Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 11 Σεπτεμβρίου 2017
Evaluation of a fever-management algorithm in a pediatric cancer center in a low-resource setting
Abstract
Background
In low- and middle-income countries (LMICs), inconsistent or delayed management of fever contributes to poor outcomes among pediatric patients with cancer. We hypothesized that standardizing practice with a clinical algorithm adapted to local resources would improve outcomes. Therefore, we developed a resource-specific algorithm for fever management in Davao City, Philippines. The primary objective of this study was to evaluate adherence to the algorithm.
Procedure
This was a prospective cohort study of algorithm adherence to assess the types of deviation, reasons for deviation, and pathogens isolated. All pediatric oncology patients who were admitted with fever (defined as an axillary temperature >37.7°C on one occasion or ≥37.4°C on two occasions 1 hr apart) or who developed fever within 48 hr of admission were included. Univariate and multiple linear regression analyses were used to determine the relation between clinical predictors and length of hospitalization.
Results
During the study, 93 patients had 141 qualifying febrile episodes. Even though the algorithm was designed locally, deviations occurred in 70 (50%) of 141 febrile episodes on day 0, reflecting implementation barriers at the patient, provider, and institutional levels. There were 259 deviations during the first 7 days of admission in 92 (65%) of 141 patient episodes. Failure to identify high-risk patients, missed antimicrobial doses, and pathogen isolation were associated with prolonged hospitalization.
Conclusions
Monitoring algorithm adherence helps in assessing the quality of pediatric oncology care in LMICs and identifying opportunities for improvement. Measures that decrease high-frequency/high-impact algorithm deviations may shorten hospitalizations and improve healthcare use in LMICs.
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Pathology and genomics of pediatric melanoma: A critical reexamination and new insights
Abstract
The clinicopathologic features of pediatric melanoma are distinct from those of the adult counterpart. For example, most childhood melanomas exhibit a uniquely favorable biologic behavior, save for those arising in large/giant congenital nevi. Recent studies suggest that the characteristically favorable biologic behavior of childhood melanoma may be related to extreme telomere shortening and dysfunction in the cancer cells. Herein, we review the genomic profiles that have been defined for the different subtypes of pediatric melanoma and particularly emphasize the potential prognostic value of telomerase reverse transcriptase alterations for these tumors.
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Addition of oral iron to plasma transfusion in human congenital hypotransferrinemia: A 10-year observational follow-up with the effects on hematological parameters and growth
Abstract
Congenital hypotransferrinemia (OMIM 209300) is an extremely rare disorder of inherited iron metabolism. Since its description in 1961, only 16 cases have been reported. The defective gene and molecular defect causing this disorder and clinicolaboratory findings seen in the homozygous and heterozygous states have been documented in both humans and mice. However, due to the lack of follow-up studies of the described cases, the long-term prognosis remains unknown. We present a 10-year observational follow-up of a patient previously diagnosed on a molecular basis who was treated with a unique therapy of plasma transfusion fortified with oral iron, with satisfactory clinicolaboratory responses.
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Supraventricular tachycardia diagnosed by smartphone ECG
Diagnosis of paroxysmal supraventricular tachycardia (PSVT) may be difficult due to its episodic nature, which can be brief and self-limited, limiting the ability for clinicians to diagnose the specific rhythm disorder in a timely manner. We present a case of PSVT, which was unable to be diagnosed through typical evaluation with an event monitor despite several years of symptoms. The patient was ultimately diagnosed using the AliveCor Mobile ECG, a smartphone-based ECG device and application, which he purchased himself and captured a typical atrioventricular node re-entrant tachycardia. The patient was then able to email his cardiologist the tracing, which led to an electrophysiology study and successful slow pathway ablation procedure. Smartphone-based technology has the potential to push diagnostic evaluations outside of the healthcare system and empower patients.
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Dilation of epidural space and posterior soft tissue veins in Hirayama disease
Description
An 18-year-old man presented with distal weakness and amyotrophy of the right hand for a few months. He had no familial or personal medical history. Clinical examination showed atrophy and a marked weakness of right hypothenar and interossei muscles (grade 1/5 on Medical Research Council scale) and a mild weakness of right thumb abduction and wrist extension (4/5). Biceps, brachioradial and triceps tendon reflexes were normal and symmetric. There were no fasciculation, sensory abnormality or pain. Motor nerve conduction studies showed a reduced amplitude of compound muscle action potential of the right ulnar nerve but normal parameters of left ulnar and two median nerves. No focal slowing or conduction block was found. Studies of bilateral median, ulnar and right medial antebrachial cutaneous sensory nerves were normal. Electromyographic examination found active denervation (fibrillation potentials and neurogenic recruitment) in right C8-T1 innervated muscles (abductor pollicis brevis, first dorsal interosseus, extensor...
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Brainstem encephalitis and acute polyneuropathy associated with hepatitis E infection
A 59-year-old man presented with feverish illness. His Glasgow Coma Scale was 15, had reduced visual acuity in the left eye with partial left ptosis and mild left hemiparesis with an extensor left plantar. Over 48 hours, he accrued multiple cranial nerves palsies and progressed to a flaccid paralysis necessitating admission to an intensive care unit.
Cerebrospinal fluid (CSF) study showed 20 lymphocytes and raised protein. Viral and bacterial PCRs were negative. Samples for Lyme, blood-borne viruses, syphilis and autoantibodies were also negative. MRI brain showed T2 abnormalities within the brainstem. Nerve conduction studies revealed an acute motor and sensory axonal neuropathy pattern of Guillian Barre Syndrome (GBS). The patient was treated for both infective and inflammatory causes of brainstem encephalitis and GBS.
Retrospective studies confirmed the presence of hepatitis E virus (HEV) RNA in CSF and serum studies showed positive HEV IgG and IgM prior to intravenous infusion. After 3 months of intensive rehabilitation, the patient was discharged home walking with a frame.
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Intussusception caused by heterotopic gastric mucosa in small intestine: a case report
Intestinal intussusception is the most frequent cause of small bowel obstruction in children between the ages of 2 months and 5 years and often remains idiopathic in etiology, even after surgery. On microscopi...
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Expression of PD-L1 in Hormone-naïve and Treated Prostate Cancer Patients Receiving Neoadjuvant Abiraterone Acetate plus Prednisone and Leuprolide
Purpose: Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer (PCa), with poor immunogenicity and subsequent low PD-L1 expression in PCa being proposed as an explanation. However, recent studies indicate that a subset of PCa may express significant levels of PD-L1. Further, the androgen antagonist enzalutamide has been shown to up-regulate PD-L1 expression in PCa preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in PCa. Experimental Design: Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate-to-high risk PCa who underwent RP after Neo-AAPL treatment. Untreated PCa tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by immunohistochemistry using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8+ cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1-positive tumors. Results: Neo-AAPL-treated tumors showed a trend toward decreased PD-L1 positivity compared to matched controls (7% vs 21% having ≥1% positive tumor cells; p = 0.062). Treated tumors also harbored significantly less tumor-infiltrating CD8+ cells (p = 0.029). In 130 untreated PCas, African American, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in one of twenty-one PD-L1-positive tumors. Conclusions: A subset of PCa expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic.
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Preoperative Panel Testing for Hereditary Cancer Syndromes Does Not Significantly Impact Time to Surgery for Newly Diagnosed Breast Cancer Patients Compared with BRCA1/2 Testing
Abstract
Background
This study seeks to determine whether there is a delay in time to surgery in breast cancer patients with panel tests compared with traditional BRCA testing.
Methods
This study was a retrospective review of women diagnosed with breast cancer who underwent genetic evaluation from our institution's Genetic Counselor Database from January 2013 to August 2015. Patients were excluded if they were male, clinical information was unavailable, the patient underwent neoadjuvant chemotherapy, had a diagnosis of recurrent breast cancer during time of study, or had postoperative genetics evaluation.
Results
Included in the study were 138 patients. The time from diagnosis to surgery for BRCA1/2 tested patients was 43.5 days compared with 51.0 days in the panel group (p = 0.186). Turnaround time for genetic testing decreased during the period studied and was approximately 6 days longer for panel testing than BRCA testing. It took 12.2 days for BRCA results and 18.9 days for the panel results (p < 0.01). Turnaround time for BRCA1/2 testing in 2014 and 2015 was 12.4 and 10.5 days respectively, whereas panel testing was 20.5 and 18.2 days (p ≤ 0.001). Of the variables included in multivariable linear regression, only mastectomy significantly contributed to time to surgery (p < 0.001).
Discussion
Panel genetic testing did not delay time to surgery compared with BRCA testing alone. The use of panel testing has increased over time, and lab turnaround time has decreased. Mastectomy was the only clinical variable contributing to longer time to surgery.
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The Androgen Receptor: Is It a Promising Target?
Abstract
A growing body of literature supports the conclusion that the androgen receptor (AR) plays an important role in breast cancer pathogenesis and may prove to be a relevant therapeutic target for patients with AR-driven breast cancer. This has been most apparent in the subset of patients with triple-negative breast cancer (TNBC), in whom approximately 50% of tumors may have androgen dependence. Recent phase 2 clinical trials of agents that antagonize AR or reduce androgen production have shown clinical benefit and efficacy to varying degrees. This review highlights three of these recent trials of AR+ TNBC and acknowledge ongoing research in this exciting area.
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Factors Influencing Management and Outcome in Patients with Occult Breast Cancer with Axillary Lymph Node Involvement: Analysis of the National Cancer Database
Abstract
Background
Occult breast cancer (OBC) is rare and optimal local–regional (LR) management has not been defined. Using a patient registry database, we examine factors associated with treatment and outcomes in OBC.
Methods
Female patients with cT0 N1/2 M0 BC were selected from the National Cancer Database (2004–2013) and categorized into four treatment groups: MAST = mastectomy with axillary lymph node dissection (ALND) ± radiation (RT); RT + ALND = RT with ALND, no breast surgery; ALND = ALND alone; OBS = no breast surgery, RT, or ALND. Patient characteristics and overall survival (OS) were compared between groups, and multivariable analysis was used to identify factors associated with treatment and OS.
Results
Among 2.03 million BC cases, 1853 females (0.09%) with cT0 N1/2 M0 disease were identified and 1231 patients were categorized into a treatment group: MAST = 592, RT + ALND = 342, ALND = 106, OBS = 191. On logistic regression, care at an academic center was associated with a higher likelihood of RT + ALND compared with MAST (odds ratio 2.03, 95% confidence interval [CI] 1.50–2.74, p < 0.001). Patients treated with RT + ALND had significantly better OS on univariate survival analysis compared with patients treated with MAST (hazard ratio [HR] 0.475, 95% CI 0.306–0.736, p = 0.001). RT + ALND was independently associated with OS on multivariable survival analysis (HR 0.509, 95% CI 0.321–0.808, p = 0.004), after adjusting for covariates.
Conclusions
Patients with OBC were more likely to undergo RT + ALND if they received care at an academic center. Patients treated with RT + ALND had significantly better OS compared with patients treated with MAST, after adjusting for covariates. This supports the use of RT + ALND as LR treatment for patients with OBC.
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Expanded Gene Panel Use for Women With Breast Cancer: Identification and Intervention Beyond Breast Cancer Risk
Abstract
Background
Clinicians ordering multi-gene next-generation sequencing panels for hereditary breast cancer risk have a variety of test panel options. Many panels include lesser known breast cancer genes or genes associated with other cancers. The authors hypothesized that using broader gene panels increases the identification of clinically significant findings, some relevant and others incidental to the testing indication. They examined clinician ordering patterns and compared the yield of pathogenic or likely pathogenic (P/LP) variants in non-BRCA genes of female breast cancer patients.
Methods
This study analyzed de-identified personal and family histories in 1085 breast cancer cases with P/LP multi-gene panel findings in non-BRCA cancer genes and sorted them into three groups by the panel used for testing: group A (breast cancer genes only), group B (commonly assessed cancers: breast, gynecologic, and gastrointestinal), and group C (a more expanded set of tumors). The frequency of P/LP variants in genes with established management guidelines was compared and evaluated for consistency with personal and family histories.
Results
This study identified 1131 P/LP variants and compared variants in clinically actionable genes for breast and non-breast cancers. Overall, 91.5% of these variants were in genes with management guidelines. Nearly 12% were unrelated to personal or family history.
Conclusion
Broader panels were used for 85.6% of our cohort (groups B and C). Although pathogenic variants in non-BRCA genes are reportedly rare, the study found that most were in clinically actionable genes. Expanded panel testing improved the identification of hereditary cancer risk. Small, breast-limited panels may miss clinically relevant findings in genes associated with other heritable cancers.
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Breast Cancer-Related Lymphedema Risk is Related to Multidisciplinary Treatment and Not Surgery Alone: Results from a Large Cohort Study
Abstract
Background
Breast cancer-related lymphedema (BCRL) is a significant complication for women undergoing treatment. We assessed BCRL incidence and risk factors in a large population-based cohort.
Methods
We utilized the Olmsted County Rochester Epidemiology Project Breast Cancer Cohort from 1990–2010 and ascertained BCRL and risk factors. The cumulative incidence estimator was used to estimate the rate of BCRL; competing risks regression was used for multivariable analysis.
Results
A total of 1794 patients with stage 0–3 breast cancer with a median of 10 years follow-up were included. The cumulative incidence of BCRL diagnosis within 5 years was 9.1% [95% confidence interval (CI) 7.8–10.5%]. No BCRL events occurred among patients without axillary surgery. In the axillary surgery subset (n = 1512), the 5-year incidence of BCRL was 5.3% in sentinel lymph node (SLN) surgery and 15.9% in axillary dissection (ALND) patients (p < 0.001). In patients treated with surgery only, BCRL rates were not different between ALND versus SLN (3.5 and 4.1% at 5 years, p = 0.36). Addition of breast or chest wall radiation more than doubled the BCRL rate in ALND patients (3.5 vs. 9.5% at 5 years, p = 0.01). The groups with highest risk (>25% at 5 years) all involved ALND with nodal RT and/or anthracycline/cytoxan + taxane chemotherapy. In multivariable analysis of patients with any axillary surgery factors significantly associated with BCRL were ALND, chemotherapy, radiation, and obesity.
Conclusions
BCRL is a sequelae of multimodal breast cancer treatment and risk is multifactorial. BCRL rates are higher in patients receiving chemotherapy, radiation, ALND, more advanced disease stage, and higher body mass index.
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Clinical Decision-Making in Patients with Variant of Uncertain Significance in BRCA1 or BRCA2 Genes
Abstract
Background
How diagnosis with a variant of uncertain significance (VUS) in a BRCA gene impacts clinical decision-making is not well known.
Methods
We queried for all patients attending Mayo Clinic Rochester from 2004 to 2016 who tested positive for BRCA1 or BRCA2 VUS and reviewed patient management choices. Groups were compared by using Wilcoxon rank-sum and Chi-square tests.
Results
We identified 97 patients (95 females, 2 males) with BRCA VUS. For patients without cancer history (n = 20), 80% had a mother or sister with breast cancer, and median Tyrer-Cuzick (IBIS) lifetime breast cancer risk score was 27% (range 16–62%). Management included bilateral prophylactic mastectomy (BPM) in 39%, where choice for BPM was significantly associated with IBIS score (median 32 vs. 24%, p = 0.02) and first-degree family history of breast cancer (100 vs. 64%, p = 0.03) but not Gail score or total number of family members with cancer. For patients with breast cancer who had known VUS status prior to surgery (n = 9), the rate of contralateral prophylactic mastectomy (CPM) was 22% compared with 25% without known VUS and 83% with known BRCA pathogenic mutation. In 21 of 97 (22%) patients, the BRCA VUS has been reclassified (95% benign, 5% deleterious).
Conclusions
BRCA VUS carriers with cancer elected surgical choices similar to average-risk breast cancer patients. However, VUS carriers without cancer had high rates of BPM, associated with first-degree family history and IBIS score. Over time, a significant proportion of BRCA VUS were reclassified, illustrating the importance of appropriate counseling regarding VUS.
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Contralateral Prophylactic Mastectomy with Immediate Breast Reconstruction Increases Healthcare Utilization and Cost
Abstract
Background
The rates of contralateral prophylactic mastectomy (CPM) in women with unilateral breast cancer continue to rise, especially in women undergoing immediate breast reconstruction (IBR).
Methods
We utilized administrative claims data from a large US commercial insurance database (OptumLabs) to identify women age 18–64 years who underwent IBR between January 2004 and December 2013. We compared 2-year unadjusted utilization rates and total costs of care between unilateral mastectomy (UM) and bilateral mastectomy (BM) for implant-based and autologous reconstruction. Comparisons were tested using t-test and differences in cost were estimated using the Wilcoxon rank-sum test.
Results
Overall, 11,235 women undergoing mastectomy with IBR were identified; 7319 with implant reconstruction [1923 UM (26%) and 5396 BM (74%)] and 3916 with autologous reconstruction [1687 UM (43%) and 2229 BM (57%)]. The overall rate of office visits (2386 vs. 2391 per 100 women, p = 0.42) and hospital readmission rate (29.1 per 100 women vs. 27.4, p = 0.06) were similar between BM + IBR and UM + IBR. Women undergoing BM + IBR had a higher emergency room (ER) visit rate (34.1 per 100 women vs. 29.8, p < 0.0001). The total 2-year cost of care was higher for BM + IBR than UM + IBR for implant reconstruction ($106,711 vs. $97,218, p < 0.0001) and for autologous reconstruction ($114,725 vs. $87,874, p < 0.0001).
Conclusions
BM + IBR (autologous or implant) was associated with increased ER visits and higher total cost of care over 2 years compared with UM + IBR. Patients considering CPM should be counseled on the additional risks and costs associated with BM + IBR.
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Evaluating the Risk of Upstaging HER2-Positive DCIS to Invasive Breast Cancer
Abstract
Background
Overexpression of human epidermal growth factor 2 (HER2) in invasive breast cancer (IBC) is an independent poor prognostic factor. However, the significance of HER2 overexpression in ductal carcinoma in situ (DCIS) is not well defined. The current study assessed the correlation of HER2+ DCIS with the rate of upstaging to IBC on the final pathology.
Methods
The study retrospectively analyzed patients with the diagnosis of DCIS on core needle biopsy (CNB) at the authors' institution from 2009 to 2016. Data were analyzed using two-sample t tests. Multivariate analysis was performed using logistic regression.
Results
The study found that HER2+ DCIS had significantly higher rates of upstaging to IBC than HER2− DCIS (odds ratio [OR] 1.89; p = 0.012). In addition, triple-positive disease was more than two times more likely to be upstaged (OR 2.5; p = 0.01), whereas patients with estrogen (ER)-positive, progesterone (PR)-positive, and HER2− diseases were half as likely to be upstaged (OR 0.5; p = 0.04). Upstaging did not differ for patients with triple-negative disease (OR 0.89; p = 0.8). Additionally, patients with HER2+ DCIS were significantly younger regardless of ER/PR status (p = 0.03). The overexpression of HER2 in patients with an initial diagnosis of DCIS on CNB were twice as likely to have IBC on the final pathology as those who did not.
Conclusion
The results suggest that overexpression of HER2 may serve as a biomarker for risk stratification of patients with DCIS and may help to guide treatment strategies in the future. For institutions in which HER2 testing may be performed on DCIS, patients should be counseled appropriately about the risk of upgrade to IBC.
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A 10-Year Experience with Mastectomy and Tissue Expander Placement to Facilitate Subsequent Radiation and Reconstruction
Abstract
Background
An integrated approach to skin sparing mastectomy with tissue expander placement followed by radiotherapy and delayed reconstruction was initiated in our institution in 2002. The purpose of this study was to assess the surgical outcomes of this strategy.
Methods
Between September 2002 and August 2013, a total of 384 reconstructions had a tissue expander placed at the time of mastectomy and subsequently underwent radiotherapy. Rates and causes of tissue expander explantation before, during, and after radiotherapy, as well as tumor specific outcomes and reconstruction approaches, were collected.
Results
Median follow-up after diagnosis was 5.6 (range 1.3–13.4) years. In the study cohort, 364 patients (94.8%) had stage II–III breast cancer, and 7 patients (1.8%) had locally recurrent disease. The 5-year rates of actuarial locoregional control, disease-free survival, and overall survival were 99.2, 86.1, and 92.4%, respectively. The intended delayed-immediate reconstruction was subsequently completed in 325 of 384 mastectomies (84.6% of the study cohort). Of the remaining 59 tissue expanders, 1 was explanted before radiotherapy, 1 during radiotherapy, and 7 patients (1.8%) were lost to follow-up. Fifty patients (13.0%) required tissue expander explantation after radiation and before their planned final reconstruction, primarily due to cellulitis. Nonetheless, the cumulative rate of completed reconstructions was 89.6%. The median time from placement of the tissue expander until reconstruction was 12 (interquartile range 9–15) months.
Conclusions
Tissue expander placement at skin-sparing mastectomy in patients who require radiotherapy appears to be a viable strategy for combining reconstruction and radiotherapy.
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Predicting Nodal Positivity in Women 70 Years of Age and Older with Hormone Receptor-Positive Breast Cancer to Aid Incorporation of a Society of Surgical Oncology Choosing Wisely Guideline into Clinical Practice
Abstract
Purpose
One of the Society of Surgical Oncology Choosing Wisely guidelines recommends avoiding routine sentinel lymph node (SLN) surgery in clinically node-negative women ≥70 years of age with hormone receptor-positive (HR+) breast cancer. We sought to assess the impact of tumor stage and grade on nodal positivity, and to develop a model to identify patients at low-risk of nodal positivity to aid adoption of the guideline.
Methods
We identified women ≥70 years of age with HR+ cN0 invasive breast cancer in the National Cancer Database (NCDB; 2010–2013) and examined the impact of tumor stage and grade on nodal positivity to identify low-risk combinations. A multivariable logistic regression model was developed to incorporate additional factors. The area under the curve (AUC) and relative risks (RR) were used to assess performance.
Results
Among 71,834 cases, the pathologic nodal positivity (pN+) rate was 15.3%. We identified low-risk criteria as grade 1, cT1mi-T1c (≤2.0 cm), or grade 2, cT1mi-T1b (≤1.0 cm), with pN+ rates of 7.8% compared with 22.3% in patients not meeting these criteria (RR 2.86, p < 0.001). On multivariable analysis, factors associated with pN+ status included clinical T stage, grade, and histology (each p < 0.001). The resulting model had AUC 0.70 and identified women with low predicted probability (<10%) of positive nodes, of whom 6.3% were pN+, versus 21.2% in those with predicted probability ≥10% (RR 3.34, p < 0.001).
Conclusion
The simple clinical rule (grade 1, cT1mi-T1c, or grade 2, cT1mi-T1b), as well as the predictive model, both identify women at low risk of nodal positivity where SLN surgery can be omitted.
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Influence of Distance to Hospital and Insurance Status on the Rates of Contralateral Prophylactic Mastectomy, a National Cancer Data Base study
Abstract
Introduction
We evaluated the impact of travel distance and insurance status on contralateral prophylactic mastectomy (CPM) rates in breast cancer.
Methods
We queried the National Cancer Data Base (NCDB) for women >18 years of age with a nonmetastatic primary breast cancer of ductal, lobular, or mixed histology. Patient- and facility-specific CPM rates were calculated based on insurance, race, and distance to treatment center. Standard univariable and multivariable regression analysis was performed.
Results
Overall, the CPM rate was 6.5% for the 864,105 patients identified. Most patients traveled <20 miles to a treatment center (79.5%) and had private insurance or Medicare (58.3 and 33.4%, respectively). In general, younger, White, non-Hispanic, and privately insured patients residing further from a treatment center was associated with increased rates of CPM. However, distance to the treatment center and insurance type had a greater absolute impact on rates of CPM for Black and Hispanic patients. Absolute CPM rate increases for patients >100 miles from a treatment center compared with those <20 miles from a treatment center were observed to be greater for Black and Hispanic patients (3.5 and 3.9%, respectively) compared with White and non-Hispanic patients (2.5 and 2.6%). Additionally, further patient travel distance was associated with higher treatment center-specific CPM rates.
Conclusion
Increased travel distance is independently associated with increased rates of CPM for all patients and increased facility-specific rates of CPM. Black and Hispanic patients were found to be more vulnerable to the impact of travel distance and insurance status on rates of CPM.
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Intraoperative Radiation Using Low-Kilovoltage X-Rays for Early Breast Cancer: A Single Site Trial
Abstract
Introduction
Two prospective, randomized trials, TARGIT-A and ELIOT, have shown intraoperative radiation therapy (IORT) to be a safe alternative to whole breast radiation therapy following breast-conserving surgery for selected low-risk patients. However, minimal data are available about the clinical effectiveness of this modality of treatment using the Xoft® Axxent® Electronic Brachytherapy (eBx®) System®.
Methods
A total of 201 patients with 204 early-stage breast cancers were enrolled in a prospective X-ray IORT trial from June 2010 to September 2013. All tumors were treated with breast-conserving surgery and IORT. Data were collected at 1 week, 1 month, 6 months, 1 year, and yearly thereafter.
Results
With a median follow-up of 50 months, there have been seven ipsilateral breast tumor events (IBTE), no regional or distant recurrences, and no breast cancer-related deaths. One IBTE was within the IORT field, four outside of the IORT field but within the same quadrant as the index cancer, and two were new biologically different cancers in different quadrants. Three events were in patients who deviated from the protocol criteria. Kaplan–Meier analysis projects that 2.9% of patients will recur locally at 4 years.
Conclusions
Recurrence rates observed in this trial were comparable to those of the TARGIT-A and ELIOT trials as well as the retrospective TARGIT-R trial. The low complication rates previously reported by our group as well as the low recurrence rates reported in this study support the cautious use and continued study of IORT in selected women with low-risk breast cancer.
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Differences Among a Modern Cohort of BRCA Mutation Carriers Choosing Bilateral Prophylactic Mastectomies Compared to Breast Surveillance
Abstract
Background
Women with a BRCA mutation have significantly elevated breast cancer risk, which can be reduced by >90% with bilateral prophylactic mastectomy (BPM). We sought to compare a cohort of BRCA mutation carriers choosing BPM versus breast surveillance to better elucidate factors that may impact decision making.
Methods
Women with a BRCA mutation were retrospectively identified from a prospectively maintained database. The surveillance cohort (n = 313) consisted of women seen in a high-risk clinic between 2014 and 2016, while the surgery cohort (n = 142) consisted of women who underwent BPM between 2010 and 2016. Clinical and familial factors were compared between the groups.
Results
Women choosing BPM were more likely to have a BRCA1 than BRCA2 mutation compared with the surveillance group (57 vs. 45%, p = 0.02) and were less likely to have a personal history of ovarian cancer (10 vs. 20%, p = 0.01). Furthermore, women undergoing BPM were more likely to be married (78 vs. 62%, p = 0.01), to have more children (median 2 vs. 1, p < 0.001), and to have undergone a prophylactic oophorectomy (61 vs. 37%, p < 0.001). Women choosing BPM had more first-degree relatives (63 vs. 48%, p = 0.01) or a sister (23 vs. 14%, p = 0.02) with a history of breast cancer and were more likely to have a family member with ovarian cancer under the age of 40 years (9 vs. 4%, p = 0.03). There was no difference in the number of prior breast biopsies or history of atypia/lobular carcinoma in situ.
Conclusion
The decision to undergo BPM appears multifactorial, with gene mutation, family history, and relationships appearing to have the strongest influence on decision making.
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MACRA and the Changing Medicare Payment Landscape
Abstract
Background
The Medicare Access and CHIP Reauthorization Act (MACRA) is being implemented in 2017 by the Centers for Medicare and Medicaid Services (CMS) as the Quality Payment Program (QPP) and will have important and far reaching effects on how physicians are reimbursed and on how they practice. The QPP modifies the Medicare physician payment system by eliminating the Sustainable Growth Rate formula and incorporating the existing Physician Quality Reporting System, EHR Incentive Program, and the Value Modifier into a single new Merit-based Incentive Payment System (MIPS).
Methods
The authors reviewed the MACRA legislation as well as the CMS resources on the QPP and other sources to summarize the regulations pertaining to the new program, particularly for the first performance period.
Results
CMS has taken great care to create a smooth transition for Medicare physicians. Clinicians can avoid any penalty for performance in 2017 by submitting a minimal amount of quality data, attesting to a single improvement activity, or successfully attaining the base score for the advancing care information portion of MIPS. The reduced reporting period also makes it possible for participants to begin collecting data as late as October 2nd and still achieve the full possible score in the program.
Conclusions
Surgeons should be taking steps now to ensure that they are prepared to succeed in the QPP. The transition period creates a clear pathway for avoiding penalties while providing an opportunity to test one's ability to participate and improve performance.
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Prospective Study Comparing Surgeons’ Pain and Fatigue Associated with Nipple-Sparing versus Skin-Sparing Mastectomy
Abstract
Background
Nipple-sparing mastectomy (NSM) is more technically challenging than skin-sparing mastectomy (SSM) but offers quality-of-life and cosmetic advantages. However, surgeon physical symptoms related to NSM workload have not been documented.
Methods
This was a prospective study using questionnaires to compare surgeon-reported physical symptoms before, during, and after NSM versus SSM. Surgeons also answered general questions about each mastectomy. Bilateral cases were performed simultaneously by two surgeons, who completed independent questionnaires.
Results
Questionnaires were completed after 82 SSMs and 44 NSMs. On a 0–10 scale, surgeons reported NSM was more physically demanding than SSM (7.0 vs. 4.5, p < 0.001). Mean visualization was more difficult (5.7 vs. 3.2, p < 0.001) and mean fatigue score was greater (5.6 vs. 3.1, p < 0.001) after NSM than SSM. The mean increase in neck pain (on a 0–4 scale) was greater for NSM than SSM, both from before-to-during surgery (0.8 vs. 0.2, p = 0.003) and before-to-after surgery (0.9 vs. 0.2, p = 0.002). The mean increase in lower back pain was greater for NSM than SSM, both from before-to-during surgery (0.7 vs. 0.2, p = 0.008) and before-to-after surgery (0.9 vs. 0.2, p = 0.003). Surgeons reported that NSM was more mentally demanding (p < 0.001), complex (p = 0.01), and difficult (p < 0.001) than SSM.
Conclusion
Surgeons experienced greater physical symptoms, mental strain, and fatigue with NSM than SSM. This raises concern that mild but repetitive pain over the course of a breast surgeon's career may lead to repetitive stress injury.
http://ift.tt/2jkERnf
Selective Use of Sentinel Lymph Node Surgery in Patients Undergoing Prophylactic Mastectomy Using Intraoperative Pathology
Abstract
Background
Routine sentinel lymph node (SLN) surgery during prophylactic mastectomy (PM) is unnecessary, because most PMs do not contain cancer. Our institution utilizes intraoperative pathology to guide the surgical decision for resection of SLNs in PM. The purpose of this study was to review the effectiveness of this approach.
Methods
We identified all women aged ≥18 years who underwent bilateral PM (BPM) or contralateral PM (CPM) at our institution from January 2008 to July 2016. We evaluated the frequency of SLN resection and rate of occult breast cancer (DCIS or invasive disease) in the PM. We used the following definitions: over-treatment—SLN surgery in patients without cancer; under-treatment—no SLN surgery in patients with cancer; appropriate treatment—no SLN in patients without cancer or SLN surgery in patients with cancer.
Results
PM was performed on 1900 breasts: 1410 (74.2%) CPMs and 490 (25.8%) BPMs. Cancer was identified in 58 (3.0%) cases (32 invasive disease and 26 DCIS) and concurrent SLN surgery was performed in 44 (75.9%) of those cases. Overall, SLN surgery guided by intraoperative pathology resulted in appropriate treatment of 1787 (94.1%) cases: 1319 (93.5%) CPMs and 468 (95.5%) BPMs, by avoiding SLN in 1743/1842 cases without cancer (94.6%), and performing SLN surgery in 44/58 cases with cancer (75.9%).
Conclusions
Use of intraoperative pathology to direct SLN surgery in patients undergoing PM minimizes over-treatment from routine SLN in PM and minimizes under-treatment from avoiding SLN in PM, demonstrating the value of intraoperative pathology in this era of focus on appropriateness of care.
http://ift.tt/2f0OohF
Efficacy and safety of controlled-release oxycodone/naloxone versus controlled-release oxycodone in Korean patients with cancer-related pain: a randomized controlled trial
Controlled-release oxycodone/naloxone (OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The present...
http://ift.tt/2w3pPrL
An unusual presentation of chronic cyanide toxicity from self-prescribed apricot kernel extract
Hypoxia under general anaesthesia is a potentially life-threatening condition. A seemingly well 67-year-old man appeared hypoxic with peripheral pulse oximetric measurement during routine anaesthesia. Postoperatively, the patient admitted to daily self-prescription of apricot kernel extract for a period of 5 years. Apricot kernel is a commonly taken extract used for a range of ailments, and is associated with cyanide toxicity, which was confirmed through blood analysis. Our explanation for the hypoxic measurement was the presence of free cyanide interfering with functioning of the peripheral pulse oximeter. On cessation of the apricot kernel extract, peripheral oxygen saturations returned to normal. Cardiac and respiratory causes together with rare haemoglobinopathies were excluded. This case illustrates how chronic dosing of complementary medicines can result in harmful toxicities, which may carry potential for serious consequences and how these chronic toxicities may present to physicians in atypical ways.
http://ift.tt/2f02b8w
Efficacy and safety of controlled-release oxycodone/naloxone versus controlled-release oxycodone in Korean patients with cancer-related pain: a randomized controlled trial
Abstract
Background
Controlled-release oxycodone/naloxone (OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The present study was designed to assess the non-inferiority of OXN-CR to controlled-release oxycodone (OX-CR) for the control of cancer-related pain in Korean patients.
Methods
In this randomized, open-labeled, parallel-group, phase IV study, we enrolled patients aged 20 years or older with moderate to severe cancer-related pain [numeric rating scale (NRS) pain score ≥4] from seven Korean oncology/hematology centers. Patients in the intention-to-treat (ITT) population were randomized (1:1) to OXN-CR or OX-CR groups. OXN-CR was administered starting at 20 mg/10 mg per day and up-titrated to a maximum of 80 mg/40 mg per day for 4 weeks, and OX-CR was administered starting at 20 mg/day and up-titrated to a maximum of 80 mg/day for 4 weeks. The primary efficacy endpoint was the change in NRS pain score from baseline to week 4, with non-inferiority margin of −1.5. Secondary endpoints included analgesic rescue medication intake, patient-reported change in bowel habits, laxative intake, quality of life (QoL), and safety assessments.
Results
Of the ITT population comprising 128 patients, 7 with missing primary efficacy data and 4 who violated the eligibility criteria were excluded from the efficacy analysis. At week 4, the mean change in NRS pain scores was not significantly different between the OXN-CR group (n = 58) and the OX-CR group (n = 59) (−1.586 vs. −1.559, P = 0.948). The lower limit of the one-sided 95% confidence interval (−0.776 to 0.830) for the difference exceeded the non-inferiority margin (P < 0.001). The OXN-CR and OX-CR groups did not differ significantly in terms of analgesic rescue medication intake, change in bowel habits, laxative intake, QoL, and safety assessments.
Conclusions
OXN-CR was non-inferior to OX-CR in terms of pain reduction after 4 weeks of treatment and had a similar safety profile. Studies in larger populations of Korean patients with cancer-related pain are needed to further investigate the effectiveness of OXN-CR for long-term pain control and constipation alleviation.
Trial registration ClinicalTrials.gov NCT01313780, registered March 8, 2011
http://ift.tt/2jjKhPd
Sophoridine induces apoptosis and S phase arrest via ROS-dependent JNK and ERK activation in human pancreatic cancer cells
Abstract
Background
Pancreatic cancer is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Novel, selective antitumor agents are pressingly needed.
Methods
CCK-8 and colony formation assay were used to investigate the cell growth. Flow cytometry analysis was used to evaluate the cell cycle and cell apoptosis. The peroxide-sensitive fluorescent probe DCFH-DA was used to measure the intracellular ROS levels. Western blot assay was used to detect the levels of cell cycle and apoptosis related proteins. Xenografts in nude mice were used to evaluate the effect of Sophoridine on pancreatic cancer cell in vivo.
Results
Sophoridine killed cancer cells but had low cytotoxicity to normal cells. Pancreatic cancer cells were particularly sensitive. Sophoridine inhibited the proliferation of pancreatic cancer cells and induced cell cycle arrest at S phase and mitochondrial-related apoptosis. Moreover, Sophoridine induced a sustained activation of the phosphorylation of ERK and JNK. In addition, Sophoridine provoked the generation of reactive oxygen species (ROS) in pancreatic cancer cells. Finally, in vivo, Sophoridine suppressed tumor growth in mouse xenograft models.
Conclusion
These findings suggest Sophoridine is promising to be a novel, potent and selective antitumor drug candidate for pancreatic cancer.
http://ift.tt/2jkezkK
Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication
Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication
Oncogenesis 6, e377 (September 2017). doi:10.1038/oncsis.2017.76
Authors: Y Ishikawa, K Nakayama, M Morimoto, A Mizutani, A Nakayama, K Toyoshima, A Hayashi, S Takagi, R Dairiki, H Miyashita, S Matsumoto, K Gamo, T Nomura & K Nakamura
http://ift.tt/2gZ2rkV
The induction of apoptosis and autophagy in human hepatoma SMMC-7721 cells by combined treatment with vitamin C and polysaccharides extracted from Grifola frondosa
Abstract
Polysaccharides extracted from the mushroom Grifola frondosa (GFP) are a potential anticancer agent. The objective of this study was to investigate the effect of GFP and vitamin C (VC) alone and in combination on the viability of human hepatocarcinoma SMMC-7721 and HepG2 cells. Studies designed to detect cell apoptosis and autophagy were also conducted to investigate the mechanism. Results from the cell viability assay indicated that a combination of GFP (0.2 or 0.25 mg/mL) and VC (0.3 mmol/L) (GFP/VC) led to 52.73 and 53.93% reduction in cell viability of SMMC-7721 and HepG2 cells separately after 24 h. Flow cytometric analysis indicated that GFP/VC treatment induced cell cycle arrest at the G2/M phase, and apoptosis occurred in approximately 43.62 and 42.46% of the SMMC-7721 and HepG2 cells separately. Moreover, results of Hoechst33258 and monodansylcadaverine staining, and transmission electron microscopy, showed that GFP/VC induced apoptosis and autophagy in SMMC-7721 and HepG2 cells. Western blot analysis showed changes in the expression of apoptosis-related proteins [upregulation of BAX and caspase-3, downregulation of Bcl-2, and activation of poly-(ADP-ribose)-polymerase] and autophagy protein markers (upregulation of beclin-1 and microtubule-associated protein 1A/1B light chain-3). We also demonstrated that the expression of both Akt and p-Akt was enhanced, suggesting the PI3K/Akt/mTOR pathway might not be involved in this process. Our study shows that the combined application of GFP and VC induced cell apoptosis and autophagy in vitro, and might have antitumor activity in vivo.
http://ift.tt/2jiUMlO
XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis
Abstract
Background
Breast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. Despite improvement in diagnosis, the survival rate of this disease has still not improved. X-linked Inhibitor of Apoptosis (XIAP) has been shown to be over-expressed in various cancers leading to poor overall survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored.
Methods
We examined the expression of XIAP in more than 1000 Middle Eastern breast cancer cases by immunohistochemistry. Apoptosis was measured by flow cytometry. Protein expression was determined by western blotting. Finally, in vivo studies were performed on nude mice following xenografting and treatment with inhibitors.
Results
XIAP was found to be over-expressed in 29.5% of cases and directly associated with clinical parameters such as tumor size, extra nodal extension, triple negative breast cancer and poorly differentiated breast cancer subtype. In addition, XIAP over-expression was also significantly associated with PI3-kinase pathway protein; p-AKT, proliferative marker; Ki-67 and anti-apoptotic marker; PARP. XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; embelin and found that embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. Finally, breast cancer cells treated with combination of embelin and PI3-kinase inhibitor; LY294002 synergistically induced apoptosis and caused tumor growth regression in vivo.
Conclusion
These data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells.
http://ift.tt/2w0VPwZ
Long-lasting complete response status of advanced stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine: two case reports
Abstract
Background
The prognosis of advanced (stage IV) cancer of the digestive organs is very poor. We have previously reported a case of advanced breast cancer with bone metastasis that was successfully treated with combined treatments including autologous formalin-fixed tumor vaccine (AFTV). Herein, we report the success of this approach in advanced stage IV (heavily metastasized) cases of gall bladder cancer and colon cancer.
Case presentation
Case 1: A 61-year-old woman with stage IV gall bladder cancer (liver metastasis and lymph node metastasis) underwent surgery in May 2011, including partial resection of the liver. She was treated with AFTV as the first-line adjuvant therapy, followed by conventional chemotherapy. This patient is still alive without any recurrence, as confirmed with computed tomography, for more than 5 years.
Case 2: A 64-year-old man with stage IV colon cancer (multiple para-aortic lymph node metastases and direct abdominal wall invasion) underwent non-curative surgery in May 2006. Following conventional chemotherapy, two courses of AFTV and radiation therapy were administered sequentially. This patient has had no recurrence for more than 5 years.
Conclusion
We report the success of combination therapy including AFTV in cases of liver-metastasized gall bladder cancer and abdominal wall-metastasized colon cancer. Both patients experienced long-lasting, complete remission. Therefore, combination therapies including AFTV should be considered in patients with advanced cancer of the digestive organs.
http://ift.tt/2gZgSW8
Cell-specific mechanisms of TMEM16A Ca 2+ -activated chloride channel in cancer
Abstract
TMEM16A (known as anoctamin 1) Ca2+-activated chloride channel is overexpressed in many tumors. TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification. TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs. In addition, TMEM16A activates different signaling pathways in different cancers, e.g. the EGFR and CAMKII signaling in breast cancer, the p38 and ERK1/2 signaling in hepatoma, the Ras-Raf-MEK-ERK1/2 signaling in head and neck squamous cell carcinoma and bladder cancer, and the NFκB signaling in glioma. Furthermore, TMEM16A overexpression has been reported to promote, inhibit, or produce no effects on cell proliferation and migration in different cancer cells. Since TMEM16A exerts different roles in different cancer cells via activation of distinct signaling pathways, we try to develop the idea that TMEM16A regulates cancer cell proliferation and migration in a cell-dependent mechanism. The cell-specific role of TMEM16A may depend on the cellular environment that is predetermined by TMEM16A overexpression mechanisms specific for a particular cancer type. TMEM16A may exert its cell-specific role via its associated protein networks, phosphorylation by different kinases, and involvement of different signaling pathways. In addition, we discuss the role of TMEM16A channel activity in cancer, and its clinical use as a prognostic and predictive marker in different cancers. This review highlights the cell-type specific mechanisms of TMEM16A in cancer, and envisions the promising use of TMEM16A inhibitors as a potential treatment for TMEM16A-overexpressing cancers.
http://ift.tt/2wWbYmc
Pain in cancer survivors; filling in the gaps
Abstract
Cancer survivorship represents a growing clinical challenge for pain clinicians. The population of cancer survivors is rapidly expanding and many of these patients experience pain as a sequelae of their disease and its treatment. The features, pathophysiology and natural history of some painful conditions observed in cancer survivors, such as direct tumour effects, cancer induced bone pain (CIBP) or chronic post-surgical pain have received extensive exposure elsewhere in the literature. In this narrative review, we attempt to 'fill in the gaps' in the knowledge, by providing a succinct outline of a range of less well known pain states encountered in the cancer survivor population. These include neuropathies as a result of graft versus host disease (GVHD), novel chemotherapeutic agents and monoclonal antibodies (mAb), and radiation induced pain states. The increasing prevalence of visceral post-surgical pain and aromatase inhibitor-induced arthralgia (AIA) is also detailed. Additionally an overview of suggested approaches to the assessment of pain in cancer survivors is provided and potential treatment strategies, with a focus on novel approaches are discussed.http://ift.tt/2gZzPb9
Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease
Abstract
Prognosis of metastatic melanoma improved with the development of checkpoint inhibitors. The role of tumor infiltrating lymphocytes (TILs) in lymph node metastases of stage III melanoma remains unclear. We retrospectively characterized TILs in primary melanomas and matched lymph node metastases (stage III melanoma) of patients treated with the checkpoint inhibitor ipilimumab. Tumor infiltrating lymphocytes were characterized for CD3, CD4, and CD8 expressions by immunohistochemistry. 4/9 patients (44%) responded to treatment with ipilimumab (1 complete and 2 partial remissions, 1 stable disease). All responders exhibited CD4 and CD8 T-cell infiltration in their lymph node metastases, whereas all non-responders did not show an infiltration of the lymph node metastasis with TILs. The correlation between the presence and absence of TILs in responders vs. non-responders was statistically significant (p = 0.008). Median distant metastases free survival, i.e., progression from stage III to stage IV melanoma, was similar in responders and non-responders (22.1 vs. 19.3 months; p = 0.462). Median progression free and overall survival show a trend in favor of the patients having TIL rich lymph node metastases (6.8 vs. 3.3 months, p = 0.09; and all alive at last follow-up vs. 8.2 months, respectively, p = 0.08). Our data suggest a correlation between the T-cell infiltration of the lymph node metastases in stage III melanoma and the response to ipilimumab once these patients progress to stage IV disease.
http://ift.tt/2wl3q4s
Collective invasion in ductal and lobular breast cancer associates with distant metastasis
Abstract
Breast cancer undergoes collective tissue invasion and, in experimental models, can collectively metastasize. The prevalence of collective invasion and its contribution to distant metastasis in clinical disease, however, remains poorly defined. We here scored the adipose tissue invasion of primary invasive ductal carcinoma (IDC), expressing E-cadherin, and E-cadherin negative invasive lobular carcinoma (ILC) and identified predominantly collective invasion patterns (86/86 samples) in both carcinoma types. Whereas collective invasion in IDC lesions retained adherens junctions, multicellular clusters and "Indian files" in ILC, despite the absence of adherens junctions (AJ) proteins E-cadherin and β-catenin, retained CD44 at cell–cell contacts. By histomorphological scoring and semi-automated image analysis, we show that the extent of collective invasion into the adipose tissue correlated with decreased distant metastasis-free survival (5-year follow-up; hazard ratio: 2.32 and 2.29, respectively). Thus, collective invasion represents the predominant invasion mode in breast cancer, develops distinct junctional subtypes in IDC and ILC, and associates with distant metastasis, suggesting a critical role in systemic dissemination.
http://ift.tt/2w1E801
CAR T-Cell Therapy Approved for Some Children and Young Adults with Leukemia
FDA has approved tisagenlecleucel (Kymriah™), a type of immunotherapy called CAR T-cell therapy, for some children and young adults with advanced acute lymphoblastic leukemia (ALL).
http://ift.tt/2gYI8nz
BRCA2 carriers with male breast cancer show elevated tumour methylation
Abstract
Background
Male breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. However, recent studies demonstrate biological and molecular differences likely to impact on tumour behaviour and therefore patient outcome. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs.
Methods
60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families were assessed for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARβ, CDH1, RUNX3, FOXC1 and GSTP1). An average methylation index (AMI) was calculated for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation. Promoter hypermethylation and AMI were correlated with BRCA carrier mutation status and clinicopathological parameters including tumour stage, grade, histological subtype and disease specific survival.
Results
Tumours arising in BRCA2 mutation carriers showed significantly higher methylation of candidate genes, than those arising in non-BRCA2 familial MBCs (average AMI 23.6 vs 16.6, p = 0.01, 45% of genes hypermethylated vs 34%, p < 0.01). RARβ methylation and AMI-high status were significantly associated with tumour size (p = 0.01 and p = 0.02 respectively), RUNX3 methylation with invasive carcinoma of no special type (94% vs 69%, p = 0.046) and RASSF1A methylation with coexistence of high grade ductal carcinoma in situ (33% vs 6%, p = 0.02). Cluster analysis showed MBCs arising in BRCA2 mutation carriers were characterised by RASSF1A, WIF1, RARβ and GTSP1 methylation (p = 0.02) whereas methylation in BRCAX tumours showed no clear clustering to particular genes. TWIST1 methylation (p = 0.001) and AMI (p = 0.01) were prognostic for disease specific survival.
Conclusions
Increased methylation defines a subset of familial MBC and with AMI may be a useful prognostic marker. Methylation might be predictive of response to novel therapeutics that are currently under investigation in other cancer types.
http://ift.tt/2wVKSeU
Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease
Abstract
Prognosis of metastatic melanoma improved with the development of checkpoint inhibitors. The role of tumor infiltrating lymphocytes (TILs) in lymph node metastases of stage III melanoma remains unclear. We retrospectively characterized TILs in primary melanomas and matched lymph node metastases (stage III melanoma) of patients treated with the checkpoint inhibitor ipilimumab. Tumor infiltrating lymphocytes were characterized for CD3, CD4, and CD8 expressions by immunohistochemistry. 4/9 patients (44%) responded to treatment with ipilimumab (1 complete and 2 partial remissions, 1 stable disease). All responders exhibited CD4 and CD8 T-cell infiltration in their lymph node metastases, whereas all non-responders did not show an infiltration of the lymph node metastasis with TILs. The correlation between the presence and absence of TILs in responders vs. non-responders was statistically significant (p = 0.008). Median distant metastases free survival, i.e., progression from stage III to stage IV melanoma, was similar in responders and non-responders (22.1 vs. 19.3 months; p = 0.462). Median progression free and overall survival show a trend in favor of the patients having TIL rich lymph node metastases (6.8 vs. 3.3 months, p = 0.09; and all alive at last follow-up vs. 8.2 months, respectively, p = 0.08). Our data suggest a correlation between the T-cell infiltration of the lymph node metastases in stage III melanoma and the response to ipilimumab once these patients progress to stage IV disease.
http://ift.tt/2wl3q4s
Distinct molecular subtypes of uterine leiomyosarcoma respond differently to chemotherapy treatment
Abstract
Background
Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood.
Methods
Expression profiling data were used to determine the possibility and optimal number of ULMS molecular subtypes. Next, clinicopathological characters and molecular pathways were analyzed in each subtype to prospect the clinical applications and progression mechanisms of ULMS.
Results
Two distinct molecular subtypes of ULMS were defined based on different gene expression signatures. Subtype I ULMS recapitulated low-grade ULMS, the gene expression pattern of which resembled normal smooth muscle cells, characterized by overexpression of smooth muscle function genes such as LMOD1, SLMAP, MYLK, MYH11. In contrast, subtype II ULMS recapitulated high-grade ULMS with higher tumor weight and invasion rate, and was characterized by overexpression of genes involved in the pathway of epithelial to mesenchymal transition and tumorigenesis, such as CDK6, MAPK13 and HOXA1.
Conclusions
We identified two distinct molecular subtypes of ULMS responding differently to chemotherapy treatment. Our findings provide a better understanding of ULMS intrinsic molecular subtypes, and will potentially facilitate the development of subtype-specific diagnosis biomarkers and therapy strategies for these tumors.
http://ift.tt/2wW0j6D
Elevated Expression of ΔNp63 in Advanced Esophageal Squamous Cell Carcinoma
Abstract
This study aims to explore the expression level of ΔNp63 in esophageal squamous cell carcinoma (ESCC). To investigate the association between ΔNp63 (p40) expression and ESCC biology, we compared the levels of ΔNp63 expression in normal and tumor tissues, with a specific focus on the diagnostic value of ΔNp63 in ESCC. We analyzed 160 consecutive patients with ESCC who underwent surgical resection without neoadjuvant-chemotherapy at Gunma University Hospital between September 2000 and January 2010. The clinicopathological characteristics and survival of patients were subclassified based on the expression of ΔNp63 as determined by immunohistochemistry, demonstrating that ΔNp63 was highly expressed in 75.6% (121/160) of ESCC patients. Clinicopathological analysis of ΔNp63 expression showed that ΔNp63-positive tumors significantly correlated with two important clinical parameters: T factor (P = 0.0316) and venous invasion (P = 0.0195). The 5-year overall survival rates of advanced ESCC patients with positive and negative expression of ΔNp63 were 35.6% and 71.7%, respectively. Multivariate analysis revealed that the expression of ΔNp63 was identified as an independent prognostic factor (P = 0.0049) in advanced ESCC. In line with this, ΔNp63α-transduced ESCC cell lines increased tumor growth in soft agar colony formation assay. We report here for the first time that ΔNp63 expression increases the oncogenic potential of ESCC and is an independent poor prognostic marker for predicting outcome in advanced ESCC. Our findings suggest that ΔNp63 could serve as a new diagnostic marker for ESCC and might be a relevant therapeutic target for the treatment of patients with this disease.
This article is protected by copyright. All rights reserved.
http://ift.tt/2vPP7p6
Study On The Tumor-Induced Angiogenesis Using Mathematical Models
Abstract
We study angiogenesis using mathematical models describing the dynamics of tip cells. We review the basic ideas of angiogenesis models and its numerical simulation technique to produce realistic computer graphics images of sprouting angiogenesis. We examine the classical model of Anderson-Chaplain using fundamental concepts of mass transport and chemical reaction with ECM degradation included. Then we construct two kind of numerical schemes, model-faithful and model-driven ones, where new techniques of numerical simulation are introduced, such as the transient probability, particle velocity, and Boolean variables.
This article is protected by copyright. All rights reserved.
http://ift.tt/2gWxXU8
Implicating anaesthesia and the perioperative period in cancer recurrence and metastasis
Abstract
Cancer, currently the leading cause of death in the population aged less than 85 years, poses a significant global disease burden and is anticipated to continue to increase in incidence in both developed and developing nations. A substantial proportion of cancers are amenable to surgery, with more than 60% of patients undergoing tumour resection. Up to 80% of patients will receive anaesthesia for diagnostic, therapeutic or palliative intervention. Alarmingly, retrospective studies have implicated surgical stress in disease progression that is predominantly characterised by metastatic disease—the primary cause of cancer-associated mortality. Our understanding of the mechanisms of surgical stress and impact of perioperative interventions is, however, far from complete. Accumulating evidence from preclinical studies suggests that adrenergic-inflammatory pathways may contribute to cancer progression. Importantly, these pathways are amenable to modulation by adapting surgical (e.g. minimally invasive surgery) and anaesthetic technique (e.g. general vs. neuraxial anaesthesia). Disturbingly, drugs used for general anaesthesia (e.g. inhalational vs. intravenous anaesthesia and potentially opioid analgesia) may also affect behaviour of tumour cells and immune cells, suggesting that choice of anaesthetic agent may also be linked to adverse long-term cancer outcomes. Critically, current clinical practice guidelines on the use of anaesthetic techniques, anaesthetic agents and perioperative adjuvants (e.g. anti-inflammatory drugs) during cancer surgery do not take into account their potential effect on cancer outcomes due to a lack of robust prospective data. To help address this gap, we provide an up-to-date review of current clinical evidence supporting or refuting the role of perioperative stress, anaesthetic techniques and anaesthetic agents in cancer progression and review pre-clinical studies that provide insights into biological mechanisms.
http://ift.tt/2wkvtRQ
Severe depression more common in patients with ductal carcinoma in situ than early-stage invasive breast cancer patients
Abstract
Purpose
Ductal carcinoma in situ (DCIS) is associated with an excellent prognosis; historical studies have shown similar levels of psychological distress in patients with DCIS and with early-stage invasive breast cancer (early-IBC). It is suggested that these results might have led to better patient education about prognosis after DCIS. This study reports the current levels of anxiety, depression, and health-related quality of life (HRQoL) in DCIS and early-IBC patients.
Methods
DCIS (n = 89) and early-IBC patients, T1-2N0, (n = 361) were selected from the UMBRELLA breast cancer cohort. Patient-reported outcomes were prospectively collected before the start of adjuvant radiotherapy (baseline) and at 3, 6, 12, 18, and 24 months thereafter. Mixed models were used to compare differences in levels of anxiety, depression, and HRQoL between DCIS and early-IBC patients.
Results
DCIS and early-IBC patients reported similar levels of anxiety, which were highest at baseline. Depression scores were comparable between groups, also after stratification by use of adjuvant chemotherapy. The proportion of patients reporting high-risk depression scores (i.e., Hospital Anxiety and Depression Sale score >8) was significantly higher among patients with DCIS at 6, 12 and 18 months, and this proportion increased over the first 18 months. Health-related quality of life was comparable between both groups.
Conclusion
Severe depression scores are more common in DCIS patients, despite their excellent prognosis. These results suggest that further improvement of patient education and effective patient doctor communication about the prognostic differences between patients with DCIS and invasive breast cancer is still highly needed.
http://ift.tt/2wVMp33
The Impact of Nodal Dissection on Staging in Adrenocortical Carcinoma
Abstract
Background
The role of lymphadenectomy in adrenocortical carcinoma (ACC) is controversial, and formal lymph node (LN) dissection is not routine. We sought to determine the minimum number of LNs that must be examined to accurately identify a patient as node negative.
Methods
The National Cancer Database was used to identify patients diagnosed with ACC from 2004 to 2013 who underwent surgical resection. Patients with distant metastases, multivisceral resection, or missing surgical or lymphadenectomy data were excluded. The primary outcome was overall survival (OS).
Results
LNs were identified on histopathology in 156 patients. Of these, 35 (22%) had at least one positive LN. Positive LNs were associated with positive surgical margins (odds ratio [OR] 5.80, p = 0.002) and increasing LN yield (OR 1.06, p = 0.02). Overall, on Cox regression analysis, LN positivity (hazard ratio [HR] 3.02, p < 0.001) and positive surgical margins (HR 2.06, p = 0.048) independently predicted poor OS after controlling for other factors that may influence survival. LN(−) disease in patients with one to three LNs examined had poorer overall survival compared with when at least four LNs were examined (p = 0.02). None of the other patient, tumor, and treatment variables had any impact on OS of the LN(−) cohort. The likelihood of identifying nodal involvement was higher on examination of at least four LNs compared with examination of one to three LNs (30 vs. 16%, p = 0.03).
Conclusions
LN positivity in ACC tumors independently predicts worse 5-year OS and a minimum of four LNs may be required to accurately determine LN negativity.
http://ift.tt/2wUUC7z
Validation of the 8th Edition of the AJCC TNM Staging System for Gastric Cancer using the National Cancer Database
Abstract
Background
The 8th edition AJCC gastric cancer staging manual was refined using Japanese and Korean data from the International Gastric Cancer Association (IGCA). This study evaluated the eighth edition's validity for U.S. populations.
Methods
National Cancer Database (NCDB) was used to obtain data on gastric cancer patients diagnosed from 2004 to 2008 who underwent surgery and to examine differences in stage grouping and survival between AJCC 7th and 8th editions. Discrimination of models derived from NCDB and IGCA data was compared.
Results
Of 12,041 patients, median age was 65, 57.6% were male, median lymph nodes retrieved was 2 (0–76), 30.9% underwent distal/partial gastrectomy, and 49.8% received no adjuvant treatment. The 8th edition differed in that T1–T3 disease was upstaged with N3b, T4aN3a was downstaged from IIIC to IIIB, and T4bN0 and T4aN2 were downstaged from IIIB to IIIA. These changes resulted in increased patients in IIIA (1436 in the 7th edition to 2310 in the 8th) and IIIB (1737–1896) and decreased in IIIC (2100–1067). This also resulted in lower median survival for IIIA (28.7–25.0 months), IIIB (19.6–17.4), IIIC (13.7–11.8). The concordance index for the 8th edition applied to NCDB data was 0.719 [95% confidence interval (CI) 0.703–0.734), which is comparable to that for the 8th edition developed from IGCA data (0.775, 95% CI 0.770–0.780) and the 7th edition applied to NCDB data (0.720, 95% CI 0.704–0.735).
Conclusions
The 8th edition is valid for U.S. populations, showing clear separation of data with preservation of group order.
http://ift.tt/2xWaSEw
The Oncologic Impact of Postoperative Complications Following Resection of Truncal and Extremity Soft Tissue Sarcomas
Abstract
Introduction
Postoperative complications (POCs) negatively impact oncologic outcomes in some malignancies; however, little is known regarding their effect in soft tissue sarcoma (STS). The aim of this study was to determine the impact of POCs on survival after resection of truncal and extremity STS.
Methods
All patients who underwent resection for a primary truncal or extremity STS at a single academic institution from 2000 to 2015 were included and analyzed. Primary outcome was disease-specific survival (DSS).
Results
Among 546 STS patients, POCs occurred in 159 (29%) patients; 57% were major and 55% were surgical site infections. Patients with POCs were older (61 vs. 53 years), had more comorbidities (50 vs. 38%), longer operative time (127 vs. 93 min), higher-grade tumors (93 vs. 86%), and were more likely to receive preoperative radiation (42 vs. 33%; all p < 0.05). There was no difference in receipt of postoperative therapy between the POCs and no POCs groups (19 vs. 18%, p = 0.74). Median follow-up for survivors was 37 months, and the 5-year DSS for the entire cohort was 78%. Compared with patients without POCs, patients with POCs had a worse DSS (68% vs. 81%, p = 0.001). Predictors for decreased DSS on univariate analysis included POCs (hazard ratio [HR] 2.12, 95% confidence interval [CI] 1.37–3.28, p = 0.001), advanced age, neurovascular/bone resection, positive margin, high grade, and preoperative and postoperative therapy (all p < 0.05). POCs (HR 1.76, 95% CI 1.08–2.87, p = 0.02) remained an independent predictor for reduced DSS on multivariate analysis, along with age (HR 1.02, p = 0.046) and tumor grade (HR 7.62, p = 0.046).
Conclusions
POCs following resection of truncal and extremity STS are associated with decreased DSS. Efforts to optimize modifiable risk factors and decrease the rate of POCs warrant further investigation.
http://ift.tt/2gWDsSO
Benefit of Adjuvant Radiotherapy for Local Control, Distant Metastasis, and Survival Outcomes in Patients with Localized Soft Tissue Sarcoma: Comparative Effectiveness Analysis of an Observational Cohort Study
Abstract
Background
This study aimed to quantify the benefit of adjuvant radiotherapy (AXRT) for local control, distant metastasis, and long-term survival outcomes in patients with localized soft tissue sarcoma (STS).
Methods
This single-center retrospective observational study enrolled 433 STS patients who underwent surgery with curative intent. An inverse probability of treatment-weighted (IPTW) analysis was implemented to account rigorously for imbalances in prognostic variables between the adjuvant treatment groups.
Results
During a median follow-up period of 5.5 years, the study observed 38 local recurrences (9%), 73 occurrences of distant metastasis (17%), 63 STS-related deaths (15%), and 57 deaths from other causes (13%). As expected, patients receiving AXRT (n = 258, 60%) were more likely to have high-grade G3 tumors (p < 0.0001) than patients not receiving AXRT. A crude analysis showed that AXRT was not associated with improved recurrence-free survival [hazard ratio (HR) 1.00; 95% confidence interval (CI) 0.72–1.38; p = 0.98]. However, after IPTW, AXRT was associated with a 38% relative reduction in the risk of recurrence or death (HR 0.62; 95% CI 0.39–1.00; p = 0.05). This benefit was driven by a strong reduction in the risk of local recurrence (HR 0.42; 95% CI 0.19–0.91; p = 0.03), whereas the relative risk of distant metastasis (HR 0.69; 95% CI 0.39–1.25; p = 0.22) and overall survival (HR 0.76; 95% CI 0.44–1.30; p = 0.32) were only nonsignificantly in favor of AXRT. An exploratory analysis showed an overall survival benefit of AXRT for patients with high-grade G3 tumors (HR 0.51; 95% CI 0.33–0.78; p = 0.002). However, this finding may have been attributable to residual confounding.
Conclusion
In this observational cohort, AXRT was associated with a 58% reduction in the relative risk of local recurrence. No consistent association between AXRT and lower risks of distant metastasis or death was observed.
http://ift.tt/2wVAn9C
External Validation of the Prognostic Nomogram (COMPASS) for Patients with Peritoneal Carcinomatosis of Colorectal Cancer
Abstract
Background
To optimize outcome, selection of patients for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is critical. Recently, Simkens et al.7 evaluated the peritoneal surface disease severity score (PSDSS) and suggested a new prognostic nomogram, the colorectal peritoneal metastases prognostic surgical score (COMPASS) based on age, peritoneal carcinomatosis index score, locoregional lymph node status, and signet ring cell histology. This COMPASS nomogram had better discriminative ability according to the Harrell c-index than PSDSS (c = 0.72 vs. 0.62). This study aimed to validate the COMPASS nomogram externally.
Methods
Data were retrieved from a prospectively maintained database, and all patients who underwent surgery between May 2005 and May 2016 were included in the study. For each patient, the PSDSS and COMPASS were calculated and then divided into subgroups. The discriminative ability of both scores for overall survival were quantified using Harrell c indices.
Results
A total of 153 patients underwent CRS + HIPEC for peritoneal carcinomatosis (PC) of colorectal cancer. The median overall survival (OS) was 46 months, and the mean PSDSS was 7.8 ± 3.7. When the PSDSS was divided into subgroups, the c index was 0.67. The mean COMPASS was 55.5 ± 25.6. When the patients were divided into four groups according to cutpoints of Simkens et al.7 a c index of 0.72 was obtained, showing its significant superiority over the discriminative ability of the PSDSS (p = 0.016).
Conclusion
External validation of the COMPASS confirms its moderate to good discriminative ability and its superiority over the PSDSS. Nevertheless, discrimination with the COMPASS score remains suboptimal, and further research on prognostic variables is essential for optimal patient selection.
http://ift.tt/2xsp0sM
External Beam Radiation Therapy for Resectable Soft Tissue Sarcoma: A Systematic Review and Meta-Analysis
Abstract
Purpose
The aim of this study was to evaluate the role of preoperative and postoperative external beam radiation therapy (EBRT) in the treatment of resectable soft tissue sarcomas (STSs) of different tumor locations.
Methods
A systematic literature search was performed to identify studies investigating the effects of EBRT (versus no EBRT) on local recurrence (LR) and overall survival (OS) or comparing different EBRT sequences. Random effects meta-analyses were calculated and presented as cumulative odds ratios (ORs).
Results
Sixteen studies (n = 3958 patients) comparing EBRT versus no EBRT, including one randomized controlled trial (RCT) in extremity sarcoma, were analyzed. EBRT appeared to reduce LR in both retroperitoneal tumors (OR 0.47, p < 0.0001) and other locations (OR 0.49, p = 0.001). OS was improved by EBRT in retroperitoneal STSs (OR 0.37, p < 0.0001) but not in other tumor locations. Eleven studies (n = 2140), including one RCT, compared preoperative and postoperative radiotherapy. LR was less frequent following preoperative EBRT in retroperitoneal STSs (OR 0.03, p = 0.02), as well as in other tumor locations (OR 0.67, p = 0.01), while wound complications in extremity sarcoma were more frequent following preoperative EBRT (OR 2.92, p < 0.0001). Several studies included in this meta-analysis bear a high risk of bias and no RCT has been published for retroperitoneal STS.
Conclusions
This meta-analysis supports the use of EBRT for local tumor control in patients with resectable STSs. Based on a small number of non-randomized studies, a positive effect on OS may exist in the subgroup of retroperitoneal STSs.
http://ift.tt/2xWaNRe
Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression
Abstract
Background
Non-coding RNAs (ncRNAs) have been shown to regulate gene expression involved in tumor progression of multiple malignancies. Our previous studies indicated that large tumor suppressor kinase 1 (LATS1), a core part of Hippo signaling pathway, functions as a tumor suppressor in gastric cancer (GC). But, the underlying molecular mechanisms by which ncRNAs modulate LATS1 expression in GC remain undetermined.
Methods
The correlation of LATS1 and has-miR-424-5p (miR-424) expression with clinicopathological characteristics and prognosis of GC patients was analyzed by TCGA RNA-sequencing data. A novel circular RNA_LARP4 (circLARP4) was identified to sponge miR-424 by circRNA expression profile and bioinformatic analysis. The binding site between miR-424 and LATS1 or circLARP4 was verified using dual luciferase assay and RNA immunoprecipitation (RIP) assay. The expression and localization of circLARP4 in GC tissues were investigated by fluorescence in situ hybridization (FISH). MTT, colony formation, Transwell and EdU assays were performed to assess the effects of miR-424 or circLARP4 on cell proliferation and invasion.
Results
Increased miR-424 expression or decreased LATS1 expression was associated with pathological stage and unfavorable prognosis of GC patients. Ectopic expression of miR-424 promoted proliferation and invasion of GC cells by targeting LATS1 gene. Furthermore, circLARP4 was mainly localized in the cytoplasm and inhibited biological behaviors of GC cells by sponging miR-424. The expression of circLARP4 was downregulated in GC tissues and represented an independent prognostic factor for overall survival of GC patients.
Conclusion
circLARP4 may act as a novel tumor suppressive factor and a potential biomarker in GC.
http://ift.tt/2y0sT5o
Two BRM Promoter Polymorphisms Predict Poor Survival in Patients with Hepatocellular Carcinoma
Abstract
BACKGROUND: Polymorphisms in the promoter of the BRM gene, a critical subunit of the chromatin remodeling SWI/SNF complex, have previously been implicated in risk and prognosis in Caucasian-predominant lung, head and neck, esophageal, and pancreatic cancers, and in hepatocellular cancers in Asians. We investigated the role of these polymorphisms in hepatocellular carcinoma (HCC) risk and prognosis.
METHODS: HCC cases were recruited in a comprehensive cancer centre while the matched controls were recruited from family practice units from the same catchment area. For risk analyses, unconditional logistic regression analyses were performed in HCC patients and matched healthy controls. Overall survival analyses were performed using Cox proportional hazard models, Kaplan-Meier curves, and log-rank tests.
RESULTS: In 266 HCC cases and 536 controls, no association between either BRM promoter polymorphism (BRM-741 or BRM-1321) and risk of HCC was identified (p>0.10 for all comparisons). There was significant worsening of overall survival as the number of variant alleles increased: BRM-741 per variant allele adjusted hazards ratio (aHR) 5.77, 95% confidence interval (CI) 2.89–11.54 and BRM-1321 per variant allele aHR 4.09, 95% CI 2.22–7.51. The effects of these two polymorphisms were at least additive, where individuals who were double homozygotes for the variant alleles had a 45-fold increase in risk of death when compared to those who were double wildtype for the two polymorphisms.
CONCLUSION: Two BRM promoter polymorphisms were strongly associated with HCC prognosis but were not associated with increased HCC susceptibility. The association was strongest in double homozygotes for the allele variants. This article is protected by copyright. All rights reserved
http://ift.tt/2wSOMpI
Risk for surgical complications after previous stereotactic body radiotherapy of the spine
Abstract
Object
Stereotactic body radiotherapy (SBRT) for vertebral metastases has emerged as a promising technique, offering high rates of symptom relief and local control combined with low risk of toxicity. Nonetheless, local failure or vertebral instability may occur after spine SBRT, generating the need for subsequent surgery in the irradiated region. This study evaluated whether there is an increased incidence of surgical complications in patients previously treated with SBRT at the index level.
Methods
Based upon a retrospective international database of 704 cases treated with SBRT for vertebral metastases, 30 patients treated at 6 different institutions were identified who underwent surgery in a region previously treated with SBRT.
Results
Thirty patients, median age 59 years (range 27–84 years) underwent SBRT for 32 vertebral metastases followed by surgery at the same vertebra. Median follow-up time from SBRT was 17 months. In 17 cases, conventional radiotherapy had been delivered prior to SBRT at a median dose of 30 Gy in median 10 fractions. SBRT was administered with a median prescription dose of 19.3 Gy (range 15–65 Gy) delivered in median 1 fraction (range 1–17) (median EQD2/10 = 44 Gy). The median time interval between SBRT and surgical salvage therapy was 6 months (range 1–39 months). Reasons for subsequent surgery were pain (n = 28), neurological deterioration (n = 15) or fracture of the vertebral body (n = 13). Open surgical decompression (n = 24) and/or stabilization (n = 18) were most frequently performed; Five patients (6 vertebrae) were treated without complications with vertebroplasty only. Increased fibrosis complicating the surgical procedure was explicitly stated in one surgical report. Two durotomies occurred which were closed during the operation, associated with a neurological deficit in one patient. Median blood loss was 500 ml, but five patients had a blood loss of more than 1 l during the procedure. Delayed wound healing was reported in two cases. One patient died within 30 days of the operation.
Conclusion
In this series of surgical interventions following spine SBRT, the overall complication rate was 19%, which appears comparable to primary surgery without previous SBRT. Prior spine SBRT does not appear to significantly increase the risk of intra- and post-surgical complications.
http://ift.tt/2jjvsMJ
Neutrophil-lymphocyte ratio complements volumetric staging as prognostic factor in patients treated with definitive radiotherapy for oropharyngeal cancer
Abstract
Background
Volumetric tumor staging has been shown as superior prognostic tool compared to the conventional TNM system in patients undergoing definitive intensity-modulated radiotherapy (IMRT) for head and neck cancer. Recently, clinical immunoscores such as the neutrophil-lymphocyte ratio (NLR) have been investigated as prognostic markers in several tumor entities. The aim of this study was to assess the combined prognostic value of NLR and tumor volume in patients treated with IMRT for oropharyngeal cancer (OC).
Methods
Data on all consecutive patients treated for locally advanced or inoperable OC with IMRT from 2002–2011 was prospectively collected. Tumor volume was assessed based on the total gross tumor volume (tGTV) calculated by the treatment planning system volume algorithm. The NLR was collected by a retrospective analysis of differential blood count before initiation of therapy.
Results
Overall, 187 eligible patients were treated with a median IMRT dose of 69.6 Gy. Three-year recurrence-free survival (RFS) for low, intermediate, high and very high tumor volume groups was 88%, 74%, 62% and 25%, respectively (p = 0.007). Patients with elevated NLR (>4.68) showed a significantly decreased 3-year RFS of 44% vs. 81% (p < 0.001) and 3-year OS of 56% vs. 84% (p < 0.001). The NLR remained a significant prognostic factor for RFS and OS when tested among tumor volume groups. Univariate and multivariate regression analysis confirmed both tumor volume and NLR as independent prognostic factors. The NLR offered further statistically significant prognostic differentiation of the small/intermediate/large tumor volume groups.
Conclusion
The NLR remains an independent prognostic factor for patients with OC undergoing radiotherapy independent of the tumor volume.
http://ift.tt/2gYm4tn
ICG-001 suppresses growth of gastric cancer cells and reduces chemoresistance of cancer stem cell-like population
Abstract
Background
ICG-001, a small molecule, binds CREB-binding protein (CBP) to disrupt its interaction with β-catenin and inhibits CBP function as a co-activator of Wnt/β-catenin-mediated transcription. Given its ability to inhibit Wnt/β-catenin signaling pathway, ICG-001 has been used in some tumor types to exert its anticarcinogenic effect. Here, we examined ICG-001 and its potential role as a therapeutic in gastric cancer (GC).
Methods
The gastric cancer cell lines SGC-7901, MGC-803, BGC-823 and MKN-45 were used in vitro and in vivo. The abilities of cell proliferation, tumor sphere formation, metastasis, tumorgenesis and chemoresistance to chemotherapy drugs in vitro were evaluated by MTT assay, colony formation assay, flow cytometry, migration and invasion assay, and tumor spheres culture. The in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice. Alterations at RNA and protein levels were followed by qRT-PCR, western blot, coimmunoprecipitations and immunofluorescence assay.
Results
In this study, we showed that ICG-001 significantly inhibited growth and metastasis of multiple GC cell lines, induced cell apoptosis, and augmented in vitro tumor spheres suppression when used in combination with chemotherapy drugs probably through robustly blocking association of β-catenin with CBP and N-cadherin, but promoting association of β-catenin with P300 and E-cadherin, instead of altering the distribution and expression of β-catenin.
Conclusions
Our findings suggest that ICG-001 suppresses GC cell line growth, metastasis and reduces its stem cell-like properties and chemoresistance, indicating that ICG-001 is a potentially useful small molecule therapeutic for GC.
http://ift.tt/2xVeQNI
p53-Dependent PUMA to DRAM antagonistic interplay as a key molecular switch in cell-fate decision in normal/high glucose conditions
Abstract
Background
As an important cellular stress sensor phosphoprotein p53 can trigger cell cycle arrest and apoptosis and regulate autophagy. The p53 activity mainly depends on its transactivating function, however, how p53 can select one or another biological outcome is still a matter of profound studies. Our previous findings indicate that switching cancer cells in high glucose (HG) impairs p53 apoptotic function and the transcription of target gene PUMA.
Methods and results
Here we report that, in response to drug adriamycin (ADR) in HG, p53 efficiently induced the expression of DRAM (damage-regulated autophagy modulator), a p53 target gene and a stress-induced regulator of autophagy. We found that ADR treatment of cancer cells in HG increased autophagy, as displayed by greater LC3II accumulation and p62 degradation compared to ADR-treated cells in low glucose. The increased autophagy in HG was in part dependent on p53-induced DRAM; indeed DRAM knockdown with specific siRNA reversed the expression of the autophagic markers in HG. A similar outcome was achieved by inhibiting p53 transcriptional activity with pifithrin-α. DRAM knockdown restored the ADR-induced cell death in HG to the levels obtained in low glucose. A similar outcome was achieved by inhibition of autophagy with cloroquine (CQ) or with silencing of autophagy gene ATG5. DRAM knockdown or inhibition of autophagy were both able to re-induce PUMA transcription in response to ADR, underlining a reciprocal interplay between PUMA to DRAM to unbalance p53 apoptotic activity in HG. Xenograft tumors transplanted in normoglycemic mice displayed growth delay after ADR treatment compared to those transplanted in diabetics mice and such different in vivo response correlated with PUMA to DRAM gene expression.
Conclusions
Altogether, these findings suggest that in normal/high glucose condition a mutual unbalance between p53-dependent apoptosis (PUMA) and autophagy (DRAM) gene occurred, modifying the ADR-induced cancer cell death in HG both in vitro and in vivo.
http://ift.tt/2wV0m0P
Molecular and clinical features of second-generation anaplastic lymphoma kinase inhibitors ceritinib
Future Oncology, Ahead of Print.
http://ift.tt/2wUMZhj
Stereotactic body radiotherapy for stage I non-small-cell lung cancer using higher doses for larger tumors: results of the second study
Abstract
Background
Efficacy of stereotactic body radiotherapy (SBRT) in stage I non–small-cell lung cancer (NSCLC) has almost been established. In Japan, the protocol of 48 Gy in 4 fractions over 4 days has been most often employed, but higher doses may be necessary to control large tumors. Previously, we conducted a clinical study using SBRT for stage I NSCLC employing different doses depending on tumor diameter, which was closed in 2008. Thereafter, a new study employing higher doses has been conducted, which is reported here. The purpose of this study was to review the safety and effectiveness of the higher doses.
Methods
We escalated the total dose for the improvement of local control for large tumors. In this study, 71 patients underwent SBRT between December 2008 and April 2014. Isocenter doses of 48, 50, and 52 Gy were administered for tumors with a longest diameter of < 1.5 cm, 1.5–3 cm, and > 3 cm, respectively. It was recommended to cover 95% of the PTV with at least 90% of the isocenter dose, and in all but one cases, 95% of the PTV received at least 80% of the prescribed dose. Treatments were delivered in 4 fractions, giving 2 fractions per week. SBRT was performed with 6-MV photons using 4 non-coplanar and 3 coplanar beams.
Results
The median follow-up period was 44 months for all patients and 61 months for living patients. Overall survival (OS) was 65%, progression-free survival (PFS) was 55%, and cumulative incidence of local recurrence (LR) was 15% at 5 years. The 5-year OS was 69% for 57 stage IA patients and 53% for 14 stage IB patients (p = 0.44). The 5-year PFS was 55 and 54%, respectively (p = 0.98). The 5-year cumulative incidence of LR was 11 and 31%, respectively (p = 0.09). The cumulative incidence of Grade ≥ 2 radiation pneumonitis was 25%.
Conclusions
Our newer SBRT study yielded reasonable local control and overall survival and acceptable toxicity, but escalating the total dose did not lead to improved outcomes.
Trial registration
UMIN000027231, registered on 3 May 2017. Retrospectively registered.
http://ift.tt/2wklA6p
Intimacy after prostate cancer: A brief couples' workshop is associated with improvements in relationship satisfaction
Abstract
Objective
Prostate cancer (PCa) treatments often leave men with erectile dysfunction (ED). Even when ED treatments are effective in restoring men's ability to have an erection sufficient for intercourse, couples continue to struggle sexually. Effective treatments to help couples recover sexually are needed.
Method
PCa patients and partners (N = 59 couples) attending a one-time couples' intimacy workshop, participated in an evaluation. The workshop, offered eight times over a 2-year period, emphasized a couples-based approach to treatment that enhances direct communication about sexuality and implementation of sexual recovery strategies that are consistent with the couple's values. Couples completed pre and post questionnaires (at baseline and 2 months later) assessing the primary outcome of relationship adjustment (Revised Dyadic Adjustment Scale) and secondary outcome of sexual function (Sexual Function Questionnaire). T-tests were employed to examine pre-post changes in scores. A small qualitative sub-study was conducted on the use of a Commitment to Change goal-setting exercise, completed during the workshop.
Results
Results provide insight into the specific nature of improvements. Patients and partners showed improvements in relationship satisfaction. Improvements with small-to-medium effect sizes were observed for patients and partners sexual function; however, after adjusting for multiple comparisons, these changes were no longer statistically significant. The specific goals set by couples, and their achievement status, are presented.
Conclusions
The workshop offers a comprehensive, one-session intervention to help couples implement a treatment plan to promote sexual recovery after PCa treatment. Given the observed improvements, progression to a randomized control trial is warranted. Copyright © 2016 John Wiley & Sons, Ltd.
http://ift.tt/1TjcspR
Spiritual well-being and spiritual distress predict adjustment in adolescent and young adult cancer survivors
Abstract
Objective
Spirituality is related to many aspects of cancer survivors' physical and psychological adjustment. Given their unique developmental issues, spiritual issues may be especially important to adolescent and young adult (AYA) survivors, yet little research has been conducted on spirituality with AYA survivors. The present study examines how two aspects of spirituality, spiritual well-being (comprising faith and meaning/peace), and spiritual struggle relate to later post-cancer adjustment.
Methods
At Time 1 (T1), 120 AYA survivors completed questionnaires on spirituality and adjustment (fear of recurrence, post-traumatic stress symptoms, perceived post-traumatic growth, psychological distress, and health-related quality of life). Eighty-three of these participants also completed these questionnaires at Time 2 (T2), one year later.
Results
Our sample reported fairly low spiritual well-being (meaning/peace, faith) and spiritual struggle. As expected, T1 spiritual well-being was positively correlated with some aspects of psychological adjustment at T2, whereas T1 spiritual struggle was inversely correlated with T2 psychological adjustment. Both dimensions of T1 spiritual well-being, but not struggle, were positively associated with perceived T2 posttraumatic growth. In general, T1 spiritual well-being and struggle correlated with T2 psychological adjustment even when demographics and cancer-related variables were controlled.
Conclusions
These results suggest that while spirituality is not important to all AYA survivors, both spiritual well-being and struggle have important associations with adjustment and may warrant clinical attention. Future research is needed to more fully understand the role of spirituality in AYA survivors' adjustment in more depth. Copyright © 2016 John Wiley & Sons, Ltd.
http://ift.tt/1TjcrSY
Involvement of DPP9 in gene fusions in serous ovarian carcinoma
Abstract
Background
A fusion gene is a hybrid gene consisting of parts from two previously independent genes. Chromosomal rearrangements leading to gene breakage are frequent in high-grade serous ovarian carcinomas and have been reported as a common mechanism for inactivating tumor suppressor genes. However, no fusion genes have been repeatedly reported to be recurrent driver events in ovarian carcinogenesis. We combined genomic and transcriptomic information to identify novel fusion gene candidates and aberrantly expressed genes in ovarian carcinomas.
Methods
Examined were 19 previously karyotyped ovarian carcinomas (18 of the serous histotype and one undifferentiated). First, karyotypic aberrations were compared to fusion gene candidates identified by RNA sequencing (RNA-seq). In addition, we used exon-level gene expression microarrays as a screening tool to identify aberrantly expressed genes possibly involved in gene fusion events, and compared the findings to the RNA-seq data.
Results
We found a DPP9-PPP6R3 fusion transcript in one tumor showing a matching genomic 11;19-translocation. Another tumor had a rearrangement of DPP9 with PLIN3. Both rearrangements were associated with diminished expression of the 3′ end of DPP9 corresponding to the breakpoints identified by RNA-seq. For the exon-level expression analysis, candidate fusion partner genes were ranked according to deviating expression compared to the median of the sample set. The results were collated with data obtained from the RNA-seq analysis. Several fusion candidates were identified, among them TMEM123-MMP27, ZBTB46-WFDC13, and PLXNB1-PRKAR2A, all of which led to stronger expression of the 3′ genes. In view of our previous findings of nonrandom rearrangements of chromosome 19 in this cancer type, particular emphasis was given to changes of this chromosome and a DDA1-FAM129C fusion event was identified.
Conclusions
We have identified novel fusion gene candidates in high-grade serous ovarian carcinoma. DPP9 was involved in two different fusion transcripts that both resulted in deregulated expression of the 3′ end of the transcript and thus possible loss of the active domains in the DPP9 protein. The identified rearrangements might play a role in tumorigenesis or tumor progression.
http://ift.tt/2wVaSWb
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