Updated long-term survival for patients with metastatic colorectal cancer treated with liver resection followed by hepatic arterial infusion and systemic chemotherapy

Background and Objectives

Patients who undergo liver resection for metastatic colorectal cancer (mCRC) have reported 5-year survivals ranging from 25% to 50%. The current study updated long-term survival for patients with resected liver metastases treated with adjuvant hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy.

Methods

Updated survival and recurrence free survival for patients treated on four consecutive adjuvant protocols with HAI and SYS from 1991 to 2009. Patients were divided into two groups: those treated on protocols before 2003 and after 2003. Median follow-up for all patients was 11 years.

Results

All 287 patients enrolled in four prospective protocols after liver resection are included. Patients treated before 2003 had a median follow-up of 15 years, 5 and 10-year survivals of 56% [95%CI: 49–64%] and 40% [95%CI: 32–47%], respectively, and median survival of 71 months. Patients treated after 2003 had a median follow-up of 9 years, 5 and 10-year survivals of 78% [95%CI: 70–84%] and 61% [95%CI: 51–70%], respectively, and median survival has not been reached.

Conclusions

Survival is improving for patients with mCRC who undergo liver resection. These data support the durability of long-term survival in patients who undergo resection followed by adjuvant HAI and SYS therapy. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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ERCP in potentially resectable malignant biliary obstruction is frequently unsuccessful when performed outside of a comprehensive pancreaticobiliary center

Background and Objectives

ERCP prior to pancreaticoduodenectomy is unnecessary in select patients. When performed, it should be in conjunction with endoscopic ultrasound (EUS) to increase diagnostic sensitivity and allow for metal stent placement. The aim of this study was to determine differences in endoscopic practice patterns at community medical centers (CMC) and a comprehensive pancreaticobiliary referral center (PBRC).

Methods

Retrospective cohort study of all patients seen at a PBRC for endoscopic and/or surgical management of potentially resectable malignant distal biliary obstruction from 1/2011 to 6/2014.

Results

Of 75 patients, 30 underwent endoscopic management at a CMC and 45 were initially managed at our PBRC. ERCP was attempted in 92% of patients. EUS was performed more frequently (100% vs. 13.3 %, P < 0.0001), ERCP was more successful (93% vs. 69%, P = 0.02), and metal stent placement more likely (41% vs. 5%, P = 0.005) at our PBRC compared to a CMC. The majority (81%) of patients undergoing initial endoscopy at a CMC required repeat endoscopy at our PBRC.

Conclusions

Patients who are candidates for pancreaticoduodenectomy frequently undergo ERCP. At a CMC, ERCP is often unsuccessful, is rarely accompanied by EUS, and often requires repeat endoscopy. Our findings support regionalizing the management of suspected pancreatic malignancy into dedicated specialty centers. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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An Algorithm to Detect HCC

Biomarkers for the early diagnosis of hepatocellular carcinoma (HCC) are needed to decrease mortality from this cancer. However, as new biomarkers have been slow to be brought to clinical practice, we have developed a diagnostic algorithm that utilizes commonly used clinical measurements in those at risk of developing HCC. Briefly, as α-fetoprotein (AFP) is routinely used, an algorithm that incorporated AFP values along with four other clinical factors was developed. Discovery analysis was performed on electronic data from patients who had liver disease (cirrhosis) alone or HCC in the background of cirrhosis. The discovery set consisted of 360 patients from two independent locations. A logistic regression algorithm was developed that incorporated log-transformed AFP values with age, gender, alkaline phosphatase, and alanine aminotransferase levels. We define this as the Doylestown algorithm. In the discovery set, the Doylestown algorithm improved the overall performance of AFP by 10%. In subsequent external validation in over 2,700 patients from three independent sites, the Doylestown algorithm improved detection of HCC as compared with AFP alone by 4% to 20%. In addition, at a fixed specificity of 95%, the Doylestown algorithm improved the detection of HCC as compared with AFP alone by 2% to 20%. In conclusion, the Doylestown algorithm consolidates clinical laboratory values, with age and gender, which are each individually associated with HCC risk, into a single value that can be used for HCC risk assessment. As such, it should be applicable and useful to the medical community that manages those at risk for developing HCC. Cancer Prev Res; 9(2); 172–9. ©2015 AACR.

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Interpretation of Unanticipated Clinical Trial Results

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The Case for a Pre-Cancer Genome Atlas (PCGA)

Understanding the earliest molecular and cellular events associated with cancer initiation remains a key bottleneck to transforming our approach to cancer prevention and detection. While TCGA has provided unprecedented insights into the genomic events associated with advanced stage cancer, there have been few studies comprehensively profiling premalignant and early-stage disease or elucidating the role of the microenvironment in premalignancy and tumor initiation. In this article, we make a call for development of a "Pre-Cancer Genome Atlas (PCGA)," a concerted initiative to characterize the molecular alterations in premalignant lesions and the corresponding changes in the microenvironment associated with progression to invasive carcinoma. This initiative will require a multicenter coordinated effort to comprehensively profile (cellular and molecular) premalignant lesions and their corresponding "field of injury" collected longitudinally as the lesion progresses towards or regresses from frank malignancy across multiple tumor types. Genomic characterization of alterations in premalignant lesions and their microenvironment, for both bulk tissue and single cells, will enable development of biomarkers for early detection and risk stratification as well as allow for the development of novel targeted cancer interception strategies. The multi-institutional and multidisciplinary collaborative "big-data" effort underlying the PCGA will help usher in a new era of precision medicine for cancer detection and prevention. Cancer Prev Res; 9(2); 119–24. ©2016 AACR.

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DFMO and Diclofenac in the Treatment of Sun-Damaged Skin

Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventive efficacy for cutaneous squamous cell carcinomas. We designed a randomized study of the combination of DFMO and diclofenac in the treatment of sun-damaged skin. Individuals with visible cutaneous sun damage were eligible. Subjects were randomized to one of the three groups: topical DFMO applied twice daily, topical diclofenac applied daily, or DFMO plus diclofenac. The treatment was limited to an area on the left forearm, and the duration of use was 90 days. We hypothesized that combination therapy would have increased efficacy compared with single-agent therapy. The primary outcome was change in karyometric average nuclear abnormality (ANA) in the treated skin. Individuals assessing the biomarkers were blinded regarding the treatment for each subject. A total of 156 subjects were randomized; 144 had baseline and end-of-study biopsies, and 136 subjects completed the study. The ANA unexpectedly increased for all groups, with higher values correlating with clinical cutaneous inflammation. Nearly all of the adverse events were local cutaneous effects. One subject had cutaneous toxicity that required treatment discontinuation. Significantly more adverse events were seen in the groups taking diclofenac. Overall, the study indicated that the addition of topical DFMO to topical diclofenac did not enhance its activity. Both agents caused inflammation on a cellular and clinical level, which may have confounded the measurement of chemopreventive effects. More significant effects may be observed in subjects with greater baseline cutaneous damage. Cancer Prev Res; 9(2); 128–34. ©2015 AACR.

See related article by Tsai and Hawk, p. 125

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GSTM1, UGT1A1, and Smoking Status Predict Recurrence of NMIBC

Cigarette smoking is the most important known risk factor for urinary bladder cancer. Selected arylamines in cigarette smoke are recognized human bladder carcinogens and undergo biotransformation through several detoxification pathways, such as the glutathione S-transferases (GST), and uridine-diphospho-glucuronosyltransferases (UGT) pathways. GSTM1 deletion status and UGT1A1*28 rs8175347 genotypes were assessed in 189 non–muscle-invasive bladder cancers (NMIBC) patients with pTa (77.2%) and pT1 (22.8%) tumors and a mean follow-up of 5.6 years, to investigate whether two common functional polymorphisms in GSTM1 and UGT1A1 genes and smoking history are associated with recurrence-free survival of patients with NMIBC. Most patients were current (48.7%) or previous (35.4%) cigarette smokers and 15.9% never smoked. Tumor recurrence occurred in 65.1% of patients, at a median time of 12.9 months. Upon multivariate analysis, previous and current smokers approximately tripled their risk of recurrences [HR = 2.76; 95% confidence interval (CI), 1.03–7.40 and HR = 2.93; 95% CI, 1.08–7.94, respectively]. When adjusted for age, smoking status, stage, grade, gender, and presence of carcinoma in situ, carriers of GSTM1 (+/– and –/–) and UGT1A1*28/*28 alleles were significantly at risk of NMIBC recurrence (HR = 10.05; 95% CI, 1.35–75.1 and HR = 1.91; 95% CI, 1.01–3.62, respectively). Compared with nonsmokers with UGT1A1*1/*1 and *1/*28 genotypes, previous and current smokers homozygous for the UGT1A1*28 allele demonstrated a risk of recurrence of 4.95 (95% CI, 1.02–24.0) and 5.32 (95% CI, 2.07–13.7), respectively. This study establishes a connection between GSTM1, UGT1A1, and tobacco exposure as prognostic markers of NMIBC recurrence in bladder cancer patients. These findings warrant validation in larger cohorts. Cancer Prev Res; 9(2); 189–95. ©2015 AACR.

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HPV16 Antibodies and Disease Status in Oropharyngeal Cancer

Human papillomavirus (HPV) is responsible for increasing incidence of oropharyngeal cancer. At present, there are no biomarkers in the surveillance algorithm for HPV-positive oropharyngeal cancer (HPV-OPC). HPV16 E6 antibody precedes oropharyngeal cancer diagnosis. If HPV16 E6 indeed precedes primary diagnosis, it is similarly expected to precede disease recurrence and may have a potential role as a biomarker for surveillance of HPV-OPC. To determine whether HPV antibody titers have a potential role as early markers of disease recurrence or prognosis, a retrospective pilot study was designed to determine whether HPV16 early antibody titers E6, E7, E1, and E2 decrease after treatment of HPV16-positive OPC. Trends in pretreatment, early (≤6 months after treatment), and late posttreatment (>6 months after treatment) HPV16 antibody titers were examined. There were 43, 34, and 52 subjects with serum samples available for pretreatment, early, and late posttreatment intervals. Mean pretreatment antibody levels were higher than posttreatment antibody levels. Average antibody levels decreased significantly over time for E6 (P_trend = 0.001) and E7 (P_trend < 0.001). Six disease recurrences were observed during the follow-up period (median, 4.4 years). In univariate analysis, a log-unit increase in pretreatment E6 titer was significantly associated with increased risk of disease recurrence (HR, 5.42; 95% CI, 1.1–25.7; P = 0.03). Therefore, levels of antibodies to HPV16 early oncoproteins decline after therapy. Higher E6 titers at diagnosis are associated with significant increases in the risk of recurrence. These data support the prospective evaluation of HPV16 antibodies as markers of surveillance and for risk stratification at diagnosis. Cancer Prev Res; 9(2); 135–41. ©2015 AACR.

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Black Raspberries Suppress Biomarkers of Oral Carcinogenesis

Black raspberries (BRB) demonstrate potent inhibition of aerodigestive tract carcinogenesis in animal models. However, translational clinical trials evaluating the ability of BRB phytochemicals to impact molecular biomarkers in the oral mucosa remain limited. The present phase 0 study addresses a fundamental question for oral cancer food–based prevention: Do BRB phytochemicals successfully reach the targeted oral tissues and reduce proinflammatory and antiapoptotic gene expression profiles? Patients with biopsy-confirmed oral squamous cell carcinomas (OSCC) administered oral troches containing freeze-dried BRB powder from the time of enrollment to the date of curative intent surgery (13.9 ± 1.27 days). Transcriptional biomarkers were evaluated in patient-matched OSCCs and noninvolved high at-risk mucosa (HARM) for BRB-associated changes. Significant expression differences between baseline OSCC and HARM tissues were confirmed using a panel of genes commonly deregulated during oral carcinogenesis. Following BRB troche administration, the expression of prosurvival genes (AURKA, BIRC5, EGFR) and proinflammatory genes (NFKB1, PTGS2) were significantly reduced. There were no BRB-associated grade 3–4 toxicities or adverse events, and 79.2% (N = 30) of patients successfully completed the study with high levels of compliance (97.2%). The BRB phytochemicals cyanidin-3-rutinoside and cyanidin-3-xylosylrutinoside were detected in all OSCC tissues analyzed, demonstrating that bioactive components were successfully reaching targeted OSCC tissues. We confirmed that hallmark antiapoptotic and proinflammatory molecular biomarkers were overexpressed in OSCCs and that their gene expression was significantly reduced following BRB troche administration. As these molecular biomarkers are fundamental to oral carcinogenesis and are modifiable, they may represent emerging biomarkers of molecular efficacy for BRB-mediated oral cancer chemoprevention. Cancer Prev Res; 9(2); 159–71. ©2015 AACR.

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Alternative Dosing of Letrozole in Postmenopausal Women

Aromatase inhibitors (AI) profoundly suppress estrogen levels in postmenopausal women and are effective in breast cancer prevention among high-risk postmenopausal women. Unfortunately, AI treatment is associated with undesirable side effects that limit patient acceptance for primary prevention of breast cancer. A double-blind, randomized trial was conducted to determine whether low and intermittent doses of letrozole can achieve effective estrogen suppression with a more favorable side-effect profile. Overall, 112 postmenopausal women at increased risk for breast cancer were randomized to receive letrozole at 2.5 mg once daily (QD, standard dose arm), 2.5 mg every Monday, Wednesday, and Friday (Q-MWF), 1.0 mg Q-MWF, or 0.25 mg Q-MWF for 24 weeks. Primary endpoint was suppression in serum estradiol levels at the end of letrozole intervention. Secondary endpoints included changes in serum estrone, testosterone, C-telopeptide (marker of bone resorption), lipid profile, and quality-of-life measures (QoL) following treatment. Significant estrogen suppression was observed in all dose arms with an average of 75% to 78% and 86% to 93% reduction in serum estradiol and estrone levels, respectively. There were no differences among dose arms with respect to changes in C-telopeptide levels, lipid profile, adverse events (AE), or QoL measures. We conclude that low and intermittent doses of letrozole are not inferior to standard dose in estrogen suppression and resulted in a similar side-effect profile compared with standard dose. Further studies are needed to determine the feasibility of selecting an effective AI dosing schedule with better tolerability. Cancer Prev Res; 9(2); 142–8. ©2015 AACR.

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Unconjugated Bilirubin Inhibits Metastasis in NPC

Distant metastasis is the most common cause of treatment failure and mortality in nasopharyngeal carcinoma (NPC) patients. Thus, it is important to understand the mechanism of NPC metastasis and identify reliable prognostic factors. In this study, we investigated the prognostic value of unconjugated bilirubin (UCB), which was previously considered a byproduct of heme catabolism, in NPC patients and examined the effects of UCB on NPC metastasis. The receiver operating characteristic analysis–generated UCB cutoff point for DMFS was 9.7 μmol/L. We found that higher UCB levels were significantly associated with favorable distant metastasis-free survival (DMFS, 93.3% vs. 84.2%, P < 0.001) in NPC patients and was an independent predictor for DMFS (HR, 0.416; 95% confidence interval, 0.280–0.618; P < 0.001). We next found that UCB treatment impaired the invasion capability of NPC cells and potently inhibited lung metastasis of NPC cells in nude mice. Further investigation showed that UCB inhibited reactive oxygen species production, which is involved in the repression of ERK1/2 activation and matrix metalloproteinase-2 (MMP-2) expression. Moreover, lower levels of ERK1/2 phosphorylation and MMP-2 expression were observed in the NPC lung metastases of nude mice administered UCB. Taken together, our results indicate that UCB is a significantly favorable factor for DMFS in NPC patients and may play an important role in NPC chemoprevention. Cancer Prev Res; 9(2); 180–8. ©2015 AACR.

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Lobular Involution and Mammographic Density

Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLU), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. We investigated relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (perilesional). Three measures inversely related to TDLU involution (TDLU count/mm², median TDLU span, median acini count/TDLU) assessed in benign diagnostic biopsies from 348 women, ages 40–65, were related to MD area (quantified with thresholding software) and volume (assessed with a density phantom) by analysis of covariance, stratified by menopausal status and adjusted for confounders. Among premenopausal women, TDLU count was directly associated with percent perilesional MD (P trend = 0.03), but not with absolute dense area/volume. Greater TDLU span was associated with elevated percent dense area/volume (P trend<0.05) and absolute perilesional MD (P = 0.003). Acini count was directly associated with absolute perilesional MD (P = 0.02). Greater TDLU involution (all metrics) was associated with increased nondense area/volume (P trend ≤ 0.04). Among postmenopausal women, TDLU measures were not significantly associated with MD. Among premenopausal women, reduced TDLU involution was associated with higher area and volumetric MD, particularly in perilesional parenchyma. Data indicating that TDLU involution and MD are correlated markers of breast cancer risk suggest that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction. Cancer Prev Res; 9(2); 149–58. ©2015 AACR.

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Exercise Dose and Inflammation in Postmenopausal Women

This randomized dose comparison trial examined if higher exercise volume decreased inflammatory biomarkers, associated with postmenopausal breast cancer risk, more than moderate exercise volume. The Breast Cancer and Exercise Trial in Alberta was a two-center, two-armed randomized trial in 400 inactive, healthy, postmenopausal women, aged 50 to 74 years, with a body mass index of 22 to 40 kg/m². Participants were randomized to high (300 minutes/week) or moderate (150 minutes/week) volumes of aerobic exercise while maintaining usual diet. Fasting blood concentrations of C-reactive protein (CRP), IL6, and TNFα were measured at baseline, 6 and 12 months. Intention-to-treat (ITT) analysis was performed using linear mixed models adjusted for baseline biomarker concentrations. ITT analyses of 386 (97%) participants showed no statistically significant group differences for changes in biomarker levels at 6 and 12 months. In addition, we did not observe any modification of this effect by baseline characteristics of participants. In post hoc analyses based on self-selected exercise level (measured in minutes/week), CRP decreased by 22.45% for participants who exercised >246 minutes/week (highest quintile) and increased by 0.07% for those who exercised <110 minutes/week (lowest quintile, P_trend = 0.04), adjusted for baseline covariates. When this analysis was restricted to include exercise time in the target heart rate zone only, statistically significant trends were observed for both CRP (P < 0.01) and IL6 (P = 0.04). Prescribing 300 minutes/week of moderate-to-vigorous aerobic exercise did not improve inflammatory markers compared with 150 minutes/week in postmenopausal women. Decreases in CRP were observed with higher self-selected exercise volume. Cancer Prev Res; 9(2); 196–203. ©2015 AACR.

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Individualized Radiation Dose Escalation Based on the Decrease in Tumor FDG Uptake and Normal Tissue Constraints Improve Survival in Patients With Esophageal Carcinoma

Background:

To determine whether individualized radiation dose escalation after planned chemoradiation based on the decrease in tumor and normal tissue constraints can improve survival in patients with esophageal carcinoma.

Methods:

From August 2005 to December 2010, 112 patients with squamous esophageal carcinoma were treated with radical concurrent chemoradiation. Patients received positron emission tomography-computer tomography scan twice, before radiation and after radiation dose of 50.4 Gy. All patients were noncomplete metabolic response groups according to the Response Evaluation Criteria in solid tumors. Only 52 patients with noncomplete metabolic response received individualized dose escalation based on tumor and normal tissue constraints. Survival and treatment failure were observed and analyzed using SPSS (13.0).

Results:

The rate of complete metabolic response for patients with noncomplete metabolic response after dose escalation reached 17.3% (9 of 52). The 2-year overall survival rates for patients with noncomplete metabolic response in the conventional and dose-escalation groups were 20.5% and 42.8%, respectively(P = .001). The 2-year local control rates for patients were 35.7% and 76.2%, respectively (P = .002). When patients were classified into partial metabolic response and no metabolic response, 2-year overall survival rates for patients with partial metabolic response were significantly different in conventional and dose-escalation groups (33.8% vs 78.4%; P = .000). The 2-year overall survival rates for patients with no metabolic response in two groups (8.6% vs 15.1%) did not significantly differ (P = .917).

Conclusion:

Individualized radiation dose escalation has the potential to improve survival in patients with esophageal carcinoma according to increased rate of complete metabolic response. However, further trials are needed to confirm this and to identify patients who may benefit from dose escalation.

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Correction of Bowtie-Filter Normalization and Crescent Artifacts for a Clinical CBCT System

Purpose:

To present our experiences in understanding and minimizing bowtie-filter crescent artifacts and bowtie-filter normalization artifacts in a clinical cone beam computed tomography system.

Methods:

Bowtie-filter position and profile variations during gantry rotation were studied. Two previously proposed strategies (A and B) were applied to the clinical cone beam computed tomography system to correct bowtie-filter crescent artifacts. Physical calibration and analytical approaches were used to minimize the norm phantom misalignment and to correct for bowtie-filter normalization artifacts. A combined procedure to reduce bowtie-filter crescent artifacts and bowtie-filter normalization artifacts was proposed and tested on a norm phantom, CatPhan, and a patient and evaluated using standard deviation of Hounsfield unit along a sampling line.

Results:

The bowtie-filter exhibited not only a translational shift but also an amplitude variation in its projection profile during gantry rotation. Strategy B was better than strategy A slightly in minimizing bowtie-filter crescent artifacts, possibly because it corrected the amplitude variation, suggesting that the amplitude variation plays a role in bowtie-filter crescent artifacts. The physical calibration largely reduced the misalignment-induced bowtie-filter normalization artifacts, and the analytical approach further reduced bowtie-filter normalization artifacts. The combined procedure minimized both bowtie-filter crescent artifacts and bowtie-filter normalization artifacts, with Hounsfield unit standard deviation being 63.2, 45.0, 35.0, and 18.8 Hounsfield unit for the best correction approaches of none, bowtie-filter crescent artifacts, bowtie-filter normalization artifacts, and bowtie-filter normalization artifacts + bowtie-filter crescent artifacts, respectively. The combined procedure also demonstrated reduction of bowtie-filter crescent artifacts and bowtie-filter normalization artifacts in a CatPhan and a patient.

Conclusion:

We have developed a step-by-step procedure that can be directly used in clinical cone beam computed tomography systems to minimize both bowtie-filter crescent artifacts and bowtie-filter normalization artifacts.

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IgG glycome in colorectal cancer

Purpose: Alternative glycosylation has significant structural and functional consequences on immunoglobulin G and consequently also cancer immunosurveilance. Due to technological limitations, the effects of highly heritable individual variations and the differences in the dynamics of changes in IgG glycosylation on colorectal cancer (CRC) were never investigated before. Experimental design: Using recently developed high-throughput UPLC technology for IgG glycosylation analysis we analysed IgG glycome composition in 760 CRC patients and 538 matching controls. Effects of surgery were evaluated in 28 patients sampled before and three times after surgery. A predictive model was built using regularized logistic regression and evaluated using a 10-cross validation procedure. Furthermore, IgG glycome composition was analysed in 39 plasma samples collected before initial diagnosis of CRC. Results: We have found that CRC associates with decrease in IgG galactosylation, IgG sialylation and increase in core-fucosylation of neutral glycans with concurrent decrease of core fucosylation of sialylated glycans. While a model based on age and sex did not show discriminative power (AUC=0.499), the addition of glycan variables into the model considerably increased the discriminative power of the model (AUC=0.755). However, none of these differences were significant in the small set of samples collected before the initial diagnosis. Conclusions: Considering the functional relevance of IgG glycosylation for both tumour immunosurveilance and clinical efficacy of therapy with monoclonal antibodies, individual variation in IgG glycosylation may turn out to be important for prediction of disease course or the choice of therapy, thus warranting further, more detailed studies of IgG glycosylation in CRC

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Micrometastasis Volume in Lymph Nodes Determines Disease Recurrence Rate of Stage II Colorectal Cancer: A Prospective Multicenter Trial

PURPOSE: We reported in a retrospective study that the presence of micrometastasis in lymph nodes (LNs), when assessed by CEA-specific RT-PCR, is a significant prognostic factor in stage II colorectal cancer (CRC). The aim of this study was to clarify the clinical value of micrometastasis in a prospective multicenter trial. EXPERIMENTAL DESIGN: From November 2001 to December 2005, a total of 419 CRC cases were preoperatively registered at a central data center. Of them, 315 node-negative stage II CRC were enrolled. After RNA quality check, 304 CRC cases were analyzed for CEA mRNA in LNs by both conventional RT-PCR (a band method) and quantitative RT-PCR. Long-term prognosis of the patients was determined by each method. RESULTS: A positive band for CEA mRNA was detected in 73 (24.0%) of 304 patients. Post-operative adjuvant chemotherapy was applied in 31 CEA band-positive cases with an oral 5-FU derivative HCFU (1-hexylcarbamoyl-5-fluorouracil) for one year, while chemotherapy was not administered to CEA band-negative group. Multivariate Cox regression analyses revealed that a high micrometastasis volume (High-MMV, n=95) was an independent poor prognostic factor for 5-year DFS (P=0.001) and 5-year OS (P=0.016). CONCLUSIONS: This prospective clinical trial demonstrates that micrometastasis volume is a useful marker in identifying patients who are at high or low risk for recurrence of stage II CRC. (Word count: 214)

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Androgen deprivation followed by acute androgen stimulation selectively sensitizes AR-positive prostate cancer cells to ionizing radiation

Purpose: The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen deprived prostate cancer cells leads to formation of double strand breaks (DSBs). Here, we exploit this finding and investigate the extent and timing of androgen induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR). Experimental Design: Androgen induced DNA damage was assessed by comet assays and H2A.X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models. Results: We document that androgen treatment of androgen deprived prostate cancer cell lines resulted in a dose and time dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor (AR) and topoisomerase II beta (TOP2B) but not on cell cycle progression. In vitro models demonstrated a synergistic interaction between ionizing radiation and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice. Conclusions: These results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy.

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Phase I Dose Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors

Purpose: Cross-talk between type 1 IGF receptor (IGF-1R), insulin receptor (INSR) and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of linsitinib, a potent oral IGF-1R/INSR inhibitor, with EGFR inhibitor erlotinib. Experimental Design: This open-label, dose-escalation study investigated linsitinib schedules S1: once-daily (QD) intermittent (days 1-3 weekly); S2, QD continuous; S3, twice-daily (BID) continuous; each with erlotinib 100-150mg QD; and a non-small cell lung cancer (NSCLC) expansion cohort. Results: Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150mg (S1), 400/100mg (S2). Based on prior monotherapy data, S3 dosing at 150mg BID/150mg QD was the recommended phase II dose for the expansion cohort. There was no evidence of drug-drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF-1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38/75 (51%), and 28/91 (31%) patients were on study >12 weeks. Conclusions: The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy.

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Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic Renal Cell Carcinoma

Purpose: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC). Experimental Design: We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for six months or longer. Non-responders were defined as those with disease progression during the first three months of therapy. Fisher's exact test assessed the association between mutation status in mTOR pathway genes and treatment response. Results: Mutations in MTOR, TSC1 or TSC2 were more common in responders, 12 (28%) of 43, than non-responders, 4 (11%) of 36 (p=0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than non-responders, 2(6%), (p=0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1 or TSC2 compared to 4 (11%) of 36 non-responders (p=0.03). Eight additional genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response. Conclusion: In this cohort of mRCC patients, mutations in MTOR, TSC1 or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (31 of 43, 72%) had no mTOR pathway mutation identified.

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Eventual role of EGFR-tyrosine kinase inhibitors in early-stage non-small-cell lung cancer

Future Oncology Ahead of Print.


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Low-dose radiotherapy and concurrent FOLFIRI-bevacizumab: a Phase II study

Future Oncology Ahead of Print.


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Concepts in cardio-oncology: definitions, mechanisms, diagnosis and treatment strategies of cancer therapy-induced cardiotoxicity

Future Oncology Ahead of Print.


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Molecularly targeted therapy in acute myeloid leukemia

Future Oncology Ahead of Print.


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Novel therapies for advanced squamous cell carcinoma of the lung

Future Oncology Ahead of Print.


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The PD-1/PD-L1 axis in the pathogenesis of urothelial bladder cancer and evaluating its potential as a therapeutic target

Future Oncology Ahead of Print.


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Cancer as a changed tissue's way of life (when to treat, when to watch and when to think)

Future Oncology Ahead of Print.


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The role of neoadjuvant therapy in pancreatic cancer: a review

Future Oncology Ahead of Print.


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Quantifying the utility of single nucleotide polymorphisms to guide colorectal cancer screening

Future Oncology Ahead of Print.


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Prevalence of KRAS mutations in metastatic colorectal cancer: A retrospective observational study from India

VH Veldore, MR Rao, SA Prabhudesai, R Tejaswi, S Kakara, S Pattanayak, N Krishnamoorthy, BN Tejaswini, D Hazarika, A Gangoli, SM Rahman, J Dixit, R Naik, RB Diwakar, CT Satheesh, HP Shashidhara, S Patil, KS Gopinath, BS Kumar

Indian Journal of Cancer 2014 51(4):531-537

Background: One of the genetic alterations implicated in tumor progression in colorectal cancers (CRCs) are abnormalities in Kristen Rat Sarcoma (KRAS) gene. Evaluation of KRAS mutation status is an important prognostic factor and has predictive value in deciding first line therapy based on monoclonal antibodies such as Cetuximab and Panitumumab in metastatic CRCs. Materials And Methods: In this retrospective study, we analyzed 7 different somatic mutations in Exon 2 of KRAS gene in 299 unselected incidental CRC patients who visited the hospital for clinical management during the period 2009–2013. Most of the tumors were primarily originating from colon and rectum; nevertheless, there were a few from rectosigmoid, sigmoid, ceacum and anal canal in the study group. Genomic DNA extracted from paraffin embedded tumor tissues was screened for 7 point mutations located in Codons 12 and 13 of KRAS gene, using Scorpions amplified refractory mutation system real time polymerase chain reaction technology. Statistical analysis was performed to assess bivariate relationship between different variables that includes: mutation status, mutation type, tumor location, tumor morphology, age and sex. Results: Prevalence of mutation in Codons 12 and 13 was 42.8% in the study group. Well-differentiated tumors had significantly more mutation positivity than moderately and poorly differentiated tumors (P = 0.001). 92% of the mutations were from Codon 12 and 8% in Codon 13. Glycine to Arginine was relatively more common in rectosigmoid followed by ceacum, while Glycine to Alanine mutation was relatively more prevalent in sigmoid, followed by rectum and rectosigmoid. CONCLUSION: The results suggest a prevalence of KRAS mutation at 42.8% in Indian population indicating that this testing is very crucial for targeted therapy management in metastatic CRC in India. Further analysis on mutation status of other homologues such as NRAS and downstream partner, v-raf murine sarcoma viral oncogene homolog B1, would add value to understanding the role of anti-epidermal growth factor receptor therapy in CRC management.

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Microbiology, infection control and infection related outcome in pediatric patients in an oncology center in Eastern India: Experience from Tata Medical Center, Kolkata

Arpita Bhattacharyya, Shekhar Krishnan, Vaskar Saha, Gaurav Goel, Sanjay Bhattacharya, Lalawmpuia Hmar

Indian Journal of Cancer 2014 51(4):415-417

Context: Infection is a major determinant in the outcome of patients with cancer. Aims: The aim was to know the epidemiology and outcome of patients with cancer in a cancer care center in Eastern India. Settings And Design: Retrospective study of pediatric patients in Tata Medical Center, Kolkata, India. Methods: Patients (n = 262) between the age group of 0 and 18 years were reviewed for infections and infection-related outcome (January to December 2013). Statistical Analysis: Modified Wald method was used to determine confidence interval of proportions. RESULTS: Gram-negative bacteria were found to be the most common cause of bloodstream infections (BSIs) (56.4%), followed by Gram-positive cocci (34.5%), and Candida species (9.1%). Carbapenem-resistance was noted among 24% of Gram-negative bacilli (GNB), and extended-spectrum beta-lactamase among 64% of GNBs. A single case of Vibrio cholerae septicemia was also noted. No case of vancomycin-resistant Enterococcus was observed, whereas only two cases of methicillin-resistant Staphylococcus aureus bacteremia (1/3 of all Staphylococcus aureus bacteremia) were detected. Escherichia coli, followed by Klebsiella, Pseudomonas, and Acinetobacter were the predominant organisms detected in BSIs. Among Candida spp. BSIs no resistance to caspofungin, amphotericin B, Voriconazole was noted. Candida tropicalis was the most common isolate, and 1 isolate of Candida glabrata showed dose-dependent sensitivity to fluconazole. Three out of 25 patients died of multi-drug resistant Gram-negative bacteria (12%) in 2013. Seventeen patients had radiological evidence of invasive fungal infections (no mortality was noted). Conclusions: Periodic review of infection-related data, as well as infection control practices, is essential to optimize clinical outcome in patients with pediatric malignancies.

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Colorectal carcinoma up to the second decade of life: An 8-year experience in a tertiary care center

RK Gupta, S Ali, P Sakhuja, D Mukherjee, AK Agarwal, AS Puri

Indian Journal of Cancer 2014 51(4):557-559

Aims And Objectives: To evaluate the demographic pattern, incidence, and histological characteristics of colorectal carcinomas (CRCs) in very young adults diagnosed in the center. Materials And Methods: We retrieved and reviewed slides and data pertaining to all the cases of CRCs and "segregated into decade wise age-groups" from the archives of Department of Pathology. Patients with age ≤20 years diagnosed during the last 8 years (2006–2013) were further evaluated. Results: Totally, 590 cases of CRCs diagnosed over last 8-year period, of which 4.2% (25 cases) presented in the study group (age ≤20 years) with a mean age of 17 years. About 50% of the tumors were either signet ring cell, mucin-secreting or poorly differentiated carcinomas. Four cases occurred in a background of familial adenomatous polyposis (FAP), three of which showed high-grade dysplasia, while in one case, carcinoma-in-situ was diagnosed. In all but two cases, rectum was the site of involvement except FAP cases in which colorectal location was noted. CRCs show a sharp rise in earlier age onset (≤40 years) and an increasing trend was followed in patients between age groups third, fourth, and fifth decades of life over the last 8 years. Conclusion: Colorectal carcinomas show an increasing trend in young age (≤40 years). This change may be attributed to dietary, lifestyle changes, and newer genetic alterations in developing countries. In very young age group (≤20 years), a higher grade and stage at the time of diagnosis and predominantly rectal involvements are the distinct features.

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Unexplained splenic cyst in a patient with breast cancer after receiving Tian Xian Liquid

Kamon Chaiyasit, Viroj Wiwanitkit

Indian Journal of Cancer 2014 51(4):417-417



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Nimotuzumab as a palliative treatment for liver metastasis: The first world report

K Chaiyasit, V Wiwanitkit

Indian Journal of Cancer 2014 51(4):581-581



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Bloodstream infections in pediatric patients at cancer institute, Chennai

V Radhakrishnan, V Vijaykumar, P Ganesan, R Rajendranath, G Trivadi, S Tenali

Indian Journal of Cancer 2014 51(4):418-419

Background: There is paucity of data on the epidemiology of bloodstream infections in pediatric cancer patients from India. Rationale use of antibiotics in febrile neutropenia is important for reducing morbidity and preventing the emergence of drug resistant bacteria. AIMS: The study was conducted to look at the prevalence of bloodstream bacterial infection and the antibiotic resistance profile at Cancer Institute, Chennai. Settings And Design: This was a retrospective study. Materials and Methods: Data on all blood cultures taken from pediatric cancer patients treated at Cancer Institute, Chennai, during the year 2013 were analyzed. The microbiological profile and sensitivity pattern were analyzed. Results: A total of 1045 blood culture samples were taken, and there were 82/1045 (7.5%) positive blood cultures. Gram-negative organisms accounted for 50/82 (61%) of all positive cultures. Klebsiella pneumoniae (32%) was the most common Gram-negative isolate, and Staphylococcus aureus (93.5%) was the most common Gram-positive. There was high resistance to aminoglycosides and beta-lactam/beta-lactamase inhibitor antibodies. Conclusion: Gram-negative organisms are the predominant bacteria isolated. There is high resistance to first-line combination antibiotics used as empiric therapy for treatment of febrile neutropenia.

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Young breast cancer: A single center experience

A Gogia, V Raina, SVS Deo, NK Shukla, BK Mohanti

Indian Journal of Cancer 2014 51(4):604-608

Background: Breast cancer in women aged less than 35 years is uncommon and accounts for 1-2% of all breast cancer in the West. There is a paucity of data on young breast cancer from India. The aim of this study was to analyze the clinical, pathological, prognostic factors and outcome in young breast cancer patients. Materials And Methods: This analysis was performed in 251 patients aged <35 years or less (defined as breast cancer in the young), who were registered at our institute over an 11 year period between 2001 and 2011. Results: The median age was 31 years (range 18-35). Positive family history (siblings and parents) was elicited in only 10 patients. The TNM stage distribution was: Stage I was 2.5%, stage II - 20.5%, stage III - 55% and stage IV - 22%. The median clinical tumor size was 5.1 cm. Modified radical mastectomy was the most common surgical procedure and this was done in 79% of cases. 40% of tumors were high grade and 60% had pathological node positive disease. Estrogen and Progesterone and human epidermal growth factor receptor 2/neu positivity were 33% and 29% respectively. Triple negative breast cancer constituted 31% of patients. With a median follow-up of 30 months, 3 years relapse free survival and overall survival was 51% and 66%. Conclusion: Young women constituted 8% of breast cancer cases. Advanced disease at presentation and triple negativity (nearly one third of patients) results poor outcome.

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Epidemiology of bacterial isolates among pediatric cancer patients from a tertiary care oncology center in North India

G Kapoor, N Sachdeva, S Jain

Indian Journal of Cancer 2014 51(4):420-424

Background: Infections are a major cause of morbidity and mortality in pediatric oncology. Resistance pattern of bacterial isolates determine empiric antibiotic therapy and influence outcome. AIMS: This study was planned to determine profile of bacterial isolates and their antibiotic resistance pattern among pediatric cancer patients. DESIGN: It was a retrospective, single institutional study. Materials and Methods: The study was carried out in the department of pediatric hematology-oncology of a tertiary care cancer centre in north India over a period of 24 months (2012-2014). Microbiological data pertaining to pediatric cancer patients, less than 18yrs of age was analysed. Results: Hence, 238 bacterial isolates were cultured from among 1757 blood, urine and other specimens. Gram negative bacteria were the most common (74%) pathogens identified and E. coli and Klebsiella comprised 80% of them. A high incidence of extended spectrum beta lactamase producing organisms (84%), beta-lactam beta-lactamase inhibitor (78%) and carbapenem resistance was observed (29%). Blood stream infection with multi-drug resistant Klebsiella was associated with high mortality. The gram positive bacteria isolated were predominantly staphylococcus aureus and were antibiotic sensitive. Reduction in the number of culture positive isolates in the second year of our study was probably due to rigorous implementation of infection control measures. Conclusion: These results on microbiologic profile and antibiotic sensitivity pattern of the isolates will be extremely helpful in revision of antibiotic guidelines for our patients and in developing strategies for coping with high prevalence of multi-drug resistance. Antibiotic stewardship and strict implementation of infection control practices will be important components of this effort.

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Comparison of isolates and antibiotic sensitivity pattern in pediatric and adult cancer patients; is it different?

K Prabhash, J Bajpai, A Gokarn, B Arora, PA Kurkure, A Medhekar, R Kelkar, S Biswas, S Gupta, V Naronha, N Shetty, G Goyel, SD Banavali

Indian Journal of Cancer 2014 51(4):496-501

Background: Infection is a common cause of mortality and morbidity in cancer patients. Organisms are becoming resistant to antibiotics; age appears to be one of the factors responsible. We analyzed common organisms and their antibiotic sensitivity pattern in the correlation with age. Methods: This is a single institutional, retrospective analysis of all culture positive adult and pediatric cancer patients from January 2007 to December 2007. For statistical analysis, Chi-square test for trend was used and P values were obtained. Of 1251 isolates, 262 were from children <12 years of age and 989 were from adolescents and adults (>12 years of age). Gram-negative organisms were predominant (64.95) while Gram-positive constituted 35.09% of isolates. Results: The most common source in all age groups was peripheral-blood, accounting to 47.8% of all samples. The most common organisms in adults were Pseudomonas aeruginosa (15.3%) while in children it was coagulase negative Staphylococcus aureus (19.8%). Antibiotic sensitivity was different in both groups. In pediatric group higher sensitivity was seen for Cefoparazone-sulbactum, Cefipime, Amikacin, and Tobramycin. No resistance was found for Linezolid. Conclusions: The isolates in both children and adults were predominantly Gram-negative though children had proportionately higher Gram-positive organisms. High-dose cytarabine use, cotrimoxazole prophylaxis, and frequent use of central lines in children especially in hematological malignancies could explain this observation. Children harbor less antibiotic resistance than adults; Uncontrolled, cumulative exposure to antibiotics in our community with increasing age, age-related immune factors and variable bacterial flora in different wards might explain the higher antibiotic resistance in adults. Thus age is an important factor to be considered while deciding empirical antibiotic therapy.

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Leptomeningeal metastasis: Clinical experience of 519 cases

Publication date: March 2016
Source:European Journal of Cancer, Volume 56
Author(s): Jae-Won Hyun, In Hye Jeong, AeRan Joung, Hyo Jin Cho, Su-Hyun Kim, Ho Jin Kim
BackgroundDiagnosis of leptomeningeal metastasis (LM) has become increasingly common because of enhanced detection via routine use of magnetic resonance imaging (MRI) and longer survival of patients by better systemic control. We investigated clinical features and analyzed potential prognostic factors in a large cohort of patients with LM.MethodsThe clinical features of LM developing from systemic cancers were analyzed retrospectively in patients at the National Cancer Center during 2005–2014.ResultsA total of 519 patients were enrolled; 497 had solid, 19 had hematopoietic tumors and 3 had tumors of unknown etiology. Among the solid tumors, the most common primary tumor was lung cancer (334 patients), followed by breast cancer (96) and gastrointestinal cancer (39). Median age at onset was 56 years, and the median Karnofsky performance status (KPS) was 60. Thirty-five percent of patients were diagnosed by MRI alone, 22% by cerebrospinal fluid (CSF) cytology alone, and 42% by both. Treatment included chemotherapy alone in 45%, radiation therapy alone in 10%, and both in 17%; 28% received supportive care alone. Median overall survival was 3 months. KPS ≥70, CSF protein level ≤50 mg/dl at the diagnosis of LM, and active treatment were associated independently with longer overall survival. Upon subgroup analysis of lung cancer patients, non-small cell lung cancer was a favorable prognostic factor for overall survival.ConclusionsDespite improved diagnosis via MRI and vigorous therapy, most patients with LM had poor outcomes. However, patients with a high KPS or normal CSF protein levels had favorable prognoses upon active treatment.



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Macrocytosis as a potential parameter associated with survival after tyrosine kinase inhibitor treatment

Publication date: March 2016
Source:European Journal of Cancer, Volume 56
Author(s): Jacqueline S.L. Kloth, Paul Hamberg, Pauline A.J. Mendelaar, Roderick R. Dulfer, Bronno van der Holt, Karel Eechoute, Erik A.C. Wiemer, Wim H.J. Kruit, Stefan Sleijfer, Ron H.J. Mathijssen
Aim of the studyAs a rise in mean corpuscular volume (MCV) of the erythrocyte is frequently seen during treatment with imatinib and sunitinib, we investigated whether macrocytosis (MCV > 100 fl) also occurs as a class effect in other tyrosine kinase inhibitors (TKIs) and whether occurrence of macrocytosis is associated with outcome.Materials and methodsIn 533 patients, using 5 TKIs, we investigated if macrocytosis and an increase in MCV were associated with progression-free survival and overall survival (OS) in specific tumour-treatment combinations.ResultsMacrocytosis as well as an increase in MCV from baseline of >10 fl (ΔMCV +10 fl), when included as a time-dependent covariate, were associated with improved OS in patients with renal cell cancer (RCC) treated with sunitinib (macrocytosis, hazard ratio [HR] = 0.61, p = 0.031, and ΔMCV +10 fl, HR = 0.58, p = 0.016).ConclusionIn sunitinib-treated patients with RCC, the occurrence of macrocytosis, or a substantial increase in MCV levels after start of treatment, could potentially serve as a positive prognostic factor for survival, if validated prospectively.



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Issue Information

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Management of localized and advanced prostate cancer in Canada: A lifetime cost and quality-adjusted life-year analysis

BACKGROUND

To the authors' knowledge, the literature to date lacks studies examining lifetime costs and quality-adjusted life-years (QALYs) of prostate cancer (PCa) management strategies that integrate localized and advanced disease. The objective of the current study was to assess lifetime costs and QALYs associated with contemporary PCa management strategies across risk groups by integrating localized and advanced disease.

METHODS

The authors' validated Markov chain Monte Carlo model was used to predict lifetime direct costs and QALYs. The health states modeled were active surveillance, initial treatments (radical prostatectomy or radiotherapy), PCa recurrence, PCa recurrence free, metastatic castration-resistant prostate cancer, and death (cause specific/other causes). Data regarding treatment distribution, state transition probabilities, adverse effects of management options, costs, utilities, and disutilities were derived from the published literature.

RESULTS

The total cost per patient for the overall cohort increased from $18,503 at 5 years to $28,032 and $39,143, respectively, at 10 years and 15 years. Furthermore, the results indicated the influence of risk group on total cost, with the high-risk group accruing the maximum per patient cost followed by the intermediate-risk and low-risk groups. Active surveillance was found to confer the most QALYs (12.5 years) and was the least costly strategy ($18,452) for individuals at low risk. For all risk groups, radical prostatectomy was less costly and conferred modestly more QALYs compared with intensity-modulated radiotherapy modalities.

CONCLUSIONS

Public health care systems in Canada and elsewhere are operating under budget constraints to allocate finite resources. The findings of the current study might inform discussions concerning budget planning to provide health care services. Cancer 2016. © 2016 American Cancer Society.

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Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non–small cell lung cancer (West Japan Oncology Group 5910L): An open-label, randomized, phase 2 trial

BACKGROUND

Bevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non–small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients.

METHODS

West Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS).

RESULTS

One hundred patients were randomly assigned to receive docetaxel (n = 50) or docetaxel plus bevacizumab (n = 50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P < .2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P = .11). No unexpected or severe adverse events were recorded.

CONCLUSIONS

Further evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet. Cancer 2016. © 2016 American Cancer Society.

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A systematic review of the cost and cost-effectiveness studies of proton radiotherapy

BACKGROUND

Economic analyses of new technologies, such as proton-beam radiotherapy (PBT), are a public health priority. To date, no systematic review of the cost-effectiveness of PBT has been performed.

METHODS

Systematic searches of PubMed, EMBASE, abstracts from American Society for Radiation Oncology and American Society of Clinical Oncology meetings, and the Cost-Effectiveness Analysis Registry were conducted (2000-2015) along with abstracts from the Particle Therapy Co-Operative Group of North America for both years of existence (2014-2015). Eighteen original investigations were analyzed.

RESULTS

The cost-effectiveness for prostate cancer—the single most common diagnosis currently treated with PBT—was suboptimal. PBT was the most cost-effective option for several pediatric brain tumors. PBT costs for breast cancer were increased but were favorable for appropriately selected patients with left-sided cancers at high risk of cardiac toxicity and compared with brachytherapy for accelerated partial breast irradiation. For non-small cell lung cancer (NSCLC), the greatest cost-effectiveness benefits using PBT were observed for locoregionally advanced—but not early stage—tumors. PBT offered superior cost-effectiveness in selected head/neck cancer patients at higher risk of acute mucosal toxicities. Similar cost-effectiveness was observed for PBT, enucleation, and plaque brachytherapy in patients with uveal melanoma.

CONCLUSIONS

With greatly limited amounts of data, PBT offers promising cost-effectiveness for pediatric brain tumors, well-selected breast cancers, locoregionally advanced NSCLC, and high-risk head/neck cancers. Heretofore, it has not been demonstrated that PBT is cost-effective for prostate cancer or early stage NSCLC. Careful patient selection is absolutely critical to assess cost-effectiveness. Together with increasing PBT availability, clinical trial evidence, and ongoing major technological improvements, cost-effectiveness data and conclusions from this analysis could change rapidly. Cancer 2016. © 2016 American Cancer Society.

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Bevacizumab beyond disease progression for advanced non–small cell lung cancer: Does persistence have its rewards?

Persistence pays off when it comes to the vascular endothelial growth factor inhibitor bevacizumab in non–small cell lung cancer patients who have progressed on first-line chemotherapy. Continued vascular endothelial growth factor blockade after progression on first-line therapy may provide at least a modest benefit when it is continued with second-line chemotherapy. See also pages 000–000

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Peripheral Primitive Neuroectodermal Tumor and Neurofibromatosis Type 1 in an Adolescent Male

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Erratum

Future Oncology Ahead of Print.


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Erratum

Future Oncology Ahead of Print.


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Inflammation in gastric cancer: Interplay of the COX-2/PGE2 and TLR/MyD88 pathways

Abstract

Cyclooxygenase 2 (COX-2) and its downstream product prostaglandin E₂ (PGE₂) play a key role in generation of inflammatory microenvironment in tumor tissues. Gastric cancer is closely associated with Helicobacter pylori infection, which stimulates innate immune responses through Toll-like receptors (TLRs), inducing COX-2/PGE₂ pathway through NF-κB activation. A pathway analysis of human gastric cancer shows that both COX-2 pathway and Wnt/β-catenin signaling are significantly activated in tubular-type gastric cancer, while basal levels of these pathways are also increased in other types of gastric cancer. Expression of IL-11, CXCL1, CXCL2 and CXCL5, which play tumor-promoting roles through a variety of mechanisms, is induced in a COX-2/PGE₂ pathway-dependent manner in both human and mouse gastric tumors. Moreover, the COX-2/PGE₂ pathway plays an important role in the maintenance of stemness with expression of stem cell markers, including CD44, Prom1, Cxcr4, and Noxo1, which are induced in both gastritis and gastric tumors via a COX-2/PGE₂-dependent mechanism. In contrast, disruption of Myd88 results in suppression of inflammatory microenvironment in gastric tumors even when the COX-2/PGE₂ pathway is activated, indicating that the interplay of the COX-2/PGE₂ and TLR/MyD88 pathways is needed for inflammatory response in tumor tissues. Furthermore, TLR2/MyD88 signaling plays a role in maintenance of stemness in normal stem cells as well as gastric tumor cells. Accordingly, these results suggest that targeting the COX-2/PGE₂ pathway together with TLR/MyD88 signaling, which would suppress the inflammatory microenvironment and maintain stemness, could be an effective preventive or therapeutic strategy for gastric cancer.

This article is protected by copyright. All rights reserved.

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Burden of cancer associated with type 2 diabetes mellitus in Japan, 2010-2030

Summary

Diabetes mellitus constitutes a major disease burden globally, and the prevalence of diabetes continues to increase worldwide. We aimed to estimate the burden of cancer associated with type 2 diabetes mellitus in Japan between 2010 and 2030. In this study, we estimated the Population Attributable Fraction of cancer risk associated with type 2 diabetes in 2010 and 2030 using the prevalence estimates of type 2 diabetes in Japan from 1990 to 2030, summary hazard ratios of diabetes and cancer risk from a pooled analysis of eight large-scale Japanese cohort studies, observed incidence/mortality of cancer in 2010 and predicted incidence/mortality for 2030 derived from the age-period-cohort model. Our results showed that between 2010 and 2030, the total number of cancer incidence and mortality were predicted to increase by 38.9% and 10.5% in adults aged above 20 years, respectively. In the number of excess incident cancer cases associated with type 2 diabetes, an increase of 26.5% in men and 53.2% in women is expected between 2010 and 2030. The age-specific analysis showed that the population attributable fraction of cancer will increase in adults aged >60 years over time, but will not change in adults aged 20-59 years. In conclusion, this study suggests a modest but steady increase in cancers associated with type 2 diabetes.

This article is protected by copyright. All rights reserved.

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Pan-HER Augments Radiation Response

Purpose: Aberrant regulation of the EGF receptor family (EGFR, HER2, HER3, HER4) contributes to tumorigenesis and metastasis in epithelial cancers. Pan-HER represents a novel molecular targeted therapeutic composed of a mixture of six monoclonal antibodies against EGFR, HER2, and HER3.

Experimental Design: In the current study, we examine the capacity of Pan-HER to augment radiation response across a series of human lung and head and neck cancers, including EGFR inhibitor–resistant cell lines and xenografts.

Results: Pan-HER demonstrates superior antiproliferative and radiosensitizing impact when compared with cetuximab. The mechanisms underlying these effects appear to involve attenuation of DNA damage repair, enhancement of programmed cell death, cell-cycle redistribution, and induction of cellular senescence. Combined treatment of Pan-HER with single or fractionated radiation in human tumor xenografts reveals a potent antitumor and regrowth delay impact compared with Pan-HER or radiation treatment alone.

Conclusions: These data highlight the capacity of Pan-HER to augment radiation response in lung and head and neck cancer models and support investigation of Pan-HER combined with radiation as a promising clinical therapeutic strategy. Clin Cancer Res; 22(3); 633–43. ©2015 AACR.

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MYBL1-NFIB Fusions in Adenoid Cystic Carcinoma

Purpose: Adenoid cystic carcinoma (ACC) is an indolent salivary gland malignancy, characterized by t(6;9) translocations and MYB–NFIB gene fusions in approximately 50% of the tumors. The genetic alterations underlying t(6;9)-negative and t(6;9)-positive/MYB–NFIB fusion–negative ACC remain unknown. To uncover the genetic alterations in ACC lacking the canonical translocation and fusion transcript and identify new abnormalities in translocation positive tumors.

Experimental Design: We performed whole-genome sequencing in 21 salivary ACCs and conducted targeted molecular analyses in a validation set (81 patients). Microarray gene-expression data were also analyzed to explore the biologic differences between fusion positive and negative tumors.

Results: We identified a novel MYBL1–NFIB gene fusion as a result of t(8;9) translocation and multiple rearrangements in the MYBL1 gene in 35% of the t(6;9)-negative ACCs. All MYBL1 alterations involved deletion of the C-terminal negative regulatory domain and were associated with high MYBL1 expression. Reciprocal MYB and MYBL1 expression was consistently found in ACCs. In addition, 5'-NFIB fusions that did not involve MYB/MYBL1 genes were identified in a subset of t(6;9)-positive/fusion-negative tumors. We also delineated distinct gene-expression profiles in ACCs associated with the length of the MYB or MYBL1 fusions, suggesting a biologic importance of the C-terminal part of these fusions.

Conclusions: Our study defines new molecular subclasses of ACC characterized by MYBL1 rearrangements and 5'-NFIB gene fusions. Clin Cancer Res; 22(3); 725–33. ©2015 AACR.

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Measuring Toxicity in Phase I Clinical Trials

The standard categorical system for assessing attribution of toxicity to study drug(s) in phase I trials is cumbersome and uninformative. Although a binary system ("related" vs. "unrelated") would be sufficient to define maximum tolerated dose (MTD), a probability estimation would better support dose selection for randomized dose-ranging phase II trials. Clin Cancer Res; 22(3); 527–9. ©2015 AACR.

See related article by Eaton et al., p. 553

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NKTR-214, an Engineered Cytokine for Cancer Immunotherapy

Purpose: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates.

Experimental Design: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti–CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates.

Results: In a murine melanoma tumor model, the ratio of tumor-killing CD8⁺ T cells to Foxp3⁺ regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti–CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates.

Conclusions: These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies. Clin Cancer Res; 22(3); 680–90. ©2016 AACR.

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Local Tumor Immunity and Cancer Vaccine

Cancer vaccine boost via the cervicovaginal rather than the intramuscular route of immunization appears to be crucial to induce genital CD8⁺ T cells and tumor regression. This clinical activity is correlated with the ability of the mucosal boost to elicit resident memory T cells in the genital tract. Clin Cancer Res; 22(3); 530–2. ©2015 AACR.

See related article by Sun et al., p. 657

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