indicated that S-1 plus cisplatin with concurrent thoracic radiotherapy yielded encouraging survival outcomes and an acceptable safety profile for LA-NSCLC.

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Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab

Abstract

Background

The objective of this study was to evaluate the efficacy and safety of concurrent immune checkpoint inhibitor therapy and radiotherapy (immunoradiotherapy) in patients with metastatic melanoma after progression on nivolumab.

Patients and methods

A retrospective review was performed on 16 consecutive patients with metastatic melanoma treated with concurrent immunoradiotherapy after progression on nivolumab. Best responses to immunoradiotherapy were assessed either inside or outside of the radiation fields. The target lesions ratio (the sum of the diameters of the target lesions inside the irradiated fields/all target lesions) was also assessed.

Results

Among the patients, seven received ipilimumab and radiotherapy (Ipi-RT), six received nivolumab and radiotherapy (Nivo-RT), and three sequentially received Ipi-RT and Nivo-RT. The overall response rate (all patients regardless of inside or outside radiation fields) was 30%. The response rate inside the radiation fields was 68.8% for all patients combined. The response rates of Ipi-RT and Nivo-RT inside the radiation fields were 37.5 and 100% (P = 0.03), respectively. Grade 3 adverse events were observed in three patients treated with Ipi-RT. The target lesions ratio was a predictive marker of disease control rate among patients treated with Nivo-RT.

Conclusions

This study showed that concurrent immunoradiotherapy is an option for patients with metastatic melanoma after progression on nivolumab.

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Phase I study of chemoradiotherapy using gemcitabine plus nab-paclitaxel for unresectable locally advanced pancreatic cancer

Abstract

Purpose

For unresectable locally advanced (UR-LA) pancreatic cancer, chemoradiotherapy has been recommended by the NCCN guidelines. We designed a chemoradiotherapy protocol using nab-paclitaxel combined with gemcitabine (GnP) for patients with UR-LA pancreatic cancer. The purpose of this phase I study was to determine a recommended dose (RD) for this novel regimen.

Methods

Patients with UR-LA pancreatic cancer were eligible. The frequency of dose-limiting toxicities (DLTs) was evaluated, and the RD was determined. Patients were classified according to the designated dose levels of chemoradiotherapy using the GnP regimen. After additional 6 cycles of the GnP regimen were administered, surgery was considered if the patients had stable disease and tumor marker levels had normalized.

Results

DLT (grade 4 thrombocytopenia) was observed only in 1 of 12 patients, and the RD was set at level 3. Grade 3–4 leukopenia was observed in 9 (75.0%) patients, and neutropenia in 7 (58.3%). The response rate was 41.7%, and the disease control rate was 100%. Conversion surgery was performed in 6 (50%) patients, and curative resection (R0) was performed in all 6 patients (100%). Stratification according to the Evans classification system demonstrated one patient with grade 1b, one with grade 2, two with grade 3, and two with grade 4 disease.

Conclusion

The RD for weekly administration was 800 mg/m² for gemcitabine and 100 mg/m² for nab-paclitaxel with a 50.4 Gy radiation. The GnP regimen at this dosage was promising with 6 of 12 patients proceeding to conversion surgery, and should be evaluated further in a phase II trial.

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Addition of bevacizumab to gemcitabine for platinum-resistant recurrent ovarian cancer: a retrospective analysis

Abstract

Purpose

To compare a cohort of patients with platinum-resistant recurrent ovarian cancer (PROC) treated with bevacizumab and gemcitabine (Bev–Gem) to that of patients treated only with gemcitabine (Gem).

Methods

Between 2011 and 2017, we identified the Bev–Gem and Gem PROC groups. The regimen included 1000 mg/m² of Gem on days 1, 8, and 15, and 15 mg/m² of Bev on day 1, every 4 weeks. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of the administration of Bev–Gem or Gem until disease progression or death.

Results

The Bev–Gem and Gem groups included 18 and 29 patients, respectively. More patients had advanced stage disease in the Bev–Gem group (p = 0.048); no other characteristics differed between the groups. The response rates [ratio of complete remission (CR) to partial remission (PR)] of Bev–Gem and Gem were 38.9 and 3.4%, respectively (p < 0.01). The clinical benefit rates [combined percentages of CR, PR, and stable disease] of the Bev–Gem and Gem groups were 88.9 and 41.4%, respectively (p = 0.04). PFS and OS of the Bev–Gem group were superior (p < 0.01, p = 0.03, respectively). Bev–Gem was the better prognostic factor of both PFS [hazard ratio (HR) 0.17, p < 0.01] and OS (HR 0.31, p = 0.01). The frequency of hematologic and non-hematologic adverse effects was similar in each group.

Conclusion

Bev–Gem regimens improved PFS and OS for PROC. Furthermore, the adverse effects of Bev–Gem were tolerable. Thus, Bev–Gem could be a candidate treatment strategy for PROC.

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S-1 (Teysuno) and gemcitabine in Caucasian patients with unresectable pancreatic adenocarcinoma

Abstract

Purpose

Gemcitabine has been standard of care in advanced pancreatic adenocarcinomas (PC) for almost two decades. Randomized, primarily Japanese, studies have shown promising efficacy when combined with S-1 (GemS-1); however, no data are published in Caucasian patients. We report the first study with a combination of GemS-1 in an unselected cohort of Caucasian PC patients.

Methods

In this observational cohort study, we analyzed efficacy and toxicity prospectively.

Results

From July 2012 to July 2014, 64 patients received at least one cycle of GemS-1. 16 patients started therapy with gemcitabine and capecitabine (GemCap) but switched to GemS-1 after median 3 cycles of GemCap due to toxicity (hand-foot syndrome). 48 patients received GemS-1 as initial therapy. For the complete cohort, median age was 68 years (range 44–80); 22 patients (34%) had locally advanced PC; 42 patients (66%) had metastatic disease. Five patients had received prior adjuvant therapy with gemcitabine and 9 pts had received prior first-line therapy. The most common adverse event was fatigue (86%), however, only grade 3 in 3%. Five patients (8%) developed febrile neutropenia. Median PFS was 8.1 (95% CI 6.9–9.0) months and median OS was 11.7 (95% CI 10.7–13.1) months in the whole GemS-1 population. In the 48 patients starting with GemS-1, median PFS was 7.7 (95% CI 6.7–8.9) months and median OS was 11.5 (95% CI 9.7–12.3) months.

Conclusions

The combination of gemcitabine and S-1 is safe and associated with promising efficacy in a Caucasian population; however, this needs to be confirmed in prospective clinical trials.

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Phase 1 summary of plasma concentration–QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML

Abstract

Purpose

Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval.

Method

Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed.

Results

A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation.

Conclusion

The concentration–QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development.

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Role of TPMT and ITPA variants in mercaptopurine disposition

Abstract

Purpose

To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants.

Methods

Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes.

Results

Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype patients (TPMT^LA 549 vs. 364 fmol/µg DNA, p = 0.007, ITPA^LA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(r_s = 0.37, p = 0.001), but plateaued at higher mEry-TGN levels. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMT^WT patients as compared to TPMT^LA patients but no difference in DNA-TG indices was observed between ITPA^WT and ITPA^LA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (r_s = 0.25, p = 0.001).

Conclusions

TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy.

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A phase I dose escalation trial of nab-paclitaxel and fixed dose radiation in patients with unresectable or borderline resectable pancreatic cancer

Abstract

Purpose

Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced pancreatic carcinoma.

Methods

We performed a phase 1 study using a 3 + 3 dose escalation strategy to determine the safety and tolerability of dose-escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with two cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy.

Results

Nine patients received nab-paclitaxel at a dose level of either 100 mg/m² (n = 3) or 125 mg/m² (n = 6). There were no observed grade 3 gastrointestinal toxicities. One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m² of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%) and neutropenia (11%). No grade 4 toxicities were observed. Following chemoradiotherapy, four patients (borderline resectable, n = 2 and unresectable, n = 2) underwent surgical resection, all with negative margins and with significant treatment effect with limited tumor viability.

Conclusions

The combination of fractionated radiation and weekly full dose nab-paclitaxel was safe and well-tolerated.

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2-Deoxy- d -glucose enhances TRAIL-induced apoptosis in human gastric cancer cells through downregulating JNK-mediated cytoprotective autophagy

Abstract

Purpose

TNF-related apoptosis-inducing ligand (TRAIL) resistance significantly limits its use in clinical practice. It has been reported that 2-deoxy-d-glucose (2-DG) can enhance TRAIL's cytotoxicity. Our studies were designed to investigate the mechanisms of 2-DG reversing TRAIL resistance therapy in gastric cancer cells.

Methods

Gastric cancer cells (MGC803, SGC7901) were treated with 2-DG and TRAIL. Cell viability was determined by CCK-8 assay and detection of apoptosis by flow cytometry. Autophagic and apoptosis protein expression and c-Jun NH2-terminal kinase (JNK) phosphorylation were determined by Western blotting. Autophagy response and JNK activities were inhibited by specific inhibitor, 3MA or SP600125, respectively. LDH release assay was used to detect cytotoxicity.

Results

We confirmed that TRAIL triggered an autophagic response in TRAIL-resistant gastric cancer cells, MGC803 and SGC7901, and depended on JNK activation. Blocking autophagy or JNK activation with specific inhibitor, 3MA or SP600125, potentiated cell death and caspase-3 activation. Furthermore, we confirmed that 2-DG inhibited the viability of gastric cancer cells, phosphorylation of JNK induced by TRAIL and increased gastric cancer cells to TRAIL-induced apoptosis.

Conclusions

Taken together, we show that 2-DG can sensitize TRAIL-induced apoptosis, at least in part, through suppressing JNK-mediated cytoprotective autophagic signaling in MGC803 and SGC7901cells. These results may have significant implications for the development of new strategies to reverse TRAIL resistance in gastric tumor.

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A note on improved statistical approaches to account for pseudoprogression

Abstract

Responses to immuno-oncology agents are often subject to misinterpretation as apparent tumor growth due to immune infiltration leads to the appearance of progressive disease and can result in the discontinuation of effective therapeutic agents. Better statistical strategies to determine experimental outcomes are needed to distinguish between true and pseudoprogression. We applied time-to-event statistical analyses methods that account for study design features and capture the longitudinal and panoramic aspects of pseudoprogression to test superiority of a combination of RRx-001, a novel tumor-associated macrophage polarizing agent in Phase 2, and an anti-PD-L1 antibody in a myeloma preclinical model, comparing to traditional, mean-based mixed effects modeling approaches that did not show statistical significance. Nonparametric p values for the difference of cumulative incidence rates of time to ≥ 50% tumor growth reduction and its associated restricted mean survival times are computed and found to be statistically significant. Kaplan–Meier description of time-to-volume reduction (≥ 50%) coupled with Cox's proportional hazards model follows the data longitudinally and therefore permits an analysis of immune infiltration resolution, making it an improved method for analysis of preclinical experiments with immuno-oncology agents.

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Multicenter retrospective study of cetuximab plus platinum-based chemotherapy for recurrent or metastatic oral squamous cell carcinoma

Abstract

Purpose

The purpose of this study was to assess the efficacy and safety of cetuximab plus platinum-based chemotherapy for patients specifically diagnosed with recurrent or metastatic oral squamous cell carcinoma (OSCC).

Methods

We conducted a multicenter retrospective observational study of patients who underwent first-line cetuximab plus platinum-based chemotherapy between December 2012 and June 2015. 65 patients received weekly cetuximab (week 1, 400 mg/m²; subsequent weeks, 250 mg/m²) plus a maximum of six 3-weekly cycles of cisplatin (80 or 100 mg/m², day 1) or carboplatin (at an area under the curve of 5 mg/mL/min as a 1-h intravenous infusion on day 1) and 5-fluorouracil (800 or 1000 mg/m²/day, days 1–4). Patients with stable disease who received cetuximab plus platinum-based chemotherapy continued to receive cetuximab until disease progression or unacceptable toxicities, whichever occurred first.

Results

The median follow-up was 10.5 (range 1.2–34.2) months. The best overall response and the disease control rates were 46.2 and 67.7%, respectively. The median overall survival and progression-free survival rates were 12.1 and 7.8 months, respectively. The most common grades 3–4 adverse events were skin rash (9.2%) followed by leukopenia (6.2%). None of the adverse events were fatal.

Conclusion

The results of our multicenter retrospective study, which was the largest of its kind to date, suggest that first-line cetuximab plus platinum-based chemotherapy is suitable and well-tolerated for the systemic therapy of recurrent or metastatic OSCC.

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A novel way to manage trastuzumab cardiotoxicity

Abstract

Purpose

Trastuzumab is the most widely prescribed anti-HER2 humanized monoclonal antibody. Cardiac toxicity is the only limiting toxicity of trastuzumab and it is of particular concern in patients with complete response, since the drug needs to be stopped, with a risk of disease relapse. To date, no pharmacological data on trastuzumab cardiotoxicity in patients have been made available. Here, we provide proof of concept, demonstrating that it was possible to prevent trastuzumab-induced cardiotoxicity by modifying the drug administration schedule.

Methods

In this paper, we report the case of a patient with metastatic breast cancer responding to trastuzumab, who developed severe cardiac toxicity twice using a 3-weekly regimen. Considering preclinical pharmacological data on trastuzumab cardiotoxicity, we hypothesized that a weekly schedule of trastuzumab with lower peaks of serum concentration could be safe while remaining efficient. With the patient's consent, we started a weekly combination of carboplatin (AUC2) and trastuzumab (2 mg/kg) with close monitoring of trastuzumab concentrations.

Results

We successfully controlled the disease for an additional 6 months with relevant trough concentrations of trastuzumab of around 50 mg/L. Another important aspect is that, with this weekly schedule, we observed no cardiac toxicity, and the left ventricular ejection fraction remained stabilized, at over 50%.

Conclusions

Trastuzumab is the most widely prescribed anti-HER2 monoclonal antibody for the treatment of HER2 metastatic breast cancer, and it is the only drug that has been approved for the treatment of localized HER2 breast cancer, 1-year treatment being required after surgery. In case of cardiac toxicity, particularly in women over 60 years of age, a weekly regimen with lower peaks of concentration could be an alternative to the standard 3-weekly regimen.

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A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies

Abstract

Purpose

The artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS).

Methods

Patients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1.

Results

A total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose.

Conclusion

The MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population.

ClinicalTrials.gov Identifier

NCT02353026.

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Profiling of Germline Mutations in Major Hotspot Codons of TP53 Using PCR-RFLP

Abstract

Tumor suppressor protein, TP53 also known as the "guardian of the genome" plays a key role in preventing malignant transformation. Almost 50% of human tumors carry mutations in this gene; in the remaining tumors, the TP53 network is functionally inoperative. The majority of TP53 mutations are missense mutations and more than 90% of the missense mutations affect specific codons in the DNA-binding domain, called "hotspot codons." The present study was aimed at analyzing the germline mutation status of four hotspot codons in TP53 namely, codon 175, codon 245, codon 248 (within the DNA binding domain) and codon 72 (outside the DNA binding domain) in cancer cases encountered in a tertiary care hospital in South India by PCR-RFLP. The case-control study included 85–10 subjects respectively. The results of the study indicated that majority of the cancer cases did not harbor germline mutations in the four hot spot codons of TP53. The study further highlights the usefulness of PCR-RFLP as a simple and cost effective tool for checking gene mutations.

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Role of TPMT and ITPA variants in mercaptopurine disposition

Abstract

Purpose

To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants.

Methods

Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes.

Results

Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype patients (TPMT^LA 549 vs. 364 fmol/µg DNA, p = 0.007, ITPA^LA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(r_s = 0.37, p = 0.001), but plateaued at higher mEry-TGN levels. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMT^WT patients as compared to TPMT^LA patients but no difference in DNA-TG indices was observed between ITPA^WT and ITPA^LA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (r_s = 0.25, p = 0.001).

Conclusions

TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy.

http://ift.tt/2FQUMRM

A phase I dose escalation trial of nab-paclitaxel and fixed dose radiation in patients with unresectable or borderline resectable pancreatic cancer

Abstract

Purpose

Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced pancreatic carcinoma.

Methods

We performed a phase 1 study using a 3 + 3 dose escalation strategy to determine the safety and tolerability of dose-escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with two cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy.

Results

Nine patients received nab-paclitaxel at a dose level of either 100 mg/m² (n = 3) or 125 mg/m² (n = 6). There were no observed grade 3 gastrointestinal toxicities. One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m² of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%) and neutropenia (11%). No grade 4 toxicities were observed. Following chemoradiotherapy, four patients (borderline resectable, n = 2 and unresectable, n = 2) underwent surgical resection, all with negative margins and with significant treatment effect with limited tumor viability.

Conclusions

The combination of fractionated radiation and weekly full dose nab-paclitaxel was safe and well-tolerated.

http://ift.tt/2FPDqor

Phase I study of chemoradiotherapy using gemcitabine plus nab-paclitaxel for unresectable locally advanced pancreatic cancer

Abstract

Purpose

For unresectable locally advanced (UR-LA) pancreatic cancer, chemoradiotherapy has been recommended by the NCCN guidelines. We designed a chemoradiotherapy protocol using nab-paclitaxel combined with gemcitabine (GnP) for patients with UR-LA pancreatic cancer. The purpose of this phase I study was to determine a recommended dose (RD) for this novel regimen.

Methods

Patients with UR-LA pancreatic cancer were eligible. The frequency of dose-limiting toxicities (DLTs) was evaluated, and the RD was determined. Patients were classified according to the designated dose levels of chemoradiotherapy using the GnP regimen. After additional 6 cycles of the GnP regimen were administered, surgery was considered if the patients had stable disease and tumor marker levels had normalized.

Results

DLT (grade 4 thrombocytopenia) was observed only in 1 of 12 patients, and the RD was set at level 3. Grade 3–4 leukopenia was observed in 9 (75.0%) patients, and neutropenia in 7 (58.3%). The response rate was 41.7%, and the disease control rate was 100%. Conversion surgery was performed in 6 (50%) patients, and curative resection (R0) was performed in all 6 patients (100%). Stratification according to the Evans classification system demonstrated one patient with grade 1b, one with grade 2, two with grade 3, and two with grade 4 disease.

Conclusion

The RD for weekly administration was 800 mg/m² for gemcitabine and 100 mg/m² for nab-paclitaxel with a 50.4 Gy radiation. The GnP regimen at this dosage was promising with 6 of 12 patients proceeding to conversion surgery, and should be evaluated further in a phase II trial.

http://ift.tt/2FPmlL8

Long-term results of S-1 plus cisplatin with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer

Abstract

Purpose

The purpose of this phase I/II study was to evaluate the feasibility and efficacy of S-1 plus cisplatin at the recommended schedule with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC).

Methods

Eligible patients with LA-NSCLC were treated with cisplatin intravenously at a dose of 60 mg/m² on day 8 plus oral S-1 at a dosage of 40 mg/m² twice per day for two different treatment schedules for up to 4 cycles. Patients also concurrently received 60 Gy of thoracic radiation in 30 fractions. The primary endpoint of the phase II study was the proportion of patients who survived for more than 2 years.

Results

Between August 2005 and October 2010, a total of 45 patients were enrolled in this phase I/II study; their long-term survival was then followed for a median period of 5.8 years. Nineteen of the 39 patients in the phase II study survived for more than 2 years and met the primary endpoint of the study. The median overall survival period was 24.9 months [95% confidence interval (CI) 17.4–74.5 months], and the 2- and 5-year overall survival rates were 51.0 and 43.0%, respectively. The response rate was 85%, and the median progression-free survival period was 13.8 months (95% CI 9.5–27.1 months). Hematological toxicity was mild. Grade 3 febrile neutropenia and pneumonitis was observed in 5 and 5%, respectively.

Conclusion

Our study indicated that S-1 plus cisplatin with concurrent thoracic radiotherapy yielded encouraging survival outcomes and an acceptable safety profile for LA-NSCLC.

http://ift.tt/2CWlWnj

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab

Abstract

Background

The objective of this study was to evaluate the efficacy and safety of concurrent immune checkpoint inhibitor therapy and radiotherapy (immunoradiotherapy) in patients with metastatic melanoma after progression on nivolumab.

Patients and methods

A retrospective review was performed on 16 consecutive patients with metastatic melanoma treated with concurrent immunoradiotherapy after progression on nivolumab. Best responses to immunoradiotherapy were assessed either inside or outside of the radiation fields. The target lesions ratio (the sum of the diameters of the target lesions inside the irradiated fields/all target lesions) was also assessed.

Results

Among the patients, seven received ipilimumab and radiotherapy (Ipi-RT), six received nivolumab and radiotherapy (Nivo-RT), and three sequentially received Ipi-RT and Nivo-RT. The overall response rate (all patients regardless of inside or outside radiation fields) was 30%. The response rate inside the radiation fields was 68.8% for all patients combined. The response rates of Ipi-RT and Nivo-RT inside the radiation fields were 37.5 and 100% (P = 0.03), respectively. Grade 3 adverse events were observed in three patients treated with Ipi-RT. The target lesions ratio was a predictive marker of disease control rate among patients treated with Nivo-RT.

Conclusions

This study showed that concurrent immunoradiotherapy is an option for patients with metastatic melanoma after progression on nivolumab.

http://ift.tt/2Fcq0By

Addition of bevacizumab to gemcitabine for platinum-resistant recurrent ovarian cancer: a retrospective analysis

Abstract

Purpose

To compare a cohort of patients with platinum-resistant recurrent ovarian cancer (PROC) treated with bevacizumab and gemcitabine (Bev–Gem) to that of patients treated only with gemcitabine (Gem).

Methods

Between 2011 and 2017, we identified the Bev–Gem and Gem PROC groups. The regimen included 1000 mg/m² of Gem on days 1, 8, and 15, and 15 mg/m² of Bev on day 1, every 4 weeks. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of the administration of Bev–Gem or Gem until disease progression or death.

Results

The Bev–Gem and Gem groups included 18 and 29 patients, respectively. More patients had advanced stage disease in the Bev–Gem group (p = 0.048); no other characteristics differed between the groups. The response rates [ratio of complete remission (CR) to partial remission (PR)] of Bev–Gem and Gem were 38.9 and 3.4%, respectively (p < 0.01). The clinical benefit rates [combined percentages of CR, PR, and stable disease] of the Bev–Gem and Gem groups were 88.9 and 41.4%, respectively (p = 0.04). PFS and OS of the Bev–Gem group were superior (p < 0.01, p = 0.03, respectively). Bev–Gem was the better prognostic factor of both PFS [hazard ratio (HR) 0.17, p < 0.01] and OS (HR 0.31, p = 0.01). The frequency of hematologic and non-hematologic adverse effects was similar in each group.

Conclusion

Bev–Gem regimens improved PFS and OS for PROC. Furthermore, the adverse effects of Bev–Gem were tolerable. Thus, Bev–Gem could be a candidate treatment strategy for PROC.

http://ift.tt/2FcrGez

S-1 (Teysuno) and gemcitabine in Caucasian patients with unresectable pancreatic adenocarcinoma

Abstract

Purpose

Gemcitabine has been standard of care in advanced pancreatic adenocarcinomas (PC) for almost two decades. Randomized, primarily Japanese, studies have shown promising efficacy when combined with S-1 (GemS-1); however, no data are published in Caucasian patients. We report the first study with a combination of GemS-1 in an unselected cohort of Caucasian PC patients.

Methods

In this observational cohort study, we analyzed efficacy and toxicity prospectively.

Results

From July 2012 to July 2014, 64 patients received at least one cycle of GemS-1. 16 patients started therapy with gemcitabine and capecitabine (GemCap) but switched to GemS-1 after median 3 cycles of GemCap due to toxicity (hand-foot syndrome). 48 patients received GemS-1 as initial therapy. For the complete cohort, median age was 68 years (range 44–80); 22 patients (34%) had locally advanced PC; 42 patients (66%) had metastatic disease. Five patients had received prior adjuvant therapy with gemcitabine and 9 pts had received prior first-line therapy. The most common adverse event was fatigue (86%), however, only grade 3 in 3%. Five patients (8%) developed febrile neutropenia. Median PFS was 8.1 (95% CI 6.9–9.0) months and median OS was 11.7 (95% CI 10.7–13.1) months in the whole GemS-1 population. In the 48 patients starting with GemS-1, median PFS was 7.7 (95% CI 6.7–8.9) months and median OS was 11.5 (95% CI 9.7–12.3) months.

Conclusions

The combination of gemcitabine and S-1 is safe and associated with promising efficacy in a Caucasian population; however, this needs to be confirmed in prospective clinical trials.

http://ift.tt/2FPmgXQ

Phase 1 summary of plasma concentration–QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML

Abstract

Purpose

Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval.

Method

Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed.

Results

A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation.

Conclusion

The concentration–QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development.

http://ift.tt/2F9Z6KQ

Effects of posaconazole (a strong CYP3A4 inhibitor), two new tablet formulations, and food on the pharmacokinetics of idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors

Abstract

Purpose

Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. To optimize its dosing conditions, a number of clinical pharmacology characteristics were examined in this multi-center trial in patients with advanced solid tumors.

Method

This was an open-label, single-dose, crossover clinical pharmacology study investigating the effects of strong CYP3A4 inhibition with posaconazole (Part 1), two new oral formulations (Part 2), as well as high-energy/high-fat and low-energy/low-fat meals (Part 3) on the relative bioavailability of idasanutlin. After completing Part 1, 2, or 3, patients could have participated in an optional treatment with idasanutlin. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) of MIC-1 elevation (Part 1 only), and safety/tolerability.

Results

The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease (7%) in C_max and a modest increase (31%) in AUC for idasanutlin, a marked reduction in C_max (~ 60%) and AUC0 (~ 50%) for M4 metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. C_max and AUC were both 45% higher for the SDP formulation. While the low-fat meal caused a less than 20% increase in all PK exposure parameters with the 90% CI values just outside the upper end of the equivalence criteria (80–125%), the high-fat meal reached bioequivalence with dosing under fasting.

Conclusion

In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally affected idasanutlin PK and PD without clinical significance. The SDP formulation improved rBA/exposures by ~ 50% without major food effect.

http://ift.tt/2FPDpRp

2-Deoxy- d -glucose enhances TRAIL-induced apoptosis in human gastric cancer cells through downregulating JNK-mediated cytoprotective autophagy

Abstract

Purpose

TNF-related apoptosis-inducing ligand (TRAIL) resistance significantly limits its use in clinical practice. It has been reported that 2-deoxy-d-glucose (2-DG) can enhance TRAIL's cytotoxicity. Our studies were designed to investigate the mechanisms of 2-DG reversing TRAIL resistance therapy in gastric cancer cells.

Methods

Gastric cancer cells (MGC803, SGC7901) were treated with 2-DG and TRAIL. Cell viability was determined by CCK-8 assay and detection of apoptosis by flow cytometry. Autophagic and apoptosis protein expression and c-Jun NH2-terminal kinase (JNK) phosphorylation were determined by Western blotting. Autophagy response and JNK activities were inhibited by specific inhibitor, 3MA or SP600125, respectively. LDH release assay was used to detect cytotoxicity.

Results

We confirmed that TRAIL triggered an autophagic response in TRAIL-resistant gastric cancer cells, MGC803 and SGC7901, and depended on JNK activation. Blocking autophagy or JNK activation with specific inhibitor, 3MA or SP600125, potentiated cell death and caspase-3 activation. Furthermore, we confirmed that 2-DG inhibited the viability of gastric cancer cells, phosphorylation of JNK induced by TRAIL and increased gastric cancer cells to TRAIL-induced apoptosis.

Conclusions

Taken together, we show that 2-DG can sensitize TRAIL-induced apoptosis, at least in part, through suppressing JNK-mediated cytoprotective autophagic signaling in MGC803 and SGC7901cells. These results may have significant implications for the development of new strategies to reverse TRAIL resistance in gastric tumor.

http://ift.tt/2FdDEnZ

A novel way to manage trastuzumab cardiotoxicity

Abstract

Purpose

Trastuzumab is the most widely prescribed anti-HER2 humanized monoclonal antibody. Cardiac toxicity is the only limiting toxicity of trastuzumab and it is of particular concern in patients with complete response, since the drug needs to be stopped, with a risk of disease relapse. To date, no pharmacological data on trastuzumab cardiotoxicity in patients have been made available. Here, we provide proof of concept, demonstrating that it was possible to prevent trastuzumab-induced cardiotoxicity by modifying the drug administration schedule.

Methods

In this paper, we report the case of a patient with metastatic breast cancer responding to trastuzumab, who developed severe cardiac toxicity twice using a 3-weekly regimen. Considering preclinical pharmacological data on trastuzumab cardiotoxicity, we hypothesized that a weekly schedule of trastuzumab with lower peaks of serum concentration could be safe while remaining efficient. With the patient's consent, we started a weekly combination of carboplatin (AUC2) and trastuzumab (2 mg/kg) with close monitoring of trastuzumab concentrations.

Results

We successfully controlled the disease for an additional 6 months with relevant trough concentrations of trastuzumab of around 50 mg/L. Another important aspect is that, with this weekly schedule, we observed no cardiac toxicity, and the left ventricular ejection fraction remained stabilized, at over 50%.

Conclusions

Trastuzumab is the most widely prescribed anti-HER2 monoclonal antibody for the treatment of HER2 metastatic breast cancer, and it is the only drug that has been approved for the treatment of localized HER2 breast cancer, 1-year treatment being required after surgery. In case of cardiac toxicity, particularly in women over 60 years of age, a weekly regimen with lower peaks of concentration could be an alternative to the standard 3-weekly regimen.

http://ift.tt/2CWlVQh

A note on improved statistical approaches to account for pseudoprogression

Abstract

Responses to immuno-oncology agents are often subject to misinterpretation as apparent tumor growth due to immune infiltration leads to the appearance of progressive disease and can result in the discontinuation of effective therapeutic agents. Better statistical strategies to determine experimental outcomes are needed to distinguish between true and pseudoprogression. We applied time-to-event statistical analyses methods that account for study design features and capture the longitudinal and panoramic aspects of pseudoprogression to test superiority of a combination of RRx-001, a novel tumor-associated macrophage polarizing agent in Phase 2, and an anti-PD-L1 antibody in a myeloma preclinical model, comparing to traditional, mean-based mixed effects modeling approaches that did not show statistical significance. Nonparametric p values for the difference of cumulative incidence rates of time to ≥ 50% tumor growth reduction and its associated restricted mean survival times are computed and found to be statistically significant. Kaplan–Meier description of time-to-volume reduction (≥ 50%) coupled with Cox's proportional hazards model follows the data longitudinally and therefore permits an analysis of immune infiltration resolution, making it an improved method for analysis of preclinical experiments with immuno-oncology agents.

http://ift.tt/2FeGiK8

Multicenter retrospective study of cetuximab plus platinum-based chemotherapy for recurrent or metastatic oral squamous cell carcinoma

Abstract

Purpose

The purpose of this study was to assess the efficacy and safety of cetuximab plus platinum-based chemotherapy for patients specifically diagnosed with recurrent or metastatic oral squamous cell carcinoma (OSCC).

Methods

We conducted a multicenter retrospective observational study of patients who underwent first-line cetuximab plus platinum-based chemotherapy between December 2012 and June 2015. 65 patients received weekly cetuximab (week 1, 400 mg/m²; subsequent weeks, 250 mg/m²) plus a maximum of six 3-weekly cycles of cisplatin (80 or 100 mg/m², day 1) or carboplatin (at an area under the curve of 5 mg/mL/min as a 1-h intravenous infusion on day 1) and 5-fluorouracil (800 or 1000 mg/m²/day, days 1–4). Patients with stable disease who received cetuximab plus platinum-based chemotherapy continued to receive cetuximab until disease progression or unacceptable toxicities, whichever occurred first.

Results

The median follow-up was 10.5 (range 1.2–34.2) months. The best overall response and the disease control rates were 46.2 and 67.7%, respectively. The median overall survival and progression-free survival rates were 12.1 and 7.8 months, respectively. The most common grades 3–4 adverse events were skin rash (9.2%) followed by leukopenia (6.2%). None of the adverse events were fatal.

Conclusion

The results of our multicenter retrospective study, which was the largest of its kind to date, suggest that first-line cetuximab plus platinum-based chemotherapy is suitable and well-tolerated for the systemic therapy of recurrent or metastatic OSCC.

http://ift.tt/2FTZHl7

A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies

Abstract

Purpose

The artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS).

Methods

Patients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1.

Results

A total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose.

Conclusion

The MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population.

ClinicalTrials.gov Identifier

NCT02353026.

http://ift.tt/2FRavjV

Total Plasma Exchange in Hypertriglyceridemia-Induced Pancreatitis: Case Report and Literature Review

Objective. To emphasize the role of apheresis in management of pancreatitis. Methods. The clinical course of a patient admitted for hypertriglyceridemia-induced pancreatitis (HTGP) complicated by multiorgan dysfunction is described, who demonstrated dramatic improvement in his clinical status after total plasma exchange (TPE). In addition, the current guidelines for TPE and the alternative treatment options for HTGP are also presented. Results. A patient presenting with pancreatitis associated with severe systemic inflammatory response was admitted to our hospital with an initial triglyceride level of 1181 mg/dL. Given the patient's worsening clinical condition, he was started on TPE with a rapid fall in his serum TG levels, in turn leading to early clinical recovery. Conclusion. Though various therapeutic options for the treatment of HTGP are described in literature, there are no set guidelines available to tackle this difficult clinical situation. TPE, albeit not very well known in this context, is one of the many therapies available. Though it leads to a rapid, precipitous fall in the TG levels and early symptom resolution, the data about the long-term morbidity as well as the effectiveness of this therapy is still lacking.

http://ift.tt/2teSlFT

Infective Endocarditis in a Young Adult due to Lactococcus lactis: A Case Report and Review of the Literature

Infective endocarditis (IE) is a condition mainly associated with valvular disease or prosthetic valve and intravenous drug use as a risk factor. Here, we describe a rare case of a previously healthy patient with endocarditis due to Lactococcus lactis associated with cattle contact, where antibiotic treatment resulted in full recovery.

http://ift.tt/2FhIiVx

A Seizure and Hemiplegia following Contrast Exposure: Understanding Contrast-Induced Encephalopathy

Contrast-induced encephalopathy is a rare, reversible phenomenon known to occur after intravenous or intra-arterial contrast exposure. This report describes a case involving a 73-year-old female admitted for an elective thoracic aortic aneurysm repair. During the procedure, a large volume of nonionic iodinated contrast was necessary for arteriography. Postoperatively, the patient developed seizure activity followed by left-sided hemiplegia. Computed tomography (CT) of the brain without contrast and magnetic resonance imaging (MRI) were negative for acute stroke but did show residual contrast surrounding the brain. Antiepileptic medications were administered with resolution of the seizure activity. The patient was treated with supportive management and improved to baseline over the next seven days. This case demonstrates a rare, nonionic iodinated contrast-induced encephalopathy with seizure activity and transient hemiplegia. The unique imaging findings differentiate it from other neurologic conditions.

http://ift.tt/2taIXTI

Stereotactic body radiotherapy (SBRT) for multiple pulmonary oligometastases: Analysis of number and timing of repeat SBRT as impact factors on treatment safety and efficacy

Stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by an excellent safety profile; however, experiences are mostly based on treatment of one single metastasis. It was the aim of this study to evaluate safety and efficacy of SBRT for multiple pulmonary metastases.

http://ift.tt/2oCJclV

Germline control of somatic Kras mutations in mouse lung tumors

Abstract

Somatic KRAS mutations are common in human lung adenocarcinomas and are associated with worse prognosis. In mice, Kras is frequently mutated in both spontaneous and experimentally induced lung tumors, although the pattern of mutation varies among strains, suggesting that such mutations are not random events. We tested if the occurrence of Kras mutations is under genetic control in two mouse intercrosses. Codon 61 mutations were prevalent, but the patterns of nucleotide changes differed between the intercrosses. Whole genome analysis with SNPs in (A/J x C57BL/6)F4 mice revealed a significant linkage between a locus on chromosome 19 and two particular codon 61 variants (CTA and CGA). In (AIRmax x AIRmin)F2 mice, there was a significant linkage between SNPs located on distal chromosome 6 (around 135 Mbp) and the frequency of codon 61 mutation. These results reveal the presence of two loci, on chromosomes 6 and 19, that modulate Kras mutation frequency in different mouse intercrosses. These findings indicate that somatic mutation frequency and type are not simple random events, but are under genetic control. This article is protected by copyright. All rights reserved

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TGFβ-induced Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells is mediated via TRPM7 expression

ABSTRACT

Growth factors, such as the transforming growth factor beta (TGFβ), play an important role in promoting metastasis of prostate cancer, thus understanding how TGFβ could induce prostate cancer cell migration may enable us to develop targeted strategies for advanced metastatic prostate cancer. To more clearly define the mechanism(s) involved in prostate cancer cell migration, we undertook a series of studies utilizing non-malignant prostate epithelial cells RWPE1 and prostate cancer DU145 and PC3 cells. Our studies show that increased cell migration was observed in prostate cancer cells, which was mediated through epithelial-to-mesenchymal transition (EMT). Importantly, addition of Mg²⁺, but not Ca²⁺, increased cell migration. Furthermore, TRPM7 expression which function as an Mg²⁺ influx channel, was also increased in prostate cancer cells. Inhibition of TRPM7 currents by 2-APB, significantly blocked cell migration in both DU145 and PC3 cells. Addition of growth factor TGFβ showed a further increase in cell migration, which was again blocked by the addition of 2-APB. Importantly, TGFβ addition also significantly increased TRPM7 expression and function, and silencing of TRPM7 negated TGFβ-induced cell migration along with a decrease in EMT markers that shows loss of cell adhesion. Furthermore, resveratrol, which decreases prostate cancer cell migration, inhibited TRPM7 expression and function including TGFβ-induced cell migration and activation of TRPM7 function. Together, these results suggest that Mg²⁺ influx via TRPM7 promotes cell migration by inducing EMT in prostate cancer cells and resveratrol negatively modulates TRPM7 function thereby inhibiting prostate cancer metastasis. This article is protected by copyright. All rights reserved

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NDRG4 in Gastric Cancer Determines Tumor Cell Proliferation and Clinical Outcome

Abstract

As a novel candidate tumor suppressor, NDRG4 is largely unstudied in human malignancies. In this study, we investigated the protein expression level of NDRG4 in gastric cancer and its association with outcome of patients. In the present study, we recruited 286 patients with gastric cancer and investigated the protein and mRNA expression of NDRG4 in cancer and adjacent normal specimens by immunohistochemistry assay and real-time PCR. The association of NDRG4 level with clinicopathological characteristics was investigated by appropriate statistical analysis. NDRG4 overexpression and knockdown cell lines were established in order to detect its impact on proliferation and apoptosis. Significant decreased protein and mRNA expression of NDRG4 was found in gastric cancer, compared with adjacent normal specimens. Besides, it was found that NDRG4 protein expression in gastric cancer was significantly associated with tumor differentiation, invasion, metastasis and stage. Patients with tumors of decreased NDRG4 level were more likely to have unfavorable disease-free and overall survival, in both univariate and multivariate analysis. In addition, overexpression of NDRG4 suppressed cell proliferation of gastric cancer cells in vitro; conversely, the proliferation of gastric cancer cells were enhanced by knockdown of NDRG4. These results proved for the first time that NDRG4 could be a potential tumor suppressor and prognostic marker of gastric cancer. This article is protected by copyright. All rights reserved

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Triptolide sensitizes breast cancer cells to Doxorubicin through the DNA damage response inhibition

Abstract

Triptolide is an active component from a Chinese herb, Tripterygium wilfordii which has been applied for treating immune-related diseases over centuries. Recently, it was reported that a variety of cancer cell lines could be sensitized to DNA-damage based chemotherapy drugs in combination with Triptolide treatment. In the present study, we show that a short time exposure (3 hours) to Triptolide,which did not trigger apoptosis, could specifically increase breast cancer cells sensitivity to Doxorubicin rather than other chemotherapy drugs including Paclitaxel, Fluorouracil, and Mitomycin .C. Further studies revealed Triptolide downregulated ATM expression and inhibited DNA damage response to DNA double- strand breaks. Moreover, the chemosensitization effect to Doxorubicin from Triptolide was attenuated by overexpression of ATM in breast cancer cells. Our findings suggest that Triptolide specifically chemosensitizes breast cancer cells to Doxorubicin prior to apoptosis initiation through downregulating ATM expression and inhibiting DNA damage response. This article is protected by copyright. All rights reserved

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Germline control of somatic Kras mutations in mouse lung tumors

Abstract

Somatic KRAS mutations are common in human lung adenocarcinomas and are associated with worse prognosis. In mice, Kras is frequently mutated in both spontaneous and experimentally induced lung tumors, although the pattern of mutation varies among strains, suggesting that such mutations are not random events. We tested if the occurrence of Kras mutations is under genetic control in two mouse intercrosses. Codon 61 mutations were prevalent, but the patterns of nucleotide changes differed between the intercrosses. Whole genome analysis with SNPs in (A/J x C57BL/6)F4 mice revealed a significant linkage between a locus on chromosome 19 and two particular codon 61 variants (CTA and CGA). In (AIRmax x AIRmin)F2 mice, there was a significant linkage between SNPs located on distal chromosome 6 (around 135 Mbp) and the frequency of codon 61 mutation. These results reveal the presence of two loci, on chromosomes 6 and 19, that modulate Kras mutation frequency in different mouse intercrosses. These findings indicate that somatic mutation frequency and type are not simple random events, but are under genetic control. This article is protected by copyright. All rights reserved

http://ift.tt/2FRsTJ6

TGFβ-induced Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells is mediated via TRPM7 expression

ABSTRACT

Growth factors, such as the transforming growth factor beta (TGFβ), play an important role in promoting metastasis of prostate cancer, thus understanding how TGFβ could induce prostate cancer cell migration may enable us to develop targeted strategies for advanced metastatic prostate cancer. To more clearly define the mechanism(s) involved in prostate cancer cell migration, we undertook a series of studies utilizing non-malignant prostate epithelial cells RWPE1 and prostate cancer DU145 and PC3 cells. Our studies show that increased cell migration was observed in prostate cancer cells, which was mediated through epithelial-to-mesenchymal transition (EMT). Importantly, addition of Mg²⁺, but not Ca²⁺, increased cell migration. Furthermore, TRPM7 expression which function as an Mg²⁺ influx channel, was also increased in prostate cancer cells. Inhibition of TRPM7 currents by 2-APB, significantly blocked cell migration in both DU145 and PC3 cells. Addition of growth factor TGFβ showed a further increase in cell migration, which was again blocked by the addition of 2-APB. Importantly, TGFβ addition also significantly increased TRPM7 expression and function, and silencing of TRPM7 negated TGFβ-induced cell migration along with a decrease in EMT markers that shows loss of cell adhesion. Furthermore, resveratrol, which decreases prostate cancer cell migration, inhibited TRPM7 expression and function including TGFβ-induced cell migration and activation of TRPM7 function. Together, these results suggest that Mg²⁺ influx via TRPM7 promotes cell migration by inducing EMT in prostate cancer cells and resveratrol negatively modulates TRPM7 function thereby inhibiting prostate cancer metastasis. This article is protected by copyright. All rights reserved

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NDRG4 in Gastric Cancer Determines Tumor Cell Proliferation and Clinical Outcome

Abstract

As a novel candidate tumor suppressor, NDRG4 is largely unstudied in human malignancies. In this study, we investigated the protein expression level of NDRG4 in gastric cancer and its association with outcome of patients. In the present study, we recruited 286 patients with gastric cancer and investigated the protein and mRNA expression of NDRG4 in cancer and adjacent normal specimens by immunohistochemistry assay and real-time PCR. The association of NDRG4 level with clinicopathological characteristics was investigated by appropriate statistical analysis. NDRG4 overexpression and knockdown cell lines were established in order to detect its impact on proliferation and apoptosis. Significant decreased protein and mRNA expression of NDRG4 was found in gastric cancer, compared with adjacent normal specimens. Besides, it was found that NDRG4 protein expression in gastric cancer was significantly associated with tumor differentiation, invasion, metastasis and stage. Patients with tumors of decreased NDRG4 level were more likely to have unfavorable disease-free and overall survival, in both univariate and multivariate analysis. In addition, overexpression of NDRG4 suppressed cell proliferation of gastric cancer cells in vitro; conversely, the proliferation of gastric cancer cells were enhanced by knockdown of NDRG4. These results proved for the first time that NDRG4 could be a potential tumor suppressor and prognostic marker of gastric cancer. This article is protected by copyright. All rights reserved

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Triptolide sensitizes breast cancer cells to Doxorubicin through the DNA damage response inhibition

Abstract

Triptolide is an active component from a Chinese herb, Tripterygium wilfordii which has been applied for treating immune-related diseases over centuries. Recently, it was reported that a variety of cancer cell lines could be sensitized to DNA-damage based chemotherapy drugs in combination with Triptolide treatment. In the present study, we show that a short time exposure (3 hours) to Triptolide,which did not trigger apoptosis, could specifically increase breast cancer cells sensitivity to Doxorubicin rather than other chemotherapy drugs including Paclitaxel, Fluorouracil, and Mitomycin .C. Further studies revealed Triptolide downregulated ATM expression and inhibited DNA damage response to DNA double- strand breaks. Moreover, the chemosensitization effect to Doxorubicin from Triptolide was attenuated by overexpression of ATM in breast cancer cells. Our findings suggest that Triptolide specifically chemosensitizes breast cancer cells to Doxorubicin prior to apoptosis initiation through downregulating ATM expression and inhibiting DNA damage response. This article is protected by copyright. All rights reserved

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Multiple primary non-breast tumors in breast cancer survivors

Abstract

Purpose

The aim of this study was to assess the frequency of second primary non-breast cancer after breast cancer diagnosis and treatment, and its correlation with clinicopathological features.

Methods

Data from 21,527 patients with primary breast cancer were collected retrospectively in a single cancer centre; 4.1% of the women developed a second non-breast cancer. The most frequently observed second primary tumor affected the digestive tract (27.8%). The frequency of observed cancers was similar to that expected in the general population, excepting for an excess of melanoma [SIR 1.98 (1.52–2.53)], uterine cancers [SIR 1.44 (1.17–1.74)], ovarian cancers [SIR 1.67 (1.31–2.10)], thyroid tumors [SIR 1.54 (1.23–1.92)], and leukemia [SIR 1.57 (1.11–2.16)].

Results

Clinicopathological breast cancer stratification showed a general increased risk of developing a second cancer in older patients, excluding ovarian cancer. An increased risk of developing ovarian cancer after breast cancer diagnosis was observed, in particular, in triple-negative [HR 3.47 (1.91–6.29)], G3 tumors [HR 2.54 (1.10–5.83)] and in positive breast cancer family history [HR 2.19 (1.22–3.94)]. Breast cancer survivors in hormonal therapy treatment are at higher risk for developing a second thyroid cancer [HR 4.00 (1.46–10.9)]. Conversely, adjuvant chemotherapy offered a protective effect on thyroid cancer risk development [HR 0.46 (0.28–0.76)].

Conclusions

Older age represents the major risk of developing a second primary non-breast cancer, excluding ovarian cancer. Clinical surveillance is required to prevent ovarian and thyroid cancers, respectively, in patients with positive family history, triple negative, G3 breast cancer and during hormonal therapy treatment in postmenopausal status.

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Multiple primary non-breast tumors in breast cancer survivors

Abstract

Purpose

The aim of this study was to assess the frequency of second primary non-breast cancer after breast cancer diagnosis and treatment, and its correlation with clinicopathological features.

Methods

Data from 21,527 patients with primary breast cancer were collected retrospectively in a single cancer centre; 4.1% of the women developed a second non-breast cancer. The most frequently observed second primary tumor affected the digestive tract (27.8%). The frequency of observed cancers was similar to that expected in the general population, excepting for an excess of melanoma [SIR 1.98 (1.52–2.53)], uterine cancers [SIR 1.44 (1.17–1.74)], ovarian cancers [SIR 1.67 (1.31–2.10)], thyroid tumors [SIR 1.54 (1.23–1.92)], and leukemia [SIR 1.57 (1.11–2.16)].

Results

Clinicopathological breast cancer stratification showed a general increased risk of developing a second cancer in older patients, excluding ovarian cancer. An increased risk of developing ovarian cancer after breast cancer diagnosis was observed, in particular, in triple-negative [HR 3.47 (1.91–6.29)], G3 tumors [HR 2.54 (1.10–5.83)] and in positive breast cancer family history [HR 2.19 (1.22–3.94)]. Breast cancer survivors in hormonal therapy treatment are at higher risk for developing a second thyroid cancer [HR 4.00 (1.46–10.9)]. Conversely, adjuvant chemotherapy offered a protective effect on thyroid cancer risk development [HR 0.46 (0.28–0.76)].

Conclusions

Older age represents the major risk of developing a second primary non-breast cancer, excluding ovarian cancer. Clinical surveillance is required to prevent ovarian and thyroid cancers, respectively, in patients with positive family history, triple negative, G3 breast cancer and during hormonal therapy treatment in postmenopausal status.

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Effects of propofol-based total intravenous anesthesia on gastric cancer: a retrospective study

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The efficacy and safety of alectinib in the treatment of ALK+ NSCLC: a systematic review and meta-analysis

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TSPAN12 is overexpressed in NSCLC via p53 inhibition and promotes NSCLC cell growth in vitro and in vivo

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rs11614913 polymorphism in miRNA-196a2 and cancer risk: an updated meta-analysis

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Genetic association between HER2 and ESR2 polymorphisms and ovarian cancer: a meta-analysis

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Response to crizotinib in a non-small-cell lung cancer patient harboring an EML4-ALK fusion with an atypical LTBP1 insertion

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Colorectal cancer cell-derived exosomes containing miR-10b regulate fibroblast cells via the PI3K/Akt pathway.

Colorectal cancer cell-derived exosomes containing miR-10b regulate fibroblast cells via the PI3K/Akt pathway.

Bull Cancer. 2018 Feb 26;:

Authors: Dai G, Yao X, Zhang Y, Gu J, Geng Y, Xue F, Zhang J

Abstract
BACKGROUND: Cancer-associated fibroblasts (CAFs) contribute to the proliferation of colorectal cancer(CRC) cells. However, the mechanism by which CAFs develop in the tumor microenvironment remains unknown. Exosomes may be involved in activating CAFs.
METHODS: Using a miRNA expression profiling array, we determined the miRNA expression profile of secretory exosomes in CRC cells and then identified potential miRNAs with significant differential expression compared to normal cells via enrichment analysis. Predicted targets of candidate miRNAs were then assessed via bioinformatics analysis. Realtime qPCR, western blot, and cell cycle analyses were performed to evaluate the role of candidate exosomal miRNAs. Luciferase reporter assays were applied to confirm whether candidate exosomal miRNAs control target pathway expression. A CRC xenograft mouse model was constructed to evaluate tumor growth in vivo.
RESULTS: Exosomes from CRC cells contained significantly higher levels of miR-10b than did exosomes from normal colorectal epithelial cells. Moreover, exosomes containing miR-10b were transferred to fibroblasts. Bioinformatics analysis identified PIK3CA, as a potential target of miR-10b. Luciferase reporter assays confirmed that miR-10b directly inhibited PIK3CA expression. Co-culturing fibroblasts with exosomes containing miR-10b significantly suppressed PIK3CA expression and decreased PI3K/Akt/mTOR pathway activity. Finally, exosomes containing miR-10b reduced fibroblast proliferation but promoted expression of TGF-β and SM α-actin, suggesting that exosomal miR-10b may activate fibroblasts to become CAFs that express myofibroblast markers. These activated fibroblasts were able to promote CRC growth in vitro and in vivo.
CONCLUSION: CRC-derived exosomes actively promote disease progression by modulating surrounding stromal cells, which subsequently acquire features of CAFs.

PMID: 29496262 [PubMed - as supplied by publisher]

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Issue Information

Cover of this issue. Cladogran of taxa of microbiota in the mice in the model and Bifico group. See also Song et al. (pp. 666–677 of this issue).

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In this Issue

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Issue Information

Cover of this issue. Cladogran of taxa of microbiota in the mice in the model and Bifico group. See also Song et al. (pp. 666–677 of this issue).

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Mitochondrial mRNA expression in fibroblasts of Down syndrome subjects

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Mitochondrial mRNA expression in fibroblasts of Down syndrome subjects

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Septic shock from descending necrotizing mediastinitis – combined treatment with IgM-enriched immunoglobulin preparation and direct polymyxin B hemoperfusion: a case report

Descending necrotizing mediastinitis is a common and progressive polymicrobial infection involving the neck and chest with a high death rate (10 to 40%). From a microbiological point of view, descending necrot...

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

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Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery

Abstract

The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60–15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC.

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The effect of escalating the boost dose for patients with involved resection margin after breast-conserving surgery

Abstract

Background

This study aims to investigate the impact of boost dose escalation on ipsilateral breast tumor recurrence (IBTR) in breast cancer patients with involved resection margins following breast-conserving surgery.

Methods

Between January 1998 and December 2010, 192 patients were treated with a boost dose of over 10 Gy for involved resection margins. We retrospectively analyzed outcomes in 192 patients who underwent whole breast irradiation of 50.4 Gy followed by a median boost dose of 15.0 Gy (range, 12–16 Gy). Boost doses of 12.5 Gy and 15 Gy were delivered to patients with carcinoma in situ and invasive carcinoma, respectively, at the positive margins. We evaluated the impact of the boost dose on the IBTR rate.

Results

Median follow-up duration was 6.7 years (0.4–15.6 years). The 5-year cumulative risk of IBTR as a first event was 5.0%. IBTR occurred as a first recurrence in 13 of 192 patients. In-boost-field recurrences were found in 11 patients (85%). Five patients (39%) experienced out-of boost field recurrences, and three experienced both types of recurrences. In multivariate analysis, age (<40 years), pT stage, and positive radial resection margin were prognostic factors for IBTR (P = 0.029, P = 0.024 and P = 0.035, respectively).

Conclusions

A median boost dose of 15 Gy might be insufficient in patients younger than 40 years, with tumor size greater than 2 cm, or with involved radial resection margins. On the other hand, in cases of positive superficial or deep margins, dose-escalated boost or re-excision may not be necessary.

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Neuroblastoma

Abstract

Neuroblastoma is one of the most common solid tumors in children and has a diverse clinical behavior that largely depends on the tumor biology. Neuroblastoma exhibits unique features, such as early age of onset, high frequency of metastatic disease at diagnosis in patients over 1 year of age and the tendency for spontaneous regression of tumors in infants. The high-risk tumors frequently have amplification of the MYCN oncogene as well as segmental chromosome alterations with poor survival. Recent advanced genomic sequencing technology has revealed that mutation of ALK, which is present in ~10% of primary tumors, often causes familial neuroblastoma with germline mutation. However, the frequency of gene mutations is relatively small and other aberrations, such as epigenetic abnormalities, have also been proposed. The risk-stratified therapy was introduced by the Japan Neuroblastoma Study Group (JNBSG), which is now moving to the Neuroblastoma Committee of Japan Children's Cancer Group (JCCG). Several clinical studies have facilitated the reduction of therapy for children with low-risk neuroblastoma disease and the significant improvement of cure rates for patients with intermediate-risk as well as high-risk disease. Therapy for patients with high-risk disease includes intensive induction chemotherapy and myeloablative chemotherapy, followed by the treatment of minimal residual disease using differentiation therapy and immunotherapy. The JCCG aims for better cures and long-term quality of life for children with cancer by facilitating new approaches targeting novel driver proteins, genetic pathways and the tumor microenvironment.

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Maintenance hormonal therapy after treatment with medroxyprogesterone acetate for patients with atypical polypoid adenomyoma

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Prevention of IVR: a need for investigation

Abstract

Intravesical recurrence (IVR) after RNU for UTUC is a frequent event, occurring in 20–50% of patients, mostly in the first postoperative year. Several retrospective studies have shown that predictors of IVR include clinical characteristics, surgical features and as well pathological characteristics (previous history of bladder cancer, pathological stage, lymph node involvement, cis, endoscopic distal ureter, etc.) management. Two prospective studies provide level I evidence for the safety and efficacy of intravesical single postoperative chemotherapy for patients treated with radical nephroureterectomy (RNU) for UTUC in order to prevent IVR. However, some questions remain unanswered. Yamashita et al. in the current issue of the journal have shown that early ureteral ligation during RNU decreases the risk of IVR in patients with pelvycalyceal upper tract urothelial carcinoma. This study despite its limitations represent a step towards improved outcomes for our patients with UTUC, the relatively low morbidity of the procedure added to the potential benefit associated with this early ligation make it an easy implementation in daily practice.

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Author’s reply to ‘Prevention of IVR: a need for investigation’

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Cancer screening guidelines and policy making: 15 years of experience in cancer screening guideline development in Japan

Abstract

Cancer deaths have remained a heavy burden in Japan, thus cancer screening has been anticipated to be a practical strategy for reducing mortality from cancers. The Basic Plan to Promote Cancer Control Program published in 2006 stated that evidence-based cancer screening is required. At the conception of national cancer screening programs, there were no cancer screening assessments. From 1998 to 2001, Hisamichi formed committees for the assessment of cancer screening and published three reports. These reports were the cornerstone in assessing primary studies of cancer screening in Japan which served as a stimulus for the development of cancer screening guidelines. Since 2003, research groups funded by the National Cancer Center have developed cancer screening guidelines based on established methods in reference to international standards. Screening guidelines for the following cancers have been published: gastric, colorectal, lung, prostate, cervical and breast cancers. Recommendations for screening are made following assessment of the balance of benefits and harms. The recommendation has been divided for population-based screening and opportunistic screening. New screening techniques with insufficient evidence have been suggested to further undergo research. The national committee has continued to appraise their evidence for cancer screening based on established guidelines and has discussed implementation problems. The screening methods for breast and gastric cancers have been revised based on cancer screening guidelines. Cancer screening guidelines have increasingly contributed to the promotion of evidence-based cancer screening for national programs. To provide appropriate cancer screening evidence, additional studies to further improve the methodology for guideline development are warranted.

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A Phase I/II study of the combination of lapatinib and oral vinorelbine in HER2-positive metastatic breast cancer

Abstract

Background

The combination of lapatinib and oral vinorelbine for HER2 positive metastatic breast cancer (MBC) is convenient but with uncertain toxicity profiles. A Phase I/II study was designed to understand the tolerability and efficacy of this combination treatment.

Method

Female MBC patients with HER2 positive were eligible. Lapatinib was given once daily and oral vinorelbine was given on Days 1 and 8 of a 21-day cycle. A 3 + 3 standard dose–escalation rule was applied in the Phase I study. The primary endpoint of the Phase II study was PFS. In the Phase II part, because no DLT was observed in the first 20 patients, vinorelbine dose–escalation was permitted if no significant toxicities after the first cycle was observed.

Result

From June 2009 to February 2013, 46 patients were enrolled in Phase I (n = 15) and II (n = 31) studies. Median age was 52.8 (range 34.3–84.0); 28 (60.9%) patients were ER positive. In the Phase I study, two patients had DLTs (neutropenia (n = 2), diarrhea (n = 1)). The MTD was determined at lapatinib 1000 mg plus oral vinorelbine 50 mg/m². In the Phase II study, 11 patients safely had vinorelbine escalated to 60 mg/m² on cycle 2. The median PFS was 5.6 months (95% CI 5.2–5.9); 6 (19.4%) patients had PR; the clinical benefit rate was 38.7%. Six patients had disease control over 2 years.

Conclusion

Lapatinib 1000 mg and oral vinorelbine 50 mg/m² were tolerable with manageable toxicities. Escalation to vinorelbine 60 mg/m² is feasible if no significant toxicities after the first cycle. Clinical efficacy was demonstrated with long-term responders observed.

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Characteristics of cellular composition in malignant pericardial effusion and its association with the clinical course of carcinomatous pericarditis

Abstract

To date, the cellular composition of malignant pericardial effusion (MPE) and its association with the clinical course of carcinomatous pericarditis remain unclear. We aimed to determine the MPE cellular composition and its association with carcinomatous pericarditis. Forty-four cases indicated for pericardial drainage due to symptomatic carcinomatous pericarditis were retrospectively reviewed; the blood cell count and composition of MPE were examined. The most dominant cells in MPE were neutrophils. The appearance ratio of an atypical cell in cytologically positive MPE was 95.5%. Low neutrophil and high lymphocyte counts were significantly associated with good effusion failure-free survival at 1 month. The survival after pericardial drainage was significantly shorter when the neutrophil/lymphocyte ratio was 3.5 or more (P = 0.041). Patients whose performance status improved due to drainage had significantly high leukocyte counts in MPE (P = 0.02). Prediction of the course of drainage through basic examination of MPE cellular composition might be beneficial in clinical practice.

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Impact of minimum point dose on local control and toxicity in T3–4 nasopharyngeal carcinoma treated with intensity-modulated radiation therapy plus chemotherapy

Abstract

Background

We aim to explore the relationship between minimum point dose (D_min) to the primary gross tumor volume (GTV_P) and local control in treating T3–4 nasopharyngeal carcinoma (NPC).

Methods

Ninety-six non-metastatic T3–4 NPC patients were enrolled between January 2009 and November 2013. Intensity-modulated radiation therapy (IMRT) plus docetaxel, cisplatin and fluorouracil (TPF) chemotherapy was administered. The prescribed dose was 66–70.4 Gy to the GTV_P while maintaining all the critical neurologic organs within dose constraints.

Results

The local response rate was 88.6% after induction chemotherapy. With a median follow-up of 48.5 months, the 3-year local failure-free survival (LFFS) and overall survival (OS) rates were 92.4% and 89.6%, respectively. The average D_min to the GTV_P was 59.4 Gy (range, 48.3–70.4 Gy). Additionally, 54.0 Gy was identified as the optimal cut-off D_min to the GTV_P, and the D_min ≥54.0 Gy group had a better local complete response rate after IMRT (52.4% vs. 81.3%, χ² = 7.335, P = 0.007), a better 3-year LFFS (95.9% vs. 78.4%, P = 0.005) and a better OS (93.3% vs. 75.9%, P = 0.003). Furthermore, a multivariate analysis found the D_min to the GTV_P ≥54.0 Gy to be prognostically important for LFFS and OS. One patient (1%) developed asymptomatic temporal lobe necrosis, but no other neurological dysfunctions were observed.

Conclusions

For T3–4-stage NPC treated with IMRT plus TPF chemotherapy, excellent local control with few late toxicities was achieved. A D_min ≥54.0 Gy to the GTV_P may confer better local control. New ways to increase the D_min to the GTV_P as far as possible without increasing late toxicities are urgently required.

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Clinical outcomes and prognostic factors of chemoradiotherapy for postoperative lymph node recurrence of esophageal cancer

Abstract

Background

The therapeutic strategies and prognostic risk factors in patients with lymph node (LN) recurrence of esophageal cancer remain controversial. We assessed clinical outcomes and prognostic factors related to the use of chemoradiotherapy (CRT) for LN recurrence of esophageal squamous cell carcinoma (ESCC) after curative resection.

Methods

We retrospectively evaluated survival and prognostic factors in 57 patients with LN recurrence of ESCC after curative resection. Patients received CRT using 5-fluorouracil plus cisplatin (FP) or docetaxel. Radiotherapy was delivered at 2 Gy (total dose, 60–66 Gy; median, 60 Gy).

Results

The median follow-up duration was 24 (range, 3–116) months. The overall survival (OS) rates at 2, 3 and 5 years were 43.7%, 36.9% and 27.6%, respectively. In the univariate analysis of OS, treatment with FP, a single LN recurrence, and a single regional recurrence were associated with a significantly better prognosis (P = 0.04, P = 0.027 and P = 0.0001, respectively). In the multivariate analysis, the combination chemotherapy regimen [hazard ratio (HR), 2.50; 95% confidence interval (CI), 1.23–5.07] and the number of the regional LNs with recurrence (HR, 5.76; 95% CI, 1.22–27.12) were independent prognostic factors.

Conclusion

Approximately 28% of ESCC patients with LN recurrence after curative resection could achieve long-term survival with CRT. Treatment with FP or patients with a single regional recurrence might improve the treatment outcome.

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