Management and Outcomes of Patients with Recurrent Intrahepatic Cholangiocarcinoma Following Previous Curative-Intent Surgical Resection

Abstract

Background

Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma (ICC) following curative-intent surgery are not well documented. We sought to characterize the treatment of patients with recurrent ICC and define therapy-specific outcomes.

Methods

Patients who underwent surgery for ICC from 1990 to 2013 were identified from an international database. Data on clinicopathological characteristics, operative details, recurrence, and recurrence-related management were recorded and analyzed.

Results

A total of 563 patients undergoing curative-intent hepatic resection for ICC who met the inclusion criteria were identified. With a median follow-up of 19 months, 400 (71.0 %) patients developed a recurrence. At initial surgery, treatment was resection only (98.8 %) or resection + ablation (1.2 %). Overall 5-year survival was 23.6 %; 400 (71.0 %) patients recurred with a median disease-free survival of 11.2 months. First recurrence site was intrahepatic only (59.8 %), extrahepatic only (14.5 %), or intra- and extrahepatic (25.7 %). Overall, 210 (52.5 %) patients received best supportive care (BSC), whereas 190 (47.5 %) patients received treatment, such as systemic chemotherapy-only (24.2 %) or repeat liver-directed therapy ± systemic chemotherapy (75.8 %). Repeat liver-directed therapy consisted of repeat hepatic resection ± ablation (28.5 %), ablation alone (18.7 %), and intra-arterial therapy (IAT) (52.8 %). Among patients who recurred, median survival from the time of the recurrence was 11.1 months (BSC 8.0 months, systemic chemotherapy-only 16.8 months, liver-directed therapy 18.0 months). The median survival of patients undergoing resection of recurrent ICC was 26.7 months versus 9.6 months for patients who had IAT (p < 0.001).

Conclusions

Recurrence following resection of ICC was common, occurring in up to two-thirds of patients. When there is recurrence, prognosis is poor. Only 9 % of patients underwent repeat liver resection after recurrence, which offered a modest survival benefit.

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Skin Flap Necrosis After Mastectomy With Reconstruction: A Prospective Study

Abstract

Background

Rates of mastectomy with immediate reconstruction are rising. Skin flap necrosis after this procedure is a recognized complication that can have an impact on cosmetic outcomes and patient satisfaction, and in worst cases can potentially delay adjuvant therapies. Many retrospective studies of this complication have identified variable event rates and inconsistent associated factors.

Methods

A prospective study was designed to capture the rate of skin flap necrosis as well as pre-, intra-, and postoperative variables, with follow-up assessment to 8 weeks postoperatively. Uni- and multivariate analyses were performed for factors associated with skin flap necrosis.

Results

Of 606 consecutive procedures, 85 (14 %) had some level of skin flap necrosis: 46 mild (8 %), 6 moderate (1 %), 31 severe (5 %), and 2 uncategorized (0.3 %). Univariate analysis for any necrosis showed smoking, history of breast augmentation, nipple-sparing mastectomy, and time from incision to specimen removal to be significant. In multivariate models, nipple-sparing, time from incision to specimen removal, sharp dissection, and previous breast reduction were significant for any necrosis. Univariate analysis of only moderate or severe necrosis showed body mass index, diabetes, nipple-sparing mastectomy, specimen size, and expander size to be significant. Multivariate analysis showed nipple-sparing mastectomy and specimen size to be significant. Nipple-sparing mastectomy was associated with higher rates of necrosis at every level of severity.

Conclusions

Rates of skin flap necrosis are likely higher than reported in retrospective series. Modifiable technical variables have limited the impact on rates of necrosis. Patients with multiple risk factors should be counseled about the risks, especially if they are contemplating nipple-sparing mastectomy.

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A Phase I Dose-Escalation Trial of Single-Fraction Stereotactic Radiation Therapy for Liver Metastases

Abstract

Background

There is significant interest in the use of stereotactic ablative radiotherapy (SABR) as a treatment modality for liver metastases. A variety of SABR fractionation schemes are in clinical use. We conducted a phase I dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR.

Methods

Patients with liver metastases from solid tumors, for whom a critical volume dose constraint could be met, were treated with single-fraction SABR. Seven patients were enrolled to the first group, with a prescription dose of 35 Gy. Dose was then escalated to 40 Gy in a single fraction, and seven more patients were treated at this dose level. Patients were followed for toxicity and underwent serial imaging to assess lesion response and local control.

Results

Fourteen patients with 17 liver metastases were treated. There were no dose-limiting toxicities observed at either dose level. Nine of the 13 lesions assessable for treatment response showed a complete radiographic response to treatment; the remainder showed partial response. Local control of irradiated lesions was 100 % at a median imaging follow-up of 2.5 years. Two-year overall survival for all patients was 78 %.

Conclusions

For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy is tolerable and shows promising signs of efficacy at intermediate follow-up.

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Expanding the Indications for Total Skin-Sparing Mastectomy: Is It Safe for Patients with Locally Advanced Disease?

Abstract

Background

Indications for total skin-sparing mastectomy (TSSM) continue to expand. Although initially used only for early-stage breast cancer, TSSM currently is offered in many centers to patients with locally advanced disease. However, despite this practice change, limited data on oncologic outcomes in this population have been reported.

Methods

A retrospective review of a prospectively collected database of all patients undergoing TSSM and immediate reconstruction from 2005 to 2013 was performed. The outcomes for patients with stage 2b and stage 3 cancer were included in the analysis. The primary outcomes included the development of locoregional or distant recurrences.

Results

Of 753 patients undergoing TSSM, 139 (18 %) presented with locally advanced disease. Of these 139 patients, 25 (18 %) had stage 2b disease, and 114 (82 %) had stage 3 disease. Most of the patients (97 %) received chemotherapy (77 % neoadjuvant, 20 % adjuvant), whereas 3 % received adjuvant hormonal therapy alone. Of the neoadjuvant patients, 13 (12 %) had a pathologic complete response (pCR) to treatment. During a mean follow-up period of 41 months (range 4–111 months), seven patients (5 %) had a local recurrence, 21 patients (15.1 %) had a distant recurrence, and three patients (2.2 %) had simultaneous local and distant recurrences. None of the local recurrences occurred in the preserved nipple–areolar complex skin.

Conclusions

Patients with locally advanced breast cancer are most at risk for distant rather than local recurrence, even after TSSM. When used in conjunction with appropriate multimodal therapy, TSSM is not associated with an increased risk for local recurrence in this population, even in the setting of low pCR rates.

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Early Postoperative Outcomes in Breast Conservation Surgery Versus Simple Mastectomy with Implant Reconstruction: A NSQIP Analysis of 11,645 Patients

Abstract

Background

Little has been studied that compares early postoperative outcomes between breast conservation surgery (BCS) and simple mastectomy with implant reconstruction (SM). Our goal was to utilize a large-volume database to compare such outcomes in women with early stage breast cancer.

Methods

The National Surgery Quality Improvement Program (NSQIP) database was searched for patients who underwent partial or complete mastectomy between 2009 and 2012. Exclusion criteria eliminated potential confounding factors. We compared preoperative comorbidities and postoperative complication rates between each treatment group by Chi square and two-sample t tests; we also determined the odds ratios for the likelihood of adverse events in a number of categories.

Results

A total of 11,645 patients met the study criteria: 9571 underwent BCS and 2074 underwent SM with implant reconstruction. The baseline characteristics of the two groups showed significant differences for age (61.7 years in BCS, 53.5 years in SM), body mass index (29.6 kg/m² in BCS, 27.0 kg/m² in SM), and rates of hypertension (47.0 % in BCS, 25.6 % in SM), coronary artery disease (1.3 % in BCS, 0.6 % in SM), chronic obstructive pulmonary disease (2.4 % in BCS, 1.0 % in SM), and diabetes (11.7 % in BCS, 5.9 % in SM). Statistical analysis between each treatment modality revealed that the SM with implant group had significantly higher total complication (5.5 vs. 2.1 % in BCS), wound (2.8 vs. 1.4 % in BCS), infection (1.9 vs. 0.4 % in BCS), and bleeding (0.2 vs. 0.05 % in BCS) rates than the BCS group.

Conclusions

BCS has fewer overall early postoperative wound, infectious, and bleeding complications despite a significantly higher rate of preexisting risk factors.

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Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes in Patients with Breast Cancer: Implications for Axillary Metastases and Conservation

Abstract

Background

In breast cancer patients, sentinel lymph nodes (SLN) can be identified in the breast clinic using contrast-enhanced ultrasound (CEUS). This study aimed to characterize and compare the extent of axillary metastases in patients with either a benign or malignant SLN core biopsy at the end of surgical treatment.

Methods

Between 2009 and 2014, prospective data were collected on consecutive patients who underwent targeted core biopsy of SLN identified using CEUS in the breast clinic. Patients with abnormal lymph nodes (LN) detected on grey-scale ultrasound were not included. Patients whose initial SLN core biopsy was benign were compared with those who had a malignant SLN core biopsy.

Results

555 patients with invasive breast cancer had SLN successfully identified and core biopsied. 487 had a benign SLN core biopsy and 427 (88 %) did not have metastases found in surgically excised SLN. Only 2 % of patients with an initial benign SLN core biopsy were found to have 2 or more LN macrometastases. 68 patients had a malignant SLN core biopsy and 52 % had 2 or more LN macrometastases. The total volume of LN metastases was higher in the group of patients who had an initial malignant SLN core biopsy (P < 0.001).

Conclusions

Patients with a normal grey-scale ultrasound and benign SLN core biopsy are unlikely to have extensive axillary disease and may be ideally suited for axillary conservation. The decision to omit axillary LN dissection for patients with a malignant SLN core biopsy must be carefully considered because many will have undetected high-volume metastases.

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The Prognostic Significance of the Early Postoperative Neutrophil-to-Lymphocyte Ratio in Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy

Abstract

Purpose

Because the pretreatment neutrophil-to-lymphocyte ratio (NLR) is a reliable prognostic factor, the authors of this study hypothesized that posttreatment NLR also predicts the survival outcome for cancer patients. The study investigated the clinicopathologic features according to postoperative NLR and determined the prognostic significance of early postoperative NLR for bladder cancer patients undergoing radical cystectomy (RC).

Methods

The study reviewed 385 bladder cancer patients treated with RC and pelvic lymph node dissection at the authors' institution between 1999 and 2012. The primary end points of the study were cancer-specific survival (CSS) and overall survival (OS) estimates from the Kaplan–Meier analysis. Multivariate Cox regression analysis was adopted to identify the independent prognostic factors for oncologic outcomes after surgery.

Results

Patients with elevated postoperative NLR (≥2.0) had higher rates of advanced pathologic tumor stage (≥pT3), lymphovascular invasion, and lymph node involvement. Notably, they showed poorer CSS and OS rates than patients with a postoperative NLR lower than 2.0. Additionally, patients with pre- and postoperative elevated NLR (≥2.1 → ≥2.0) demonstrated worse oncologic outcomes than other groups of NLR changes. Multivariate analysis showed that early postoperative NLR remained a key predictor for CSS and OS. When divided by pathologic T or N stage, patients with localized pathologic T stage or pN0 status showed significant differences in survival according to early postoperative NLR.

Conclusion

In summary, postoperative NLR in the early recovery period can be a valuable biomarker for predicting oncologic outcomes for bladder cancer patients undergoing RC.

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Metastatic Potential of Grade I Chondrosarcoma of Bone: Results of a Multi-institutional Study

Abstract

Background

Little is known about the metastatic potential of low-grade chondrosarcoma. This study was designed to evaluate the rate of metastasis to identify possible risk factors.

Methods

The files of 225 patients with newly diagnosed, grade I chondrosarcoma of bone treated between 1975 and 2012 were retrospectively analyzed. Median follow-up was 80 months for survivors (range 24–445 months). Nonparametric analyses were performed with the Mann–Whitney U test. Survival curves were calculated with the Kaplan–Meier method and compared with the log-rank test.

Results

Fourteen patients developed metastases after a median of 49 months. Metastasis-free survival probability (MFS) was 95 % at 5 years and 92 % at 10 years. Post-metastasis survival probability amounted to 27 % after 5 years. Tumor size at diagnosis (P = 0.698) and surgical margin width (P = 0.514) had no influence on MFS. Patients who developed local recurrences had a significantly lower 10-year MFS than patients without recurrences (69 % vs. 99 %, P < 0.001). Patients with grade I recurrences had a significantly poorer MFS than patients without recurrences (P = 0.013) but a significantly higher MFS than patients with grade II recurrences (P = 0.006). Patients with thoracic wall tumors had a significantly lower 10-year MFS of 66 % compared with patients with tumors of the upper (100 %, P < 0.001) and lower extremity (93 %, P = 0.033).

Conclusions

The biological behavior of low-grade chondrosarcoma appears to be more consistent with the WHO definition of rarely metastasizing bone tumors, rather than the one of locally aggressive neoplasms. Thoracic wall tumors and the development of local recurrences were associated with a higher metastasis rate in this study.

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Postoperative Lower Extremity Edema in Patients with Primary Endometrial Cancer

Abstract

Purpose

The goal of this study was to investigate clinical manifestations of lower extremity edema (LEE) after lymph node dissection in patients with primary endometrial cancer.

Methods

Women with primary endometrial cancer who underwent staging surgery between November 2001 and March 2011 were included in the study. Medical records and/or responses to the Gynecologic Cancer Lymphedema Questionnaire (GCLQ) were used for LEE evaluation.

Results

All 154 patients underwent pelvic lymph node dissection, and 126 patients (81.8 %) underwent paraaortic LN dissection. The median age of the patients was 52 years, the majority had stage I cancer (78.6 %), and most had endometrioid histology (90.9 %). The most frequent GCLQ responses were "experienced swelling" (35.7 %), "experienced numbness" (30.5 %), "experienced heaviness" (29.9 %), and "experienced aching" (29.9 %). Sixty-four patients (41.6 %) had previous (9/64, 14.1 %) and/or current (55/64, 85.9 %) patient-reported LEE. Most patients developed LEE within 12 months after surgery (39/56, 69.6 %), and LEE lasted for more than 12 months in most patients (45/56, 80.4 %). Three patients reported recurrent LEE after recovery. Multivariate logistic regression identified the number of dissected pelvic lymph node (≥21) as a risk factor for LEE [odds ratio (OR) 3.28; 95 % confidence interval (CI) 1.058–10.136] and postoperative radiotherapy (OR 3.81, 95 % CI 1.67–8.69).

Conclusions

LEE developed in more than one-third of patients with endometrial cancer after surgery, and LEE lasted for more than 12 months in most patients. A high number of dissected pelvic lymph nodes and postoperative radiotherapy is associated with LEE.

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Meta-analysis of Liver Resection Versus Nonsurgical Treatments for Pancreatic Neuroendocrine Tumors with Liver Metastases

Abstract

Purpose

Studies have reported limited evidence of the benefits and harms of various regimens, such as liver resection and medical therapy, for the treatment of pancreatic neuroendocrine tumors (pNETs) with liver metastases. This meta-analysis aimed to evaluate the efficacy of liver resection versus nonsurgical treatments in patients with pNET.

Methods

Relevant studies published in English were retrieved from the computerized databases Medline, Embase, and Cochrane. A meta-analysis was performed to investigate the differences in the efficacy of liver resection and nonsurgical treatments based on the evaluation of 30-day mortality, symptom relief rate, median survival time, and 2-, 3-, or 5-year survival using a random-effects model. Studies were independently reviewed by two investigators. Data from eligible studies were extracted, and the meta-analysis was performed using the comprehensive meta-analysis program version 2.

Results

A total of seven studies were included in the analysis. The results demonstrated that liver resection was significantly associated with a higher rate of symptom relief, longer median survival time, higher 2- or 3-year survival rates, as well as a higher 5-year survival rate. There was no significant difference in 30-day mortality among patients with pNETs who were treated by liver resection and nonsurgical therapy or survival between functional and nonfunctional pNETs. No publication bias was detected.

Conclusions

Liver resection has a favorable prognostic outcome in terms of higher postoperative symptom relief rates and longer survival rates. Further randomized, controlled trials with longer follow-up periods are required to confirm the advantages of liver resection for pNETs.

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Intramuscular Transplantation Improves Engraftment Rates for Esophageal Patient-Derived Tumor Xenografts

Abstract

Background

Recently, there has been an increase in the availability of targeted molecular therapies for cancer treatment. The application of these approaches to esophageal cancer, however, has been hampered by the relative lack of appropriate models for preclinical testing. Patient-derived tumor xenograft (PDTX) models are gaining popularity for studying many cancers. Unfortunately, it has proven difficult to generate xenografts from esophageal cancer using these models. The purpose of this study was to improve the engraftment efficiency of esophageal PDTXs.

Methods

Fresh pieces of esophageal tumors obtained from endoscopic biopsies or resected specimens were collected from 23 patients. The tumors were then coated in Matrigel and transplanted in immunocompromised mice subcutaneously (n = 6) and/or using a novel implantation technique whereby the tumor is placed in a dorsal intramuscular pocket (n = 18). They are then monitored for engraftment.

Results

With the novel intramuscular technique, successful engraftment was achieved for all 18 patient tumors. Among these PDTXs, 13 recapitulated the original patient tumors with respect to degree of differentiation, molecular and genetic profiles, and chemotherapeutic response. Lymphomatous transformation was observed in the other five PDTXs. Successful engraftment was achieved for only one of six patient tumors using the classic subcutaneous approach.

Discussion

We achieved a much higher engraftment rate of PDTXs using our novel intramuscular transplant technique than has been reported in other published studies. It is hoped that this advancement will help expedite the development and testing of new therapies for esophageal cancer.

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Aldehyde Dehydrogenase 1 Expression Predicts Chemoresistance and Poor Clinical Outcomes in Patients with Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemotherapy Prior to Radical Hysterectomy

Abstract

Background

Neoadjuvant chemotherapy (NAC) is an important treatment strategy for cervical cancer; however, few predictive markers of the response to NAC exist. Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, is associated with chemoresistance in a variety of cancers. This study attempted to investigate the value of ALDH1 as a predictive marker of chemosensitivity and its prognostic value in cervical cancer patients treated with NAC.

Methods

Immunohistochemistry was used to evaluate ALDH1 expression in matched pre- and post-NAC tumor samples from 52 patients with cervical cancer. Kaplan–Meier analysis and a Cox proportional hazards regression model were applied to determine overall survival (OS) and disease-free survival (DFS).

Results

Fourteen patients (26.9 %) had ALDH1-positive tumors pre-NAC, and ALDH1 expression pre-NAC was significantly associated with a low clinical chemotherapy response rate and clinical non-response. Twenty-two patients (42.3 %) had ALDH1-positive tumors post-NAC, and ALDH1 expression post-NAC was associated with poor DFS and OS (both p = 0.004). Multivariate analysis revealed that ALDH1 expression post-NAC was an independent prognostic factor for OS (hazard ratio 3.513; p = 0.033). Moreover, we observed that ALDH1 expression was increased after NAC in 18 patients (36.7 %). Increased levels of ALDH1 expression after NAC predicted poor DFS and OS (p = 0.013 and p = 0.08, respectively).

Conclusions

Our findings suggest that ALDH1 expression pre-NAC may be a predictive marker for response to NAC, and ALDH1 expression post-NAC could be a prognostic marker for cervical cancer.

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Intraoperative Ultrasound-Guided Lumpectomy Versus Mammographic Wire Localization for Breast Cancer Patients After Neoadjuvant Treatment

Abstract

Background

Intraoperative ultrasound (IOUS)-guided lumpectomy in early breast cancer has shown advantages over other techniques. However, the use of IOUS has been less explored after neoadjuvant treatment (NAT). This study aimed to compare IOUS- and wire localization (WL)-guided surgery in breast cancer patients after NAT.

Methods

The study enrolled patients treated with NAT who underwent breast-conserving surgery (BCS) between July 2008 and December 2012. For the patients with a hydrogel marker or residual tumor visible on ultrasound, an IOUS-guided surgery was performed (IOUS group). The patients with a standard marker or hydrogel marker not visible on ultrasound underwent a WL-guided surgery (WL group).

Results

The study investigated 214 patients: 145 (67.8 %) in the IOUS group and 69 (32.2 %) in the WL group. The patient and tumor characteristics were comparable between the two groups. For the patients who had a pathologic complete response (pCR) or microscopic disease, the volume excised was lower in the IOUS group (p = 0.03). The rate of reexcision for positive or close margins was similar in the two groups (p = 0.80). After a median follow-up period of 43 months, the local recurrence rates did not differ significantly between the two groups.

Conclusions

Compared with WL surgery, IOUS seems to lower the volume of resection in patients with pCR or minimal microscopic disease after NAT without compromising margins and local recurrences. BCS can easily be achieved with IOUS for patients with a good response after NAT.

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Indocyanine Green Fluorescence for Sentinel Lymph Node Detection in Early Breast Cancer

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A Cost Analysis of Preoperative Breast MRI Use for Patients with Invasive Lobular Cancer

Abstract

Background

Whereas the impact of magnetic resonance imaging (MRI) of the breast on the surgical management of breast cancer patients is well documented, less is known about its effect on health care costs. This study aimed to evaluate whether MRI use for women with invasive lobular carcinoma (ILC) significantly changes the cost of care.

Methods

Patients with ILC were recruited to a prospective registry study of breast MRI. Women who met the same inclusion criteria but had not undergone breast MRI were retrospectively identified for comparison. A micro-costing analysis using institutional billing records was conducted. Nonparametric bootstrapping was used to compare the unadjusted cost differences between the patients receiving MRI and those receiving no MRI.

Results

Of the patients in this study, 51 had preoperative MRI, and 60 did not. Method of diagnostic biopsy, disease stage, oncologic procedure, and rates of contralateral prophylactic mastectomy were similar between the two groups. The patients in the MRI group were younger (median age 55 vs. 64 years; p = 0.01) and more likely to undergo reconstruction (45.1 vs. 25 %; p = 0.03). The median costs of care were significantly higher in the MRI group ($24,781 vs. $18,921; p < 0.01). After adjustment for clinical factors, MRI remained significantly associated with increased cost (p = 0.03). Other factors associated with increased cost included type of oncologic procedure (mastectomy vs. lumpectomy; p < 0.01), number of operations required to achieve negative margins (1 vs. >1; p < 0.01), and use of reconstruction (p < 0.01).

Conclusion

Preoperative breast MRI increases the median total cost of care per patient. However, the contribution to the overall cost of care is modest compared with the cost of other interventions.

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A Zbtb7a proto-oncogene as a novel target for miR-125a

In our previous study, we showed that miR-125a directly targeted a WT1 oncogene, which was overexpressed in leukemia and various kinds of solid tumors including lung, breast, gastric, and colon cancers, and brain tumors and was deeply involved in leukemogenesis and tumorigenesis and that miR-125a knockout mice overexpressed WT1 and developed myeloproliferative disease. It had been also reported that miR-125a is downregulated in leukemia and various types of solid tumors such as lung cancers, suggesting its tumor suppressor function. Therefore, it is important to elucidate what is target(s) of miR-125a for understandings of such functions although few target genes for it are known. In the present study, Zbtb7a oncogene was identified as a potential target for miR-125a by gene expression profiling in miR-125a knockout mice combined with bioinformatics target prediction. EGFP-3′UTR reporter assay showed that miR-125a suppressed Zbtb7a expression through its direct binding to the Zbtb7a-3′UTR. Zbtb7a knockdown by siRNA suppressed cell proliferation and induced G1 cell cycle arrest and apoptosis in lung cancer cells. Furthermore, miR-125a expression showed a negative correlation with Zbtb7a expression in non-small cell lung cancer tissues. The present study showed for the first time that Zbtb7a was a direct target for miR-125a and was involved in cell cycle progression and apoptosis of lung cancer cells. These results also demonstrated that deregulation of miR-125a-Zbtb7a signaling was associated with the development and progression of lung cancer. © 2015 Wiley Periodicals, Inc.

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A dose-volume histogram based decision-support system for dosimetric comparison of radiotherapy treatment plans

Abstract

Background

The choice of any radiotherapy treatment plan is usually made after the evaluation of a few preliminary isodose distributions obtained from different beam configurations. Despite considerable advances in planning techniques, such final decision remains a challenging task that would greatly benefit from efficient and reliable assessment tools.

Methods

For any dosimetric plan considered, data on dose-volume histograms supplied by treatment planning systems are used to provide estimates on planning target coverage as well as on sparing of organs at risk and the remaining healthy tissue. These partial metrics are then combined into a dose distribution index (DDI), which provides a unified, easy-to-read score for each competing radiotherapy plan. To assess the performance of the proposed scoring system, DDI figures for fifty brain cancer patients were retrospectively evaluated. Patients were divided in three groups depending on tumor location and malignancy. For each patient, three tentative plans were designed and recorded during planning, one of which was eventually selected for treatment. We thus were able to compare the plans with better DDI scores and those actually delivered.

Results

When planning target coverage and organs at risk sparing are considered as equally important, the tentative plan with the highest DDI score is shown to coincide with that actually delivered in 32 of the 50 patients considered. In 15 (respectively 3) of the remaining 18 cases, the plan with highest DDI value still coincides with that actually selected, provided that organs at risk sparing is given higher priority (respectively, lower priority) than target coverage.

Conclusions

DDI provides a straightforward and non-subjective tool for dosimetric comparison of tentative radiotherapy plans. In particular, DDI readily quantifies differences among competing plans with similar-looking dose-volume histograms and can be easily implemented for any tumor type and localization, irrespective of the planning system and irradiation technique considered. Moreover, DDI permits to estimate the dosimetry impact of different priorities being assigned to sparing of organs at risk or to better target coverage.

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Rab23 is overexpressed in human bladder cancer and promotes cancer cell proliferation and invasion

Abstract

Rab23 overexpression has been implicated in several human cancers. However, its expression pattern and biological roles in human bladder cancer have not been elucidated. In this study, we examined Rab23 expression in 93 bladder cancer specimens and analyzed its correlation with clinicopathological parameters. We found that Rab23 was overexpressed in 45 of 93 (48.3 %) cancer specimens. Significant association was found between Rab23 overexpression and tumor invasion depth (p = 0.0027). Rab23 overexpression also negatively correlated with FGFR3 protein expression (p = 0.021). We found that Rab23 expression was lower in normal bladder transitional cell line SV-HUC-1 than in bladder cancer cell lines BIU-87, 5637, and T24. We knocked down Rab23 expression in T24 cancer cells and transfected a Rab23 plasmid in the BIU-87 cell line. Rab23 depletion inhibited cell growth rate and invasion, while its overexpression resulted in increased cell growth and invasion. In addition, we demonstrated that Rab23 depletion decreased and its transfection upregulated expression of cyclin E, c-myc, and MMP-9. Furthermore, we showed that Rab23 knockdown inhibited NF-κB signaling and its overexpression upregulated NF-κB signaling. BAY 11-7082 (NF-κB inhibitor) partly inhibited the effect of Rab23 on cyclin E and MMP-9 expression. In conclusion, the present study demonstrated that Rab23 overexpression facilitates malignant cell growth and invasion in bladder cancer through the NF-κB pathway.

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Association of the hypermethylation status of PTEN tumor suppressor gene with the risk of breast cancer among Kurdish population from Western Iran

Abstract

Breast cancer is the most common cancer with high morbidity and mortality among women worldwide. Aberrant hypermethylation in promoter regions of the tumor suppressor genes such as PTEN gene is a key event in the progression and development of breast cancer. The aim of the present study was to evaluate an association between PTEN gene methylation status with the risk of breast cancer in an Iranian population. We studied 255 individuals, including 103 patients with breast cancer, 102 first-degree female relatives of patients (mother, sister, or daughter of patients), and 50 healthy individuals as a control group. Genomic DNA was extracted from peripheral blood leukocytes, and the PTEN promoter methylation status was detected using methylation-specific PCR (MSP) method with specific methylated and unmethylated primers. In some samples, direct DNA sequencing was used to confirm the results obtained by the MSP method. The frequency of PTEN-methylated (MM) genotype was 6 % in the healthy control group, 23.3 % in relatives of patients, and 41.7 % in patients (χ ² = 24.62, p < 0.001). There were significant differences in the frequency of PTEN-methylated genotype between healthy control compared to that in patients (χ ² = 15.1, p < 0.001) and also compared to that in relatives of patients (χ ² = 6.9, p = 0.009). In the presence of PTEN MM genotype, there was a 3.1-fold susceptibility to breast cancer compared to the UU genotype (p < 0.001). Also, in the presence of PTEN M allele, the risk of breast cancer was 2.71-fold compared to the presence of U allele (p < 0.001). Our findings indicated increased frequency of hypermethylation of PTEN promoter in the studied patients and their relatives that could be considered as one of the epigenetic factors affecting the risk of breast cancer in Iranians.

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CUL4A expression in pediatric osteosarcoma tissues and its effect on cell growth in osteosarcoma cells

Abstract

Osteosarcoma (OS) is the most common bone malignancy in the pediatric population, and it comprises about 3 % of all pediatric tumors. Aberrant expression of the Cullin 4A (CUL4A) is found in many tumor types, but the role of CUL4A in OS progression remains largely unknown. The aim of this study was to investigate the expression and function of CUL4A in OS. CUL4A expression was detected in 30 samples of surgically resected OS and matched tumor-adjacent tissues using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. Cell proliferation was assessed by MTT, and migration and invasion were analyzed by Transwell and Matrigel assays after CUL4A knockdown in OS in vitro. Our result showed increased CUL4A expression in OS tissues. CUL4A knockdown inhibited the proliferation of MG63 cells. Furthermore, CUL4A siRNA ameliorated the migration and invasion of MG63 cell lines with altered expression of epithelial-mesenchymal transition (EMT)-associated molecules. Taken together, our findings indicate that CUL4A plays a pivotal role in OS progression and may serve as a potential marker for clinical diagnosis and target for therapy.

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Autophagy, a double-edged sword in anti-angiogenesis therapy

Abstract

Autophagy is a highly conservative cell behavior to keep the intracellular homeostasis and is frequently activated when cells encounter disgusting conditions, such as nutrition or growth factor deprive, hypoxia and cytotoxic agents. However, the precise role of autophagy under various conditions may be opposite, differ from protect cells survival to promote cells death, and the mechanism of this conditional-dependent role is still unclear. Anti-angiogenesis agents, such as bevacizumab, sorafenib and sunitinib, could reduce tumor microvascular density and increase tumor hypoxia, thus up-regulating autophagy activation of tumor cells, but the function of autophagy induced by anti-angiogenesis agents is still divergent and is considered to play a cytoprotective role in most cases. In this review, we mainly discuss the relationship between anti-angiogenesis therapy-induced hypoxia and autophagy, and pay special attention on the exact role of anti-angiogenesis agents induced autophagy in the process of anti-angiogenesis treatment.

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Bevacizumab in Combination with Chemotherapy for Colorectal Brain Metastasis

Abstract

Background

Brain metastases are rare in patients with colorectal cancer, but the incidence is expected to rise due to prolonged survival resulting from more effective regimens including anti-EGF-receptor and anti-angiogenic antibodies. Because of the potential fear of intracranial hemorrhage, patients with colorectal brain metastases have been excluded from clinical trials involving bevacizumab or aflibercept.

Patients

Five patients with colorectal brain metastases treated with bevacizumab-containing chemotherapy regimen following either neurosurgery, radiosurgery, or whole-brain radiotherapy were identified between 2009 and 2014. The clinicopathological data and outcomes for these patients were reviewed.

Results

Mean time to disease progression concerning brain metastases was 14.8 months (range 5–25). Overall survival was 26.2 months (range 7–42 months) and overall survival since diagnosis of brain metastases was 20.6 month (7–42). Best response was a partial response in two and a stable disease in three patients. Treatment-related adverse events were mild hypertension (grade 1), diarrhea (grade 1), and fatigue (grade 1). No intracranial hemorrhage was observed.

Conclusion

Bevacizumab in combination with chemotherapy is a feasible option for palliative treatment of patients with colorectal brain metastasis with a good safety profile.

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Let-7a suppresses glioma cell proliferation and invasion through TGF-β/Smad3 signaling pathway by targeting HMGA2

Abstract

It has been shown that let-7a was associated with the tumorigenesis of glioma. Our study was designed to infer how let-7a targets high-mobility AT-hook 2 (HMGA2) and suppresses glioma cell proliferation, invasion, and migration. Glioma tissues from 60 glioma patients and 10 normal brain tissues were collected in this study. Real-time quantitative reverse transcription-PCR (qRT-PCR) and in situ hybridization were used to detect the expression levels of let-7a in tissues and cells. The HMGA2 and the proteins related to transforming growth factor-beta (TGF-β)/Smad3 signaling pathway were measured by immunohistochemistry and western blot. Glioma U87 cells were transfected with either let-7a mimics, HMGA2 small interfering RNA (siRNA), let-7a mimics + HMGA2, HMGA2, or scramble. A cell counting kit-8 (CCK-8) assay was used to detect and compare the difference among various transfection groups. Glioma tumor xenograft models on mice were built to evaluate the effects of let-7a and HMGA2 siRNA on glioma tumors in vivo. The expression level of let-7a significantly downregulated in glioma tissues, while the HMGA2 positive expression rate notably increased compared with those in normal brain tissues (all P < 0.05). Moreover, the expression levels of let-7a and HMGA2 were correlated with glioma grades (all P < 0.05). The proliferation of U87 cells transfected with let-7a mimics or HMGA2 siRNA was significantly inhibited in comparison to the blank control group and the apoptosis rates of U87 cells transfected with let-7a mimics or HMGA2 siRNA were significantly higher than those in the blank control group (all P < 0.05). Let-7a or HMGA2 siRNA could remarkably attenuate the invasion and migration ability of glioma cells (all P < 0.05). Apart from that, over-expressed exogenous HMGA2 could reverse the inhibition of glioma cell metastasis and proliferation induced by let-7a. As suggested by immunohistochemistry and western blot, the expression levels of TGF-β1 and p-Smad3 significantly decreased compared with the blank or scramble group (all P < 0.05). Thus, let-7a and HMGA2 siRNA could effectively suppress the growth of tumors in glioma xenograft models. Let-7a may suppress the proliferation and invasion of glioma cells through mediating TGF-β/Smad3 signaling pathway by targeting HMGA2.

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Epigenetic control of group V phospholipase A 2 expression in human malignant cells

Abstract

Secreted phospholipases A₂ (sPLA₂) are suggested to play an important role in inflammation and tumorigenesis. Different mechanisms of epigenetic regulation are involved in the control of group IIA, III and X sPLA₂s expression in cancer cells, but group V sPLA₂ (GV-PLA₂) in this respect has not been studied. Here, we demonstrate the role of epigenetic mechanisms in regulation of GV-PLA₂ expression in different cell lines originating from leukaemia and solid cancers. In blood leukocytes from leukaemic patients, levels of GV-PLA₂ transcripts were significantly lower in comparison to those from healthy individuals. Similarly, in DU-145 and PC-3 prostate and CAL-51 and MCF-7 mammary cancer cell lines, levels of GV-PLA₂ transcripts were significantly lower in relation to those found in normal epithelial cells of prostate or mammary. By sequencing and methylation-specific high-resolution melting (MS-HRM) analyses of bisulphite-modified DNA, distinct CpG sites in the GV-PLA₂ promoter region were identified that were differentially methylated in cancer cells in comparison to normal epithelial and endothelial cells. Spearman rank order analysis revealed a significant negative correlation between the methylation degree and the cellular expression of GV-PLA₂ (r = −0.697; p = 0.01). The effects of demethylating agent (5-aza-2′-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on GV-PLA₂ transcription in the analysed cells confirmed the importance of DNA methylation and histone modification in the regulation of the GV-PLA₂ gene expression in leukaemic, prostate and mammary cancer cell lines. The exposure of tumour cells to human recombinant GV-PLA₂ resulted in a reduced colony forming activity of MCF-7, HepG2 and PC-3 cells, but not of DU-145 cells suggesting a cell-type-dependent effect of GV-PLA₂ on cell growth. In conclusion, our results suggest that epigenetic mechanisms such as DNA methylation and histone modification play an important role in downregulation of GV-PLA₂ expression in cancer cells.

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Perspective: Cooperation of Nanog, NF-κΒ, and CXCR4 in a regulatory network for directed migration of cancer stem cells

Abstract

Directed cell migration is a crucial mobility phase of cancer stem cells having stemness and tumorigenic characteristics. It is known that CXCR4 plays key roles in the perception of chemotactic gradients throughout the directed migration of CSCs. There are a number of complex signaling pathways and transcription factors that coordinate with CXCR4/CXCL12 axis during directed migration. In this review, we focus on some transcription factors such as Nanog, NF-κB, and Bmi-1 that cooperate with CXCR4/CXCL12 for the maintenance of stemness and induction of metastasis behavior in cancer stem cells.

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LncRNAs: key players and novel insights into cervical cancer

Abstract

Cervical cancer contributed the second highest number of deaths in female cancers, exceeded only by breast cancer, carrying high risks of morbidity and mortality. There was a great need and urgency in searching novel treatment targets and prognosis biomarkers to improve the survival rate of cervical cancer patients. Many long non-coding RNAs (lncRNAs) were emerging as pivotal regulators in various biological processes and took vitally an effect on the oncogenesis and progression of cervical cancer. In this review, we summarized the origin and overview function of lncRNAs; highlighted the roles of lncRNAs in cervical cancer in terms of prognosis and tumor progression, invasion and metastasis, apoptosis, and radio-resistance; and outlined the molecular mechanisms of lncRNAs in cervical cancer from the aspects of the interaction of lncRNAs with proteins/mRNAs (especially in HPV protein) and miRNAs, as well as RNA N-methyladenosine (m6A) methylation of lncRNAs. Meanwhile, the application of lncRNAs as biomarkers in cervical cancer prognosis and predictors for metastasis was also discussed. An overview of these researches will be valuable for broadening horizons into mechanisms, selection of meritorious biomarkers for diagnosis as well as prognosis, and future targeted therapy of cervical cancer.

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Circulating miR-205: a promising biomarker for the detection and prognosis evaluation of bladder cancer

Abstract

MicroRNA (miRNA) expression profile analysis indicated that miR-205 was upregulated in bladder cancer tissue compared to healthy tissue. The aim of this study is to analyze value of circulating miR-205 for the detection and prognosis evaluation of bladder cancer (BC). Eighty-nine patients with BC and 56 healthy controls (HC) were enrolled in the study. miR-205 expression was determined using TaqMan quantitative real-time polymerase chain reaction assay and further correlated with patients' clinicopathological parameters and follow-up data. The results indicated that plasma miR-205 was upregulated in BC compared with HC (P < 0.001) and in muscle invasive BC (MIBC) compared to nonmuscle invasive BC (NMIBC) (P = 0.016). miR-205 yielded an area under the receiver-operating characteristic curve of 0.950 with 76.4 % sensitivity and 96.4 % specificity in discriminating BC from HC, and 0.668 with 57.1 % sensitivity and 77.0 % specificity in distinguishing MIBC from NMIBC. Plasma miR-205 expression was significantly associated with tumor stage (P < 0.001) and pathological grade (P = 0.048). The results indicated that BC patients with high miR-205 expression experienced shorter disease-free survival and disease-specific survival (P = 0.022 and P = 0.026; P = 0.027 and P = 0.034; respectively), which was not proven by multivariate Cox regression analysis (multi-Cox) (P = 0.0765 and P = 0.279, respectively). Log-rank test showed that NMIBC patients with high miR-205 expression experienced shorter cancer-free survival (P = 0.044). Log-rank test and univariate and multivariate Cox regression analyses did not indicate that high miR-205 expression in NMIBC patients was associated with cancer-specific survival (P = 0.079, P = 0.089, and P = 0.201, respectively). In conclusion, miR-205 may be a promising biomarker for the detection and prognosis evaluation of BC.

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Association of Wnt signaling pathway genetic variants in gallbladder cancer susceptibility and survival

Abstract

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with adverse prognosis and poor survival. Wnt signaling plays an important role in embryonic development and regeneration of tissues in all the species. Deregulation of expression and mutations in this pathway may lead to disease state such as cancer. In this study, we assessed the association of common germline variants of Wnt pathway genes (SFRP2, SFRP4, DKK2, DKK3, WISP3, APC, β-catenin, AXIN-2, GLI-1) to evaluate their contribution in predisposition to GBC and treatment outcomes. The study included 564 GBC patients and 250 controls. Out of 564, 200 patients were followed up for treatment response and survival. Tumor response (RECIST 1.1) was recorded in 116 patients undergoing non-adjuvant chemotherapy (NACT). Survival was assessed by Kaplan-Meier curve and Cox-proportional hazard regression. Single locus analysis showed significant association of SFRP4 rs1802073G > T [p value = 0.0001], DKK2 rs17037102C > T [p value = 0.0001], DKK3 rs3206824C > T [p value = 0.012], APC rs4595552 A/T [p value = 0.021], APC rs11954856G > T [p value = 0.047], AXIN-2 rs4791171C > T [p value = 0.001], β-catenin rs4135385A > G [p value = 0.031], and GLI-1 rs222826C > G [p value = 0.001] with increased risk of GBC. Gene-gene interaction using GMDR analysis predicted APC rs11954856 and AXIN2 rs4791171 as significant in conferring GBC susceptibility. Cox-proportional hazard model showed GLI-1 rs2228226 CG/GG and AXIN-2 rs4791171 TT genotype higher hazard ratio. In recursive partitioning, AXIN-2 rs4791171 TT genotype showed higher mortality and hazard. Most of studied genetic variants influence GBC susceptibility. APC rs11954856, GLI-1 rs2228226, and AXIN-2 rs4791171 were found to be associated with poor survival in advanced GBC patients.

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Prognostic significance of two lipid metabolism enzymes, HADHA and ACAT2, in clear cell renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) is one of the leading causes of cancer mortality in adults, but there is still no acknowledged biomarker for its prognostic evaluation. Our previous proteomic data had demonstrated the dysregulation of some lipid metabolism enzymes in clear cell RCC (ccRCC). In the present study, we elucidated the expression of two lipid metabolism enzymes, hydroxyl-coenzyme A dehydrogenase, alpha subunit (HADHA) and acetyl-coenzyme A acetyltransferase 2 (ACAT2), using Western blotting analysis, then assessed the prognostic potential of HADHA and ACAT2 using immunohistochemistry (IHC) on a tissue microarray of 145 ccRCC tissues. HADHA and ACAT2 were downregulated in ccRCC (P < 0.05); further IHC analysis revealed that HADHA expression was significantly associated with tumor grade, stage, size, metastasis, and cancer-specific survival (P = 0.004, P < 0.001, P < 0.001, P = 0.049, P < 0.001, respectively) and ACAT2 expression was significantly associated with tumor stage, size, and cancer-specific survival (P < 0.001, P = 0.001, P < 0.001, respectively). In addition, a strong correlation was found between HADHA and ACAT2 expression (R = 0.655, P < 0.001). Further univariate survival analysis demonstrated that high stage, big tumor size, metastasis, and HADHA and ACAT2 down-expression were associated with poorer prognosis on cancer-specific survival (P = 0.007, P = 0.005, P = 0.006, P < 0.001, P = 0.001, respectively), and multivariate analysis revealed that HADHA, stage, and metastasis were identified as independent prognostic factors for cancer-specific survival in patients with ccRCC (P = 0.018, P = 0.046, P = 0.001, respectively). Collectively, these findings indicated that HADHA could serve as a promising prognostic marker in ccRCC, which indicated lipid metabolism abnormality might be involved in ccRCC tumorigenesis.

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Anaplastic Large-Cell Lymphoma of the Left Ventricle Presenting With Arrhythmia and Cerebral Infarction due to Cardiogenic Embolism

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A Child With Dyserythropoietic Anemia and Megakaryocyte Dysplasia Due to a Novel 5′UTR GATA1s Splice Mutation

We describe a child with dyserythropoietic anemia, thrombocytosis, functional platelet defect, and megakaryocyte dysplasia. We show that (i) this constellation of hematopoietic abnormalities was due to a germline mutation within the 5′ untranslated region (5′UTR) of globin transcription factor 1 (GATA1); (ii) the mutation impaired a 5′UTR GATA1 splicing site, with promoted production of the shortened GATA1 isoform lacking the N-terminus; and (iii) expression of the GATA1 N-terminus is restricted to erythroblasts and megakaryocytes in normal marrow, consistent with the patient's abnormal erythropoiesis and megakaryopoiesis. Our findings provide insights into the clinically relevant in vivo function of the N-terminal domain of GATA1 in human hematopoiesis.

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Gorham–Stout Disease of the Skull Base With Hearing Loss: Dramatic Recovery and Antiangiogenic Therapy

Gorham–Stout disease (GSD) is a rare disorder of unknown etiology. We present a 6-year-old male with GSD involving the skull base who presented with recurrent cerebrospinal fluid (CSF) rhinorrhea, severe hearing loss, and facial palsy secondary to cerebellar herniation into the internal auditory canal. After 2 months of treatment with pegylated interferon (IFN) α-2b (50 μg/week), his hearing recovered dramatically. Two years later, new bone formation appeared radiologically and IFN was switched to sirolimus. One year after the switch, CSF rhinorrhea disappeared. Antiangiogenic therapy might inhibit proliferation of vascular endothelial cells in osteolytic lesions and lead to new bone formation.

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Characteristics of Children With Cancer Discharged or Admitted From the Emergency Department

Background

Emergency department (ED) utilization by children with cancer is poorly understood. Among children with cancer, we explored reasons for ED visits and factors associated with admission within U.S. children's hospitals.

Methods

A retrospective study of the 2011–2013 Pediatric Health Information System (PHIS) was conducted. Eligible ED visits included those within 365 days from the first inpatient encounter with an International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) code for cancer. Patient characteristics and reasons for ED visits were assessed. Factors associated with admission from the ED were examined with multivariable regression.

Results

There were 26,770 ED visits by 17,943 children with cancer at 39 children's hospitals during the study period. Half of children with cancer visited the ED within 1 year after their first cancer hospitalization in PHIS. Fifty-six percent of ED visits resulted in admission. Fever or neutropenia accounted for the largest proportion of reasons for visits (34.6%). Risk factors for admission were as follows: "Other" race/ethnicity as compared to white, non-Hispanic (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.2–1.6), history of transplant (OR = 1.7, 95% CI 1.4–2.1), and ED visits reasons including neutropenia (OR = 43.4, 95% CI 36.0–52.3), blood stream infection (OR = 3.3, 95% CI 2.8–3.9), pancytopenia (OR = 28.8, 95% CI 18.1–45.9), dehydration (OR = 2.3, 95% CI 1.9–2.9), or pneumonia (OR = 3.8, 95% CI 2.8–5.1).

Conclusions

Children with cancer have high ED usage within 1 year after their first cancer hospitalization. Age, demographic factors, and reasons for ED visits significantly impacted admission from the ED. Further research should focus on ED utilization among children with cancer.

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Severe Tumor Lysis Syndrome and Acute Pulmonary Edema Requiring Extracorporeal Membrane Oxygenation Following Initiation of Chemotherapy for Metastatic Alveolar Rhabdomyosarcoma

We present an 8-year-old male with metastatic alveolar rhabdomyosarcoma (ARMS) who developed precipitous cardiopulmonary collapse with severe tumor lysis syndrome (TLS) 48 hr after initiation of chemotherapy. Despite no detectable pulmonary metastases, acute hypoxemic respiratory failure developed, requiring extracorporeal membrane oxygenation (ECMO). Although TLS has been reported in disseminated ARMS, this singular case of life-threatening respiratory deterioration developing after initiation of chemotherapy presented unique therapeutic dilemmas. We review the clinical aspects of this case, including possible mechanisms of respiratory failure, and discuss the role of ECMO utilization in pediatric oncology.

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MRI Measurements of Iron Load in Transfusion-Dependent Patients: Implementation, Challenges, and Pitfalls

Magnetic resonance imaging (MRI) has played a key role in studies of iron overload in transfusion-dependent patients, providing insights into the relations among liver and cardiac iron loading, iron chelator dose, and morbidity. Currently, there is rapid uptake of these methods into routine clinical practice as part of the management strategy for iron overload in regularly transfused patients. Given the manifold methods of data acquisition and analysis, there are several potential pitfalls that may result in inappropriate decision making. Herein, we review the challenges of establishing suitable MRI techniques for tissue iron measurement in regularly transfused patients.

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Coffee consumption and the risk of incident gastric cancer-A meta-analysis of prospective cohort studies.

Coffee consumption and the risk of incident gastric cancer-A meta-analysis of prospective cohort studies.

Nutr Cancer. 2015 Dec 28;:1-8

Authors: Deng W, Yang H, Wang J, Cai J, Bai Z, Song J, Zhang Z

Abstract
As several epidemiological studies on the association of coffee consumption with gastric cancer risk have produced inconsistent results, this meta-analysis was designed to synthesize current evidence of this potential relationship. We searched PubMed, EMBASE, and the Cochrane Library up to September 2014 to retrieve relevant articles. Prospective cohort studies were included if the relative risks (RRs) or hazard ratios and 95% confidence intervals (CIs) for gastric cancer according to coffee consumption were reported. Fixed- or random-effects models were used based on heterogeneity. The search yielded 13 eligible cohort studies of 3484 incident gastric cancer patients from among 1,324,559 participants. A significantly increased risk was found between gastric cardia cancer and coffee consumption (RR = 1.50, 95% CI: 1.09-2.07). Compared with Europeans (RR = 1.12, 95% CI: 0.86-1.46) and Asians (RR = 0.96, 95% CI: 0.72-1.27), Americans (RR = 1.36, 95% CI: 1.06-1.74) demonstrated a significantly positive association. However, the significant differences of the pooled results vanished after adjusting for smoking or body mass index. Our meta-analysis results suggest that a high level of coffee consumption is a risk factor for gastric cancer. However, these results should not be overinterpreted because residual confounding effects of other factors could exist.

PMID: 26710312 [PubMed - as supplied by publisher]

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Variation of resting energy expenditure after the first chemotherapy cycle in acute leukemia patients.

Variation of resting energy expenditure after the first chemotherapy cycle in acute leukemia patients.

Nutr Cancer. 2015 Dec 28;:1-8

Authors: Galati PC, Chiarello PG, Simões BP

Abstract
Changes in resting energy expenditure (REE) of cancer patients vary depending on type of tumor, treatment time point and kind of treatment. Little is known about REE of acute leukemia adult patients after treatment, especially with results related to body weight or fat free mass (FFM). This study aimed to assess changes in REE of acute leukemia adult patients before and after the first remission induction. Evaluation of REE was performed by indirect calorimetry and predicted REE was calculated by Harris-Benedict equation. Weight and height were measured and compared to a control group of healthy individuals. FFM was assessed by bioelectrical impedance for adjusting REE values. We evaluated 18 patients and 26 healthy individuals. At diagnosis, patients presented REE, REE/weight, and REE/FFM higher than the controls. Reductions of REE, REE/weight, and REE/FFM were also observed in patients after the first cycle of chemotherapy. The predicted REE for the patients group showed significant lower value compared with measured REE. Before the first cycle of chemotherapy REE was increased but undergoes a reduction after treatment, reaching values similar to the controls. For predictive Harris-Benedict equation, stress factors should be added to avoid underestimation of REE before and after chemotherapy.

PMID: 26710189 [PubMed - as supplied by publisher]

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Risk factors for colorectal cancer in man induce aberrant crypt foci in rats: Preliminary findings.

Risk factors for colorectal cancer in man induce aberrant crypt foci in rats: Preliminary findings.

Nutr Cancer. 2015 Dec 28;:1-11

Authors: Yang K, Fard S, Furrer R, Archer MC, Bruce WR, Lip H, Mehta R, O'Brien PJ, Giacca A, Ward WE, Femia AP, Caderni G, Medline A, Banks K

Abstract
Epidemiological studies have demonstrated clear associations between specific dietary and environmental risk factors and incidence of colorectal cancer, but the mechanisms responsible for these associations are not known. An animal model could facilitate such an understanding. Both genotoxic and nongenotoxic carcinogens induce aberrant crypt foci (ACF) in the colons of F344 rats. F344 rats were provided with diets that contained putative risk factors for CRC: low calcium and low vitamin D, high iron, high fructose, and decreased light (UV) exposure or a control diet for 14 wk. The rats were then assessed with biochemical measures and by topological examination for evidence of colon abnormalities. Circulating ionized calcium was decreased from 2.85 to 1.69 mmol/L, and ACF were increased from 0.7 to 13.6 lesions/colon (both P < 0.001). Rats exposed to the multiple environmental conditions associated with colon cancer, developed ACF similar to the heterogeneous or ill-defined ACF in the human colon. Heterogeneous ACF are the most frequently seen in humans and are also seen in rats shortly after exposure to the non-genotoxic colon carcinogen, dextransulfate sodium. The rodent model could be used to assess the pathways from diet and environment to colon cancer and to provide guidance for clinical studies.

PMID: 26709971 [PubMed - as supplied by publisher]

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Association between omega-3 fatty acids and serum prostate-specific antigen.

Association between omega-3 fatty acids and serum prostate-specific antigen.

Nutr Cancer. 2015 Dec 28;:1-5

Authors: DeFina LF, Bassett MH, Finley CE, Barlow CE, Willis BL, Cooper T, Clark SM, Harris WS, Radford NB

Abstract
We examined the association between omega-3 fatty acids (O3FAs) and prostate-specific antigen (PSA) in a cross-sectional analysis of 6219 men examined at the Cooper Clinic from 2009 to 2013. We assayed O3FAs from red blood cell membranes and measured PSA levels in study participants. Multiple logistic regression was used to examine the association between O3FAs and PSA. The mean age of study participants was 55.5 years (SD = 9.8) with a mean PSA level of 1.31 ng/mL (SD = 1.5). Unadjusted analyses indicated that there was a slight, direct association with PSA and each of the O3FAs tested. However, after adjusting for age and body mass index (BMI), the associations were reversed but nonsignificant [odds ratio (OR) for PSA > 4 ng/mL: total omega-3 OR = 0.98 per each 1% of total fatty acids, 95% confidence interval (CI) = 0.93-1.03; docosahexaenoic acid OR = 1.01, 95% CI = 0.92-1.11; omega-3 index OR = 0.99, 95% CI = 0.93-1.05). Similar results were obtained after age and BMI adjustment when the omega-3 index was divided into undesirable (0.01-3.99%), intermediate (4.0-7.99%), and desirable ranges ( ≥ 8.0%). Given that the study had >80% power to detect an odds ratio <0.9 or >1.1, we conclude that associations between O3FAs and PSA levels are either nonexistent or quite weak in the population that this healthy sample represents.

PMID: 26709868 [PubMed - as supplied by publisher]

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Effect of chemoradiotherapy on nutrition status of patients with nasopharyngeal cancer.

Effect of chemoradiotherapy on nutrition status of patients with nasopharyngeal cancer.

Nutr Cancer. 2015 Dec 28;:1-7

Authors: Hong JS, Wu LH, Su L, Zhang HR, Lv WL, Zhang WJ, Tian J

Abstract
We aimed to assess the effect of chemoradiotherapy on the nutritional status of patients with nasopharyngeal cancer (NPC) and to detect the risk factors for poor nutrition status in NPC patients after radiotherapy. A total of 104 NPC patients participated in this clinical observational study. Psychological distress and nutritional indicators were measured prior to chemoradiotherapy. During the course of radiation therapy, side effect symptoms were assessed weekly. At the end of radiotherapy, nutritional indicators were measured again. Logistic regression was used to identify the risk factors for poor nutritional status after radiotherapy. The values of the 9 nutritional indicators were significantly lower after radiotherapy (P < 0.001) than the initial values before treatment. After radiotherapy, 20.19% of patients had more than 10% weight loss. At a significance level of α = 0.05, the risk factors for poor nutritional status were old age (P = 0.042), female gender (P < 0.001), late stage of the disease (P = 0.013), depression (P = 0.024), high side effect score (P = 0.007), and moderate nutritional status before radiotherapy (P = 0.015). Radiotherapy affects the nutritional status of NPC patients. To prevent malnutrition during radiotherapy, nutritional assessment and intervention should be an integral part of treatment.

PMID: 26709739 [PubMed - as supplied by publisher]

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Which is the most suitable lymph node predictor for overall survival after primary surgery of head and neck cancer: pN, the number or the ratio of positive lymph nodes, or log odds?

Abstract

Purpose

To investigate the best lymph node (LN) metastasis predictor for overall survival (OS) in head neck cancer (HNC): pN classification, number of positive lymph nodes (PNOD), lymph node ratio (LNR), or log odds of positive lymph nodes (LODDS).

Methods

In total, 225 surgically treated HNC patients were evaluated for the different LN classifications and OS.

Results

Five-year OS was 71.8 %. Mean number of yielded LN and PNOD was 25.3 ± 16.7 and 2.7 ± 5.9, respectively. 64.8 % had a LNR > 0.10 and 64.4 % a LODDS > 10. In univariable analysis, multimodal therapy (p = 0.039), advanced pT (p < 0.0001), advanced UICC stage (p = 0.029), LNR > 0.10 (p = 0.049), and LODDS > −1.0 (p = 0.021) were associated with lower OS. In multivariable analysis, advanced pT [hazard ratio (HR) 2.194; 95 % confidence interval (CI) 1.294–3.722; p = 0.004] and LODDS > −1.0 (HR 1.634; 95 % CI 1.002–2.665; p = 0.059) remained independent predictors for lower OS.

Conclusions

It seems useful to analyze the prognostic significance of LODDS in other samples of HNC.

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ERG expression in prostate cancer: biological relevance and clinical implication

Abstract

Introduction

Screening for increased levels of prostate-specific antigen (PSA) has allowed early detection of a large majority of prostate cancer (PCa) cases. However, the relative lack of specificity of PSA has resulted in significant over-diagnosis and unnecessary treatment for indolent tumors. The fusion of the transmembrane protease serine 2 with E26 transformation-specific family genes, particularly ERG, is the most widespread genetic alteration in prostate cancer, and data suggest that it is more specific for neoplastic prostate disease and may be of added prognostic value and point toward molecular subtype of PCa.

Methods

In this review, retrospective studies and clinical trials were analyzed to highlight the recent advances in our understanding of the cellular consequence of ERG rearrangement, describe its interactions with other genetic and molecular pathways, and discuss its potential diagnostic and prognostic value.

Conclusion

ERG over-expression has an emerging role in the diagnosis of PCa pathology, although there is still debate about its prognostic value. Elucidation of the mechanisms of ERG gene rearrangements and expression promises novel therapeutic and diagnostic avenues for prostate cancer.

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Both heat and new chemotherapeutic drug dioxadet in hyperthermic intraperitoneal chemoperfusion improved survival in rat ovarian cancer model

Background and Objectives

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the time of Cytoreductive Surgery (CRS) is an actively researched treatment in patients with advanced ovarian cancer. Relative contribution of heat and chemotherapeutic agents during HIPEC as well as efficacy of a new agent dioxadet for regional chemotherapy in a rat model of ovarian cancer was studied.

Methods

Sixty rats were divided into three groups: no treatment control group (n = 19), hyperthermia without chemotherapy (HIPEP) (n = 14), HIPEC + cisplatin (n = 14), HIPEC + dioxadet (n = 13). The intra-abdominal tumor was not resected. End points were: median survival (primary), cause of death (secondary).

Results

The median survival of the animals in the control group, HIPEP group, HIPEC + cisplatin, HIPEC + dioxadet were 9 (CI; 8–23), 22.5 (CI; 12–43), 25.5 (CI; 13–62), 49 (Cl; 28–70) days, respectively. The P-values control versus HIPEP, HIPEC + cisplatin versus HIPEC + dioxadet were 0.006, 0.002, and 0.001, respectively.

Conclusion

During HIPEC both the heat and the cytotoxic drug had antitumor effects in a rat ovarian cancer model. Dioxadet showed potential as a drug for regional chemotherapy. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.

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Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities

Publication date: February 2016
Source:European Journal of Cancer, Volume 54
Author(s): Barbara Bournet, Camille Buscail, Fabrice Muscari, Pierre Cordelier, Louis Buscail
Mutation of the KRAS oncogene in pancreatic cancer is responsible for permanent activation of the P21 RAS protein and the cascade of signalling pathways. Consequently, multiple cellular processes, such as transformation, proliferation, invasion, and survival are activated. The aim of this review was to present all potential clinical applications of targeting KRAS in terms of diagnosis and management of pancreatic adenocarcinoma. Quantitative polymerase chain reaction technology provides reliable assessment of KRAS mutations, both in tissues and from fine-needle aspiration biopsies. Numerous studies report that the combination of endoscopic ultrasound-guided cytopathology and a KRAS mutation assay can improve the positive and differential diagnosis of pancreatic cancer, differentiating between benign versus malignant solid pancreatic cancer, and reducing false-negative results compared to cytopathology alone. In addition, the presence of a KRAS mutation is frequently associated with a worse prognosis, both in cases of advanced and resected tumours. However, the KRAS mutation assay is not as efficient at predicting a response to both anti-epidermal growth factor receptor treatments and/or chemotherapy. Targeting of KRAS to treat pancreatic adenocarcinoma has been applied at different stages of RAS molecular intracellular processes: at the transcription level with antisense or interference RNA, at the posttranslational level with inhibitors of farnesyl transferase or anti-RAS vaccination peptides, and to target multiple signalling pathways using inhibitors of mitogen-activated protein kinase, phosphoinositide 3-kinase, AKT, mammalian target of rapamycin, RAF. Despite some encouraging results at pre-clinical and phase I stages, no significant clinical benefits have been observed. Combinatory approaches with standard chemotherapy will be welcome.



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‘Tablet burden’ in patients with metastatic breast cancer

Publication date: March 2016
Source:European Journal of Cancer, Volume 55
Author(s): Marina Milic, Anna Foster, Karim Rihawi, Alan Anthoney, Chris Twelves
The implications for patients with cancer, of the 'tablet burden' resulting from increasing use of oral anticancer drugs and medication for co-morbidities have not previously been well explored.AimWe sought to (i) quantify tablet burden in women with metastatic breast cancer (MBC), (ii) establish which groups of drug contribute most to this burden and (iii) gain insight into patients' attitudes towards oral anti-cancer treatment.MethodsOne hundred patients with MBC anonymously completed a questionnaire describing their medication histories and attitudes towards their tablets.ResultsThe patients (mean age 60, range 31–95) were all female and taking a median of six tablets (range 0–31) daily; 37 patients were taking >10 tablets. Oral anticancer treatment constituted the category of treatment taken by the highest proportion of patients, followed by symptomatic cancer treatments, proton pump inhibitors and cardiovascular medication. Numerically, however, symptomatic drugs accounted for 44% of all tablets and specific anti-cancer treatment for 15%; medication not directly related to the cancer accounted for the remaining 40% of tablets. A quarter of patients reported inconvenience in taking their tablets, the main reason being tablet size and one third reported forgetting their tablets at least once a week. Nearly two thirds of patients expressing a preference favoured oral anticancer treatment, the commonest reason being greater convenience.ConclusionTablet burden is considerable for many patients with MBC and can be problematic. A significant proportion of tablets represent treatment for co-morbidities, the significance of which may be questionable in women with MBC.



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Impact of surgical staging on prognosis in patients with borderline ovarian tumours: A meta-analysis

Publication date: February 2016
Source:European Journal of Cancer, Volume 54
Author(s): Seung-Hyuk Shim, Soo-Nyung Kim, Phill-Seung Jung, Meari Dong, Jung Eun Kim, Sun Joo Lee
BackgroundTo quantify the effect of complete surgical staging (CSS) on prognosis in borderline ovarian tumour (BOT) patients through a meta-analysis.MethodsWe systematically reviewed published studies comparing CSS with incomplete surgical staging (ISS) in BOT patients through April 2015. End-points were recurrence and mortality rates. Study design features that possibly affected participant selection, recurrence/death detection, and manuscript publication were assessed. For pooled estimates of the effect of CSS on recurrence/death, random- or fixed-effects meta-analytical models were used after assessing cross-study heterogeneity.ResultsEighteen observational studies (CSS, 1297 patients; ISS, 1473 patients) met our search criteria. Fixed-effects model-based meta-analysis indicated a reduced recurrence risk among CSS patients (odds ratio [OR]=0.64; 95% confidence interval [CI]: 0.47–0.87, P < 0.05, I² = 25.6). However, no significant between-group difference in mortality was observed (OR = 0.98; 95% CI: 0.42–2.29, P = 0.97, I² = 0). In subgroup analysis by histology, CSS was associated with a reduced recurrence risk in 16 studies of all histologic types (OR = 0.66; 95% CI: 0.48–0.91, P < 0.05, I² = 31.9) but not in two studies of only mucinous disease (OR = 0.41; 95% CI: 0.13–1.30, P = 0.13, I² = 0). In subgroup analyses with four studies with recurrence data according to fertility-sparing surgery, no significant association was found (OR = 0.51; 95% CI: 0.18–1.43, P = 0.20, I² = 0). There was no evidence of publication bias.ConclusionsIn this meta-analysis based on observational studies, CSS appeared to significantly reduce recurrence among BOT patients. No survival impact was observed. Longer-term randomised controlled trials could verify this relationship but appear infeasible for this rare tumour.



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Transition guidelines: An important step in the future care for childhood cancer survivors. A comprehensive definition as groundwork

Publication date: February 2016
Source:European Journal of Cancer, Volume 54
Author(s): R.L. Mulder, H.J.H. van der Pal, G.A. Levitt, R. Skinner, L.C.M. Kremer, M.C. Brown, E. Bárdi, R. Windsor, G. Michel, E. Frey
Evidence-based clinical practice guidelines are essential to ensure that childhood cancer survivors at risk of chronic health conditions receive effective long-term follow-up care. However, adult survivors of childhood cancer are not always engaged in recommended health promotion and follow-up practices, as many centres do not have a formal transition programme that prepares survivors and their families for successful transfer from child-centred to adult-oriented healthcare. The need for a specific pan-European guideline for the transition of care for childhood cancer survivors has been recognised. The first step is to define the concept of transition of care for survivors of childhood cancer based on existing evidence.



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Opioid switching in cancer pain: from the beginning to nowadays

Publication date: Available online 29 December 2015
Source:Critical Reviews in Oncology/Hematology
Author(s): Sebastiano Mercadante, Eduardo Bruera
Opioid switching is the process of changing from one opioid to another to obtain a satisfactory clinical balance between analgesia and adverse effects. This pharmacological technique has been introduced about 20 years ago to enhance the opioid response in advanced cancer patients with chronic pain. More information is now available. This review will examine many different aspects of opioid switching, including the history and evolution through the last decades, some clinical aspects based on the most recent experience, controversies on the indications, conversion ratios and modalities of switching in some specific circumstances, and evidence based recommendations.



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Erythropoiesis-stimulating agents in gynecological malignancies: a study-level meta-analysis

Publication date: Available online 29 December 2015
Source:Critical Reviews in Oncology/Hematology
Author(s): C. Marchetti, F.De Felice, I. Palaia, D. Musio, L. Muzii, V. Tombolini, P.Benedetti Panici
This meta-analysis was planned to define the role of erythropoiesis-stimulating agents (ESAs) in gynecological cancer patients, receiving myelosuppressive treatment.Pubmed, Medline and Scopus were searched to select English-language articles. Only randomized controlled trials (RCTs) were included. Endpoints were incidence of transfusions, thrombotic events (TE), deaths, and failures. Odd ratio (OR) with 95% confidence interval (CI) was calculated using fixed or random effects model.In seven RCTs ESAs studies of 892 patients under treatment, use of ESAs correlates with a significant reduction of transfusions rate (OR=0.35; 95% CI: 0.19–0.65; p=0.008). OR for overall mortality was 1.10 (95% CI 0.82 - 1.49; p=0.53). ESAs OR for disease failure in 5 studies was 1.71 (95% CI: 0.90 - 3.24; p=0.1).This meta-analysis, even if limited by few RCTs, suggests that ESAs reduce transfusions without increasing mortality or disease progression in gynecological cancer patients receiving treatment.



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The choice dilemma in chronic hematological conditions: Why choosing is not only a medical issue? A psycho-cognitive perspective

Publication date: Available online 28 December 2015
Source:Critical Reviews in Oncology/Hematology
Author(s): Chiara Renzi, Silvia Riva, Marianna Masiero, Gabriella Pravettoni
Research in cognitive psychology focused on risk perception and decision making was shown to facilitate treatment choice and patient's satisfaction with decision in a number of medical conditions, increasing perceived alliance between patient and physician, and adherence to treatment. However, this aspect has been mostly neglected in the literature investigating choice of treatment for chronic hematological conditions. In this paper, a patient centered model and a shared decision making (SDM) approach to treatment switch in chronic hematological conditions, in particular chronic myeloid leukemia, atrial fibrillation, and β-thalassemia is proposed. These pathologies have a series of implications requiring important decisions about new available treatments. Although new generation treatmentsmay provide a significant improvement in patient's health and health-related quality of life (HrQoL), a significant percentage of them is uncertain about or refuse treatment switch, even when strongly suggested by healthcare guidelines. Possible cognitive and emotional factors which may influence decision making in this field and may prevent appropriate risk-and-benefits evaluation of new treatment approaches are reviewed. Possible adaptive strategies to improve quality of care, patient participation, adherence to treatment and final satisfaction are proposed, and implications relatively to new treatment options available are discussed.



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Determination of ETV6-RUNX1 genomic breakpoint by next-generation sequencing

Abstract

The t(12;21)(p13;q22) ETV6-RUNX1 gene fusion is one of the most common chromosomal translocation in childhood acute lymphoblastic leukemia (ALL). It is associated with favorable prognosis. The identification of the genomic sequence of the breakpoint flanking regions of the ETV6-RUNX1 translocation should be the best strategy to monitor minimal residual disease (MRD) in patients with ETV6-RUNX1-positive ALL. In this study, the ETV6-RUNX1 translocation was sequenced by next-generation sequencing (NGS) in 26 patients with ETV6-RUNX1-positive ALL and re-sequenced by using the Sanger method. Interestingly, the three-way translocation, including ETV6-RUNX1, was detected in five patients. Four of them relapsed during or after therapy, while 21 patients without the three-way translocation were still in remission (P < 0.0001). The three-way translocation pattern was identical between the diagnosis and relapse samples in three patients, excluding one patient (SCMC-001245). The relapse samples retained the translocation of ETV6-RUNX1 relative to the three-way translocation t(8;12;21) at diagnosis, suggesting that the three-way translocation might be an important risk factor for relapse in patients with ETV6-RUNX1-positive ALL and should be further studied.

The identification of the genomic sequence of the breakpoint flanking regions of the t(12;21)(p13;q22) ETV6-RUNX1 translocation should be the best strategy to monitor minimal residual disease (MRD). In this study, the ETV6-RUNX1 translocation was sequenced by next-generation sequencing (NGS) in 26 patients with ETV6-RUNX1-positive ALL and re-sequenced by using the Sanger method. Interestingly, the three-way translocation, including ETV6-RUNX1, was detected in five patients and four of them relapsed.

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Treatment evolution for metastatic castration-resistant prostate cancer with recent introduction of novel agents: retrospective analysis of real-world data

Abstract

Despite increasing drug treatment options for metastatic castration-resistant prostate cancer (mCRPC) patients, real-world treatment data are lacking. We conducted retrospective analyses of commercial claims and electronic medical record (EMR) databases to understand how treatment patterns for mCRPC have changed in a US-based real-world population. Truven Health Analytics MarketScan^® (2000–2013) and EMR (2004–2013) databases were used to identify patients with an index prostate cancer diagnosis (ICD-9 codes 185X or 233.4X) and prescription claims for an mCRPC drug (mitoxantrone, estramustine, docetaxel, sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide, or radium-223). Regimen analyses for first line of therapy (LOT1), second line of therapy, and beyond were performed among cohorts based on year of first mCRPC drug usage. mCRPC drug usage and treatment duration were compared across cohorts and age groups within each cohort. The commercial claims cohort yielded 3437 evaluable patients. Most men (91%) commencing mCRPC treatment had docetaxel as LOT1 in 2010; this number had declined to 15% in 2013. In 2013, 67% and 9% of patients used abiraterone acetate and enzalutamide, respectively, as LOT1. Among both commercial claims and EMR cohorts, treatment pattern changes were most pronounced in men aged >80 years, and median treatment duration for some mCRPC drugs was shorter than expected based on available clinical trial information. These results demonstrate a shift in mCRPC treatments during the past 5 years, with greater use of newer noncytotoxic treatments than docetaxel. These real-world data aid in understanding the changing role of chemotherapy in the management of mCRPC.

The use of cytotoxic drugs for metastatic castration-resistant prostate cancer (mCRPC) has declined dramatically during the past 5 years, with greater use of newer noncytotoxic treatments for mCRPC as both first line and second line of therapy. The shift away from cytotoxic therapy was most pronounced in elderly patients, likely due to the better tolerance of highly effective antiandrogen therapy (abiraterone acetate and enzalutamide). These changes in treatment patterns hold the potential of expanding the proportion of men able to receive treatment for mCRPC.

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Racial disparities in overall survival among renal cell carcinoma patients with young age and small tumors

Abstract

We examined the overall survival of a population-based cohort of black and white patients with renal cell carcinoma (RCC) to better understand the paradox of poorer RCC survival despite more frequent diagnosis at lower stage among blacks. Renal cell carcinoma patients (699 white, 252 black) diagnosed between 2002 and 2007 in metropolitan Detroit were followed for vital status in the Detroit Surveillance, Epidemiology and End Results (SEER) registry. Hazard ratios (HR) of death for black versus white race and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models stratified by demographic and prognostic factors, and in models successively adjusted for clinical factors, comorbidities, and socioeconomic factors. Mean follow-up time was 88.4 months for white patients and 89.6 months for black patients (P = 0.49), with 202 white deaths and 89 black deaths (P = 0.06). While black race was weakly associated with poorer overall survival (P = 0.053), black patients <65 years at diagnosis or with tumors <4 cm in size had significantly poorer survival than their white counterparts (HR = 1.46, 95% CI 1.06–2.01 and HR = 2.15, 95% CI 1.51–3.06, respectively). The racial disparities within these two subgroups were minimally affected by adjustment for clinical/treatment factors (HR = 1.49, 95% CI 1.01–2.19 and HR = 1.95, 95% CI 1.27–2.99), but were substantially reduced when renal-relevant comorbidities were added (HR = 1.30, 95% CI 0.89–1.91 and HR = 1.76, 95% CI 1.16–2.66). After further adjustment for socioeconomic factors, the survival disparities were essentially null (HR = 1.14, 95% CI 0.71–1.85 and HR = 1.15, 95% CI 0.67–1.98). In this population-based sample of RCC patients, younger black patients and those with small tumors had poorer overall survival than whites. The disparity was explained primarily by racial differences in renal-relevant comorbidities, particularly chronic renal failure, and socioeconomic deprivation. Future research should focus on younger patients and those with smaller tumors to better understand how these factors may contribute to the survival disparity.

Black RCC patients, especially those under age 65 years and those with tumors 4 cm or less in size, experience poorer survival compared to white patients. This survival difference is mainly attributable to racial differences in comorbidities, particularly chronic renal failure, and factors associated with low socioeconomic status.

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Genome sequencing and analysis of a granulovirus isolated from the Asiatic rice leafroller, Cnaphalocrocis medinalis

Abstract

The complete genome of Cnaphalocrocis medinalis granulovirus (CnmeGV) from a serious migratory rice pest, Cnaphalocrocis medinalis (Lepidoptera: Pyralidae), was sequenced using the Roche 454 Genome Sequencer FLX system (GS FLX) with shotgun strategy and assembled by Roche GS De Novo assembler software. Its circular double-stranded genome is 111,246 bp in size with a high A+T content of 64.8% and codes for 118 putative open reading frames (ORFs). It contains 37 conserved baculovirus core ORFs, 13 unique ORFs, 26 ORFs that were found in all Lepidoptera baculoviruses and 42 common ORFs. The analysis of nucleotide sequence repeats revealed that the CnmeGV genome differs from the rest of sequenced GVs by a 23 kb and a 17kb gene block inversions, and does not contain any typical homologous region (hr) except for a region of non-hr-like sequence. Chitinase and cathepsin genes, which are reported to have major roles in the liquefaction of the hosts, were not found in the CnmeGV genome, which explains why CnmeGV infected insects do not show the phenotype of typical liquefaction. Phylogenetic analysis, based on the 37 core baculovirus genes, indicates that CnmeGV is closely related to Adoxophyes orana granulovirus. The genome analysis would contribute to the functional research of CnmeGV, and would benefit to the utilization of CnmeGV as pest control reagent for rice production.

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Targeting of MyD88 Homodimerization by Novel Synthetic Inhibitor TJ-M2010-5 in Preventing Colitis-Associated Colorectal Cancer

Background:

The TLR/MyD88 signaling pathway is an important driver of inflammation and cancer and is a possible target for antitumor therapy.

Methods:

We generated a MyD88 inhibitor (TJ-M2010-5), which was designed to bind to the TIR domain of MyD88 to interfere with its homodimerization, and the TLR/MyD88 signal pathway. We utilized a mouse model of azoxymethane/dextran sodium sulfate (AOM/DSS)–induced colitis-associated cancer (CAC) in combination with TJ-M2010-5 administration to investigate the anti-inflammation–related cancer effect of MyD88 inhibitor in vivo. Data were analyzed with one-way and repeated measures analysis of variance. Differences in survival between groups were compared using the log rank test. All statistical tests were two-sided.

Results:

TJ-M2010-5 inhibited MyD88 homodimerization in transfected HEK293 cells in a concentration-dependent manner and suppressed MyD88 signaling in LPS-responsive RAW 264.7 cells in vitro. In a 10-week CAC mouse model (n = 30 per group), TJ-M2010-5 treatment statistically significantly reduced AOM/DSS-induced colitis and completely prevented CAC development with less related body mass loss, resulted in 0% mortality of treated mice (compared with 53% mortality of control mice), decreased cell proliferation, and increased apoptosis in colon tissue. TJ-M2010-5 treatment also inhibited production of inflammatory cytokines and chemokines (TNF-α, IL-6,G-CSF, MIP-1β, TGF-β1, IL-11, IL-17A, IL-22 and IL-23) and infiltration of immune cells (macrophages, dendritic cells, neutropihls and CD⁺4 T cells) in colon tissues of mice.

Conclusions:

Our findings suggest that TLR/MyD88 signaling may be a therapeutic target for CAC intervention and MyD88 inhibitors may be a promising therapeutic modality for treating patients with colitis or CAC.

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Fragment-Based Drug Design of HGF/SF-Met Antagonists

In many cancers, aberrant activation of the Met receptor tyrosine kinase leads to dissociation of cells from the primary tumor, causing metastasis. Accordingly, Met is a high-profile target for the development of cancer therapies, and progress has been made through development of small molecule kinase inhibitors and antibodies. However, both approaches pose significant challenges with respect to either target specificity (kinase inhibitors) or the cost involved in treating large patient cohorts (antibodies). Here, we use a fragment-based approach in order to target the protein–protein interaction (PPI) between the α-chain of hepatocyte growth factor/scatter factor (HGF/SF; the NK1 fragment) and its high-affinity binding site located on the Met Sema domain. Surface plasmon resonance was used for initial fragment library screening and hits were developed into larger compounds using substructure (similarity) searches. We identified compounds able to interfere with NK1 binding to Met, disrupt Met signaling, and inhibit tumorsphere generation and cell migration. Using molecular docking, we concluded that some of these compounds inhibit the PPI directly, whereas others act indirectly. Our results indicate that chemical fragments can efficiently target the HGF/SF-Met interface and may be used as building blocks for generating biologically active lead compounds. This strategy may have broad application for the development of a new class of Met inhibitors, namely receptor antagonists, and in general for the development of small molecule PPI inhibitors of key therapeutic targets when structural information is not available. Mol Cancer Ther; 15(1); 1–12. ©2015 AACR.

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Ado-trastuzumab emtansine targets hepatocytes via human epidermal growth factor receptor 2 to induce hepatotoxicity

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2) and a microtubule inhibitor DM1 conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse as models to investigate the mechanisms of T-DM1-induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is co-localized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) in mice, and induces inflammation and necrosis in liver tissues and that T-DM1-induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFα in liver tissues is significantly increased in mice treated with T-DM1 as compared with that treated with trastuzumab or vehicle. We propose that T-DM1-induced upregulation of TNFα enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphological change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs.

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What does satisfaction with wait times mean to cancer patients?

Abstract

Background

Patient satisfaction is an important element of quality improvement and patient-centered care, and is an indicator of the public's confidence in the health care system. Although shorter wait times are believed intuitively to lead to higher satisfaction, studies have demonstrated the importance of many other factors which contribute to patients' satisfaction with their wait time experiences. The current study explores the factors that shape patients' satisfaction with their overall wait times (i.e. from symptom to treatment).

Methods

We conducted qualitative interviews with 60 breast, prostate, lung, or colorectal cancer patients to examine the reasons behind patients' satisfaction or dissatisfaction with their wait time experiences. We purposefully recruited satisfied and unsatisfied participants from our larger survey sample. Using a semi-structured interview guide, patients were asked about their wait time experiences and the reasons behind their (dis)satisfaction. Interviews were transcribed verbatim and coded using a thematic approach.

Results

Patients' perceptions of satisfaction with wait times were influenced by three interrelated dimensions: the interpersonal skills of treating physicians (which included expressions/demonstrations of empathy and concern, quality of information exchange, accountability for errors), coordination (which included assistance navigating the health system, scheduling of appointments, sharing information between providers, coordination in scheduling appointments, and sharing of information ), and timeliness of care (which referred to providers' responsiveness to patients' symptoms, coverage during provider absences, and shared sense of urgency between patient and providers). Providers' willingness to "trouble shoot" and acknowledge errors/delays were particularly influential in patients' overall perception of their wait times.

Conclusions

We described three dimensions of wait-related satisfaction: physicians' interpersonal skills, coordination of care, and timeliness of care, which are often interrelated and overlapping. Furthermore, while patients wait-related satisfaction was typically based on multiple interactions with different providers, positive or negative experiences with a single provider, often (but not always) the family physician, had a substantial impact on the overall satisfaction or dissatisfaction with wait time experiences. The findings provide a conceptual basis for the development of validated instruments to measure wait time-related patient satisfaction.

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