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Background: We previously reported activity of pelareorep, pembrolizumab and chemotherapy. Patients developed new T-cell clones and increased peripheral T-cell clonality, leading to an inflamed tumour. To evaluate a chemotherapy-free regimen, this study assesses if pelareorep and pembrolizumab has efficacy by inducing anti-tumour immunological changes (NCT03723915). Methods: PDAC patients who progressed after first-line therapy, received iv pelareorep induction with pembrolizumab every 21-days. Primary objective is overall response rate. Secondary objectives included evaluation of immunological changes within tumour and blood. Results: Clinical benefit rate (CBR) was 42% amongst 12 patients. One patient achieved partial response (PR) and four stable disease (SD). Seven progressed, deemed non-responders (NR). VDAC1 expression in peripheral CD8+ T cells was higher at baseline in CBR than NR but decreased in CBR upon treatment. On-treatment peripheral CD4+ Treg levels decreased in CBR but not in NR. Analysis of tumour demonstrated PD-L1+ cells touching CD8+ T cells, and NK cells were more abundant post-treatment vs. baseline. A higher intensity of PD-L1 in tumour infiltrates at baseline, particularly in CBR vs. NR. Finally, higher levels of soluble (s)IDO, sLag3, sPD-1 observed at baseline among NR vs. CBR. Conclusion: Pelareorep and pembrolizumab showed modest efficacy in unselected patients, although potential immune and metabolic biomarkers were identified to warrant further evaluation. [ABSTRACT FROM AUTHOR]

Background: The validation of breast cancer risk biomarkers in benign breast samples (BBS) is a long-sought goal, hampered by the fluctuation of gene and protein expression with menstrual phase (MP) and menopausal status (MS). Previously, we identified hormone-related gene expression and histomorphology parameters to classify BBS by MS/MP. We now evaluate both together, to validate our prior results. Patients and Methods: BBS were obtained from consenting women (86 premenopausal, 55 postmenopausal) undergoing reduction mammoplasty (RM) or contralateral unaffected breast (CUB) mastectomy. MP/MS was defined using classical criteria for menstrual dates and hormone levels on the day of surgery. BBS gene expression was measured with reverse transcription quantitative polymerase chain reaction (RT-qPCR) for three luteal phase (LP) genes (TNFSF11, DIO2, MYBPC1) and four menopausal genes (PGR, GREB1, TIFF1, CCND1). Premenopausal samples were classified into LP or non-LP, using published histomorphology parameters. Logistic regression and receiver-operator curve analysis was performed to assess area under the curve (AUC) for prediction of MP/MS. Results: In all 131 women, menopausal genes plus age > 50 years predicted true MS [AUC 0.93, 95% confidence interval (CI) 0.89, 0.97]. Among premenopausal women, high TNFSF11 expression distinguished non-LP from LP samples (AUC 0.80, 95% CI 0.70, 0.91); the addition of histomorphology improved the prediction nonsignificantly (AUC 0.87, 95% CI 0.78, 0.96). In premenopausal subsets, addition of histomorphology improved LP prediction in RM (AUC 0.95, 95% CI 0.87, 1.0), but not in CUB (0.84, 95% CI 0.72, 0.96). Conclusions: Expression of five-gene set accurately predicts menopausal status and menstrual phase in BBS, facilitating the development of breast cancer risk biomarkers using large, archived sample repositories. [ABSTRACT FROM AUTHOR]

Objective: To investigate the results of real-world application of non-myeloablative autologous HSCT for multiple sclerosis (MS). Methods: Between July 2003 and October 2019 at a single center (Northwestern University), 414 patients with relapsing remitting MS (RRMS) and 93 patients with newly diagnosed secondary progressive MS (SPMS) underwent non-myeloablative HSCT. Results: There was one treatment-related death (0.19%) due to hospital-acquired legionella pneumonia, and one patient developed neutropenic bacteremia (Klebsiella pneumonia) without sepsis. Overall 5-year survival was 98.8%. Post HSCT secondary autoimmune diseases (2nd ADs) were idiopathic thrombocytopenia (ITP) and hypo or hyperthyroidism. ITP was highest with alemtuzumab (14%) and 0 to 2.8% for the non-alemtuzumab regimens. After HSCT, 16 patients developed hypothyroidism (3.5%) and 15 developed hyperthyroidism / Grave's disease (3.3%). Relapse free survival (RFS) at 5 years for RRMS and SPMS was 80.1% and 98.1%, respectively, while progression free survival (PFS) at 4 years for RRMS and SPMS was 95% versus 66%, respectively. For patients with RRMS, the EDSS significantly improved (p < 0.0001) at each follow-up from a pre-HSCT mean of 3.87 to 2.51, 2.50, 2.41, 2.33, and 2.19 at 1, 2, 3, 4, and 5 years, respectively. For SPMS, the EDSS improved significantly only at 1 year but not thereafter. For SPMS, the mean baseline EDSS of 5.09 changed post-HSCT to 4.85 (p = 0.04), 4.88 (p = 0.2), 4.92 (p =.27), 4.72 (p = 0.07), and 4.2 (p = 0.21) at 1, 2, 3, 4, 5 years, respectively. Conclusion: In patients with RRMS, autologous non-myeloablative HSCT is an effective one-time therapy, while HSCT appears of less benefit for newly diagnosed SPMS. [ABSTRACT FROM AUTHOR]

Background: Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma.Methods: This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort.Results: 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients.Conclusions: In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Spinal ependymomas represent the most common primary intramedullary tumors for which optimal management remains undefined. When possible, gross total resection (GTR) is often the mainstay of treatment, with consideration of radiotherapy (RT) in cases of residual or recurrent tumor. The impact of extent of resection and radiotherapy remain understudied. Objective: Report on a large institutional cohort with lengthy follow-up to provide information on long-term outcomes and to contribute to limited data assessing the value of extent of resection and RT. Methods: Patients with pathologically proven primary spinal ependymoma between 1990 and 2018 were identified. Kaplan-Meier estimates were used to calculate progression-free survival (PFS); local-control (LC) and overall survival (OS). Logistic regression was used to analyze variables' association with receipt of RT. Results: We identified 69 patients with ependymoma of which 4 had leptomeningeal dissemination at diagnosis and were excluded. Of the remaining cohort (n = 65), 42 patients (65%) had Grade II spinal ependymoma, 20 (31%) had Grade I myxopapillary ependymoma and 3 (5%) had Grade III anaplastic ependymoma; 54% underwent GTR and 39% underwent RT. With a median follow-up of 5.7 years, GTR was associated with improved PFS. For grade II lesions, STR+RT yielded better outcomes than STR alone (10y PFS 77.1% vs 68.2%, LC 85.7% vs 50%). Degree of resection was the only significant predictor of adjuvant radiotherapy (p< 0.0001). Conclusion: Our findings confirm the importance of GTR in spinal ependymomas. Adjuvant RT should be utilized in the setting of a subtotal resection with expectation of improved disease-related outcomes. [ABSTRACT FROM AUTHOR]

Objective: Determine toxicity and efficacy of autologous hematopoietic stem cell transplantation (HSCT) for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are dependent on intravenous immunoglobulins or plasmapheresis. Methods: Unselected peripheral blood stem cells were re-infused on day 0 after conditioning with cyclophosphamide 200 mg/kg/intravenously (IV), rATG (thymoglobulin) 5.5 mg/kg/IV, and rituximab 1000 mg/IV. Results: Sixty-six patients underwent HSCT for CIDP. Data on sixty patients with a mean follow-up of 4.5 years (range 2–5 years) were available for analysis. There were no treatment-related deaths, and overall survival was 97%. Post-transplant immune medication-free remission was 80%, 78%, 76% 78%, and 83% at 1, 2, 3, 4, and 5 years. Ambulation without assistance improved from 33% pre-HSCT to 82% 82%, 81%, 86%, and 83% at 1, 2, 3, 4, and 5 years, respectively. Mean right/left hand grip strength (kg) improved significantly (all p values < 0.01) from 18.1/16.5 pre-HSCT to 26.3/25.4, 29.2/28.2, 28.8/28.6, 30.3/25.5, and 30.8/29.1 at 1, 2, 3, 4, and 5 years, respectively. Average nerve conduction velocity (NCV) (m/s) improved significantly (all p values ≤ 0.001) from a mean of 27.2 pre-HSCT to 33.5, 33.8, 37.7, 38.2, and 38.3 at 1, 2, 3, 4, and 5 years, respectively. Average compound motor action potential (CMAP) (mv) improved significantly (p values ≤ 0.001) from a mean of 3.6 pre-HSCT to 4.6, 4.6, 5.0, 5.1, and 4.1 at 1, 2, 3, 4, and 5 years, respectively. Conclusion: A randomized trial is indicated to verify these results and confirm that HSCT reverses disability and offers long-term immune therapy independence. [ABSTRACT FROM AUTHOR]

Purpose: Survival of neonatal and pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) ≥ 21 days has not been well described. We hypothesized that patients would have poor survival and increased long-term complications.Methods: Retrospective, single center, review and case analysis. Tertiary-care university children's hospital including neonatal, pediatric and cardiac intensive care units. After institutional review board approval, the charts of all patients < 18 years of age undergoing ECMO for ≥ 21 continuous days were performed, and they were compared to comparative patients undergoing shorter runs. Overall survival, incidence of complications, and post-discharge recovery were recorded.Results: Overall survival was 36% in patients undergoing ≥ 21 days of ECMO (N = 14). 5/8 patients with cardiopulmonary failure from acquired etiologies survived versus 0/6 patients with congenital anomalies. 1/5 survivors achieved complete recovery with no neurologic deficits. The remaining survivors suffer from multiple medical and neurodevelopmental morbidities.Conclusion: ECMO support for ≥ 21 days is associated with poor survival, particularly in neonates with congenital anomalies. Long-term outcomes for survivors ought to be carefully weighed and discussed with parents given the high incidence of neurologic morbidities in this population. [ABSTRACT FROM AUTHOR]

Purpose: Postoperative stereotactic radiosurgery (SRS) is increasingly utilized following resection of brain metastases (BM); however, there are no volumetric data guiding dose selection. We performed a volumetric analysis to guide cavity SRS dosing for resected BM.Methods: 83 consecutive patients with gross total resection who underwent postoperative SRS to 90 cavities were identified. The 12 Gy isodose lines (V12total) along with the volume of brain parenchyma receiving 12 Gy excluding cavity fluid, ventricular fluid, and calvarium (V12parenchyma) were contoured. Local recurrence (LR) and radionecrosis (RN) were calculated using cumulative incidence rates. Multivariate analysis (MVA) and cutpoint analysis were conducted.Results: Median follow-up was 12.3 months; median dose was 16 Gy. 1- and 2-year cumulative incidence rates of LR were 7.9% and 11.0%. Radiation dose [hazard ratio (HR) 2.04, p = 0.002] was significantly associated with time to LR on MVA. 1- and 2-year cumulative incidence rates of RN were 2.6% and 5.5% respectively. MVA demonstrated increased risk of RN with a larger V12parenchyma (HR 1.46, p = 0.0496). Cavities ≤ 10 cc showed a low 2-year RN risk (4.3%), but had a modest LR risk (13.9%). A radiation dose ≥ 18 Gy significantly improved LC (HR 4.79, p = 0.01).Conclusions: V12parenchyma should be examined in postoperative SRS to assess RN risk. Cavities > 10 cc treated with 16 Gy achieved excellent LC and minimal RN at 2 years. Cavities ≤ 10 cc may be better treated with a dose ≥ 18 Gy to significantly improve LC given the low RN rate observed with 16 Gy. [ABSTRACT FROM AUTHOR]

Purpose: Activation of the phosphoinositide 3-kinase (PI3K) pathway is an important resistance mechanism to anti-HER2 therapies. This study aimed to assess the safety and activity of alpelisib (a PI3Kα isoform-specific inhibitor) with T-DM1 in trastuzumab- and taxane-resistant HER2-positive MBC.Methods: Patients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. The dose-limiting toxicity (DLT), maximum tolerated dose (MTD), adverse events, overall response rate (ORR), and clinical benefit rate (CBR = CR + PR + SD > 6 months) were assessed with descriptive statistics. Progression-free survival (PFS) was calculated by the Kaplan-Meier method.Results: Seventeen patients were enrolled with a median of 3 prior therapies for metastatic disease. The DLT was a maculopapular rash and MTD was 250 mg alpelisib daily. The most frequently occurring toxicities included fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia. Fourteen patients were evaluable for response with an ORR of 43%. In patients with prior treatment and progression on T-DM1 (n = 10), the ORR was 30%. The CBR was 71% in evaluable patients and 60% in those with prior T-DM1. The median PFS was 8.1 months.Conclusions: The combination of alpelisib and T-DM1 is tolerable and demonstrates activity in trastuzumab-resistant HER2-positive MBC. Furthermore, activity was observed in T-DM1-resistant disease. These data suggest that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy, providing rationale for further study of PI3K inhibition in refractory HER2-positive MBC to validate these results. [ABSTRACT FROM AUTHOR]

Physical activity ameliorates fatigue in systemic lupus erythematosus (SLE) patients by an unknown mechanism. Adipokines, which are influenced by adiposity and physical activity, may be associated with patient-reported fatigue. We describe cross-sectional associations between adipokines and fatigue, physical activity, and SLE disease activity. We measured adipokines, self-reported fatigue, and objective physical activity in 129 SLE patients. Fatigue was assessed with the Fatigue Severity Scale (FSS) and Patient Reported Outcomes Measurement Information System® (PROMIS®) Fatigue score. Disease activity was measured with the Safety of Estrogens in Systemic Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI). Participants wore an accelerometer for 7 days to measure physical activity. Leptin, adiponectin, and resistin were measured in stored serum with a Luminex bead-based assay. Multivariable regression models assessed relationships between fatigue and adipokines, and Spearman correlation coefficients summarized associations between adipokines, physical activity, and SELENA-SLEDAI. Median adipokine levels were: leptin 30.5 ng/ml (Interquartile Range 14.0, 56.6), adiponectin 11.6 μg/ml (7.2, 16.8) and resistin 1.4 ng/ml (1.0, 2.2). Associations between adipokines and FSS or PROMIS fatigue were not significant. Body mass index (BMI) ≥ 30 kg/m2 was associated with FSS and PROMIS fatigue in regression analyses (p < 0.05). Weak correlations between leptin, adiponectin, leptin/adiponectin (L/A) ratio, and physical activity and between adiponectin and SELENA-SLEDAI score were not significant after adjusting for BMI. Adipokines were not associated with fatigue in SLE. Adipokines were correlated with physical activity (leptin, adiponectin, L/A ratio) and SLE disease activity (adiponectin), but most of these associations were explained by BMI. [ABSTRACT FROM AUTHOR]

Background: In pediatric chronic kidney disease (pCKD), traditional factors (proteinuria, etiology, and race) do not fully explain disease progression. The levels of methylated arginine derivatives (MADs: asymmetric and symmetric dimethylarginine, respectively) rise in CKD and increase with CKD progression. The impact of MADs on glomerular filtration rate (GFR) decline has not been examined in pCKD. The aim of this study was to examine the additive impact of baseline (BL) levels of MADs on directly measured GFR (mGFR) decline per year (ml/min/1.73 m2/year) for a period of up to 4 years.Methods: Plasma and data, including mGFR by plasma iohexol clearance, were provided by the prospective, observational Chronic Kidney Disease in Children study. BL MADs were analyzed by high-performance liquid chromatography-tandem mass spectrometry.Results: For 352 pCKD subjects, the median [interquartile range] BL mGFR was 45 [35, 57] ml/min/1.73 m2. The levels of BL MADs were inversely related to the initial mGFR and its decline over time (p < 0.0005) but not to the rate of decline. Covariates, non-glomerulopathy and Tanner stage of ≥ 3 demonstrated weaker relationships between BL levels and beginning mGFR (p = 0.004 and p = 0.002, respectively).Conclusions: In pCKD, higher concentrations of BL MADs were inversely related to BL mGFR. MADs did not affect the CKD progression rate. Quantification of this relationship is novel to the pCKD literature. [ABSTRACT FROM AUTHOR]

Standard treatment for GBM is radiation (RT) and temozolomide (TMZ). Arsenic trioxide (ATO) is synergistic with RT based on several mechanisms of action previously identified, however not tested herein. The MTD of ATO, RT and TMZ was determined in a Phase I trial. We now present the combined Phase I/II data. Patients with newly diagnosed malignant gliomas were eligible for treatment. Patients were treated with RT (60 GY), TMZ (75 mg/m daily × 42 days) and ATO 0.20 mg/kg daily in week 1 then twice a week ×5 weeks, after completing RT they were treated with TMZ 5/28 for up to 12 months. MRIs were performed every 8 weeks. A total of 42 patients were enrolled in both the Phase I and II trials for this study treatment. Of the 42 enrolled patients (24 M and 18 W) the median age was 54 (24-80) and median KPS 90 (60-100). 28 patients had a GBM and 14 had anaplastic glioma (AG). All patients completed RT/TMZ/ATO and went on to maintenance TMZ. Median number of post RT cycles of TMZ was 4 (0-12). Median PFS was 7 m for GBM and 75 m for AG and median OS was 17 m for GBM and NR for AG. Best response was CR in 2, SD in 28, PR in 5 and PD in 7. There were no unexpected adverse events. Grade 3 toxicities likely attributable to ATO included prolonged Qtc (n = 1), elevated liver enzymes (n = 2 for ALT/n = 1 for AST) and elevated bilirubin (n = 1). Adding ATO to RT and TMZ is feasible with no increased side effects. The addition of arsenic did not improve overall survival in the GBM patients as compared to historic data. MGMT status was analyzed in 20 of the 42 patients where tissue was available for retrieval and MGMT testing. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate outcomes after breast-conserving surgery (BCS) and intraoperative radiotherapy (IORT), and to identify risk factors associated with complications. Materials/Methods: We evaluated patients with early-stage breast cancer treated from January 1, 2011 to January 31, 2014 with BCS and IORT at a single institution. The presence of breast cancer recurrences, complications, or fat necrosis were assessed at subsequent follow-up visits using physical examination and breast imaging. Results: Overall, 113 patients, of whom three were undergoing bilateral treatments, were identified. The median length of time for IORT was 29 min and 36 s (range 15:50-59:00). Fifteen patients received additional external beam radiotherapy (EBRT), and the median follow-up was 40.3 months (range 1.6-58.3) for all patients. To date, one biopsy-proven ipsilateral recurrence has been noted (0.9%), for which the patient elected to undergo a mastectomy. Nine patients were found to have wound complications (7.7%) and two had fat necrosis (1.7%) on follow-up. Of all the evaluated risk factors, only applicator size ( p < 0.01) had a statistically significant association with an increase in complications. Conclusions: With a short follow-up, IORT appears to be a safe treatment modality for a select group of patients, leading to a reasonable increase in operating room time and complication rates following BCS. The utilization of larger applicators at the time of IORT was associated with an increase in wound complications and fat necrosis. [ABSTRACT FROM AUTHOR]

One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycles post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor. [ABSTRACT FROM AUTHOR]

Purpose/Objective(s): The purpose of this study was to compare oncologic outcomes and toxicity profile of hypofractionated conformal radiotherapy (RT) with concurrent full-dose gemcitabine versus standard fractionation RT with concurrent 5-fluorouracil (5-FU) in the treatment of unresectable non-metastatic pancreatic cancer. Materials/Methods: Patients with unresectable non-metastatic adenocarcinoma of the pancreas treated at three institutions were included. All patients were treated with chemoradiotherapy (CRT) consisting of either hypofractionated RT to the gross disease concurrent with a full-dose gemcitabine-based regimen versus standard fractionation RT to the tumor and elective nodes concurrent with 5-FU. End points included rates of gastrointestinal (GI) toxicities, overall survival (OS), and distant metastasis free survival (DMFS). Results: From January 1999 to December 2009, 170 patients were identified (118 RT/gemcitabine, 52 RT/5-FU). There were no differences in demographic or clinical factors. Acute GI toxicities (grades <3 versus ≥3) were 82.2 and 17.8 %, respectively, for patients treated with RT/gemcitabine and 78.9 and 21.2 % for those treated with RT/5-FU ( p = 0.67). Late GI toxicities (grades <3 versus ≥3) were 88.1 and 11.9 %, respectively, for RT/gemcitabine and 80.8 and 19.2 % for RT/5-FU ( p = 0.23). OS for RT/gemcitabine and RT/5-FU were 52 versus 36 % at 1 year and 14 versus 6 % at 2 years favoring the RT/gemcitabine group ( p = 0.02). DMFS at 1 and 2 years for RT/gemcitabine were 41 and 11 % versus 24 and 4 % for RT/5-FU ( p = 0.02). Conclusions: RT/gemcitabine was equivalent in toxicity to RT/5-FU but was associated with superior OS and DMFS. When RT is used in the treatment of unresectable pancreatic cancer, hypofractionated conformal RT with concurrent full-dose gemcitabine may be the preferred approach. [ABSTRACT FROM AUTHOR]

Purpose: The precise definition of the rectum is essential for localizing colorectal pathology, yet current definitions are nebulous. The objective of this study is to determine the anthropometric definition of common pelvic landmarks in relation to patient characteristics. Methods: Seventy-one patients underwent open proctectomy with intra-operative measurements from the anal verge to various pelvic landmarks, and patient characteristics were evaluated. Analyses were performed using Spearman correlation and Wilcoxon rank sum. Results: The mean landmark distance was dentate line = 1.7 cm (range 0.8-4.0 cm), puborectalis muscle = 4.2 cm (range 2.0-8.0 cm), anterior peritoneal reflection = 13.2 cm (range 8.5-21.0 cm), sacral promontory = 17.9 cm (range 13.0-26.0 cm), and confluence of the taenia = 25.5 cm (range 16.0-44.0 cm). Men had longer mean distances to the dentate line ( p = 0.0003), puborectalis muscle ( p = 0.03), and anterior peritoneal reflection ( p = 0.02). Patient weight significantly correlated with distance to all landmarks except for the confluence of the taenia, which did not correlate with any patient factor. Conclusions: The location of common pelvic landmarks is highly variable. The use of predefined absolute measurements from the anal verge to localize rectal pathology is inaccurate and fails to account for patient variability. [ABSTRACT FROM AUTHOR]

Purpose: Women at high risk of breast cancer and those with carcinoma in situ need non-toxic, well-tolerated preventive interventions. One promising approach is drug delivery through the breast skin (local transdermal therapy, LTT). Our goal was to test novel drugs for LTT, to establish that LTT is applicable to non-steroidal drugs.Methods: Athymic nude rats were treated with oral tamoxifen, transdermal 4-hydroxytamoxifen (4-OHT) or endoxifen gel applied daily to the axillary mammary gland for 6 weeks (Study 1). Study 2 was identical to Study 1, testing transdermal telapristone acetate (telapristone) gel versus subcutaneous implant. At euthanasia, mammary glands and blood were collected. In Study 3, consenting women requiring mastectomy were randomized to diclofenac patch applied to the abdomen or the breast for 3 days preoperatively. At surgery, eight tissue samples per breast were collected from predetermined locations, along with venous blood. Drug concentrations were measured using liquid chromatography-tandem mass spectroscopy.Results: Mammary tissue concentrations of 4-OHT, endoxifen, and telapristone were significantly higher in the axillary glands of the gel-treated animals, compared to inguinal glands or to systemically treated animals. Plasma concentrations were similar in gel and systemically treated animals. The clinical trial showed significantly higher mammary concentrations when diclofenac was applied to the breast skin versus the abdominal skin, but concentrations were variable.Conclusions: These results demonstrate that lipophilic drugs can be developed for LTT; although the nude rat is suitable for testing drug permeability, delivery is systemic. In human, however, transdermal application to the breast skin provides local delivery. [ABSTRACT FROM AUTHOR]

The purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21 days, and eribulin 1.4 mg/m day 1 and day 8 every 21 days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD score + BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3 %) patients enrolled in the study achieved pCR. 24 (80.0 %) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score ( P = 0.0024) and HR deficiency status ( P = 0.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR ( P = 0.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D ( P = 0.020), nuclear CDK4 ( P = 0.0030), and nuclear Smad3 ( P = 0.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population. [ABSTRACT FROM AUTHOR]

We propose an extension of the method presented in Helenowski and Demirtas () involving imputing mixed continuous and binary data to data involving categorical variables with three or more levels. In a bivariate case, the medians for the continuous variable will be computed by each level of the categorical variable and the categorical variable will be ranked as an ordinal variable with respect to these medians, so that each ordinal level assigned to a categorical level is determined by the rank order of medians of the continuous variable for that category. In a multivariate case, the categorical variables are ordered with respect to the continuous variable for which the range among the medians is the largest. Here, 'bivariate' indicates that the data set includes two variables while 'multivariate' indicates that the data set includes three or more variables. The pairwise correlation between the continuous and ordinal variable is then computed. Data will then be transformed to normally distributed values, imputed via joint modeling, and back-transformed to the original scale via the Barton and Schruben () technique for the continuous variable and quantiles based on the original probabilities of the categorical variable. The algorithm is re-iterated until the absolute difference of the pairwise correlations from the original and imputed data is less than some constant c chosen to maximize the coverage rate and minimize standardized bias. Results from simulations applied to artificial data and to real data involving 74 colorectal patients indicate that our technique as promising. [ABSTRACT FROM AUTHOR]

When surgery and radiation are no longer treatment options, salvage systemic therapy has been used for recurrent meningiomas with little compelling evidence to suggest effectiveness. Patients with surgery and radiation refractory recurrent meningiomas were treated with the oral multifunctional tyrosine kinase inhibitor PTK787/ZK 222584 (PTK787) at a dose of 500 mg twice a day. Each treatment cycle was 4 weeks with MRI done every 8 weeks. Twenty-five patients (14 men; 11 women) with a median age of 59 years and KPS of 80 were treated. Meningioma WHO Grade was I in 2 patients, II in 14 patients and III in 8 patients; 1 patient had a hemangiopericytoma. All patients had prior surgery, external beam radiation therapy or radiosurgery and 11 patients prior systemic chemotherapy. Median number of cycles of PTK 787 administered was 4 (range <1-22). Best response in the 22 evaluable patients was stable disease in 15 (68.2 %). Predominant PTK787 related toxicities included fatigue (60 %), hypertension (24 %) and elevated transaminases (24 %). Grade II patients had a progression free survival (PFS)-6 of 64.3 %, a median PFS of 6.5 months and an overall survival (OS) of 26.0 months; grade III patients had a PFS-6 of 37.5 %, median PFS of 3.6 months and OS 23 months. PTK787 was modestly toxic at the dose of 500 mg administered twice per day. Activity as determined by PFS-6 suggests that targeting PDGF/VEGF pathway warrants further investigation. [ABSTRACT FROM AUTHOR]

Introduction: The accuracy of breast magnetic resonance imaging (MRI) for detection of ductal carcinoma in situ (DCIS) has prompted recommendations for its routine preoperative use, but its clinical benefit is debated. We reviewed our experience with MRI in DCIS patients to assess the utility of MRI for surgical planning. Methods: DCIS patients (2008-2010) were identified through a prospectively maintained database and grouped into MRI and no-MRI groups. The rates of additional biopsies, altered surgical management, and reoperation were compared. Additionally, DCIS size ascertained by mammography, MRI, and final pathology was compared. Results:: Of 352 DCIS patients, 217 received MRI and 135 did not. The type of initial operation and number of reoperations were similar between the two groups, but successful breast conservation was more frequent in the no-MRI group ( p = 0.06). The additional biopsy rate was 38 % in the MRI group versus 7 % in the no-MRI group; ≥2 additional biopsies were performed in 18 % of the MRI group and 2 % of the no-MRI group ( p < 0.0001). These yielded a cancer diagnosis in 26 % of MRI and 33 % of no-MRI patients ( p = 0.73). MRI was not superior to mammogram in detecting size of DCIS lesions preoperatively; 52 % of mammograms were accurate (within 1 cm) compared with 41 % of MRIs. Conclusions: DCIS patients who undergo preoperative breast MRI are far more likely to undergo additional biopsies. Unless these can be demonstrated to lead to improved long-term outcomes, the utility of routine preoperative MRI in DCIS patients remains questionable. [ABSTRACT FROM AUTHOR]

Brain metastases (BM) and leptomeningeal metastases (LM) are devastating neurologic complications. Pemetrexed is a multi-targeted anti-folate agent approved for treatment of nonsquamous non-small cell lung cancer but has anti-tumor activity in other solid tumors. We performed two trials using pemetrexed in patients with BM and LM to assess CSF penetration and anti-tumor activity. Patients were treated with intravenous pemetrexed at doses of 500 ( n = 3), 750 ( n = 3), 900 ( n = 12) or 1,050 mg/m ( n = 3) every 3 weeks. Neuro-imaging was done every 6 weeks. Matched CSF and plasma samples were obtained serially from three patients with Ommaya reservoirs; the remaining patients had a single paired collection. Twenty-one patients (15 women and six men) with median age of 50 years and median KPS of 90 were treated. Primary tumors included breast (13), lung (4), colorectal (1), endometrial (1), esophageal (1) and pinealoblastoma (1). Nine patients had prior whole brain RT and median number of prior chemotherapies was two including prior methotrexate in four patients. Median pemetrexed doses administered was three (range 1-14). Responses included one partial response, ten stable disease and ten progressive disease. Median time to progression and survival was 2.7 and 7.3 months; PFS six was 22 %. No major toxicities were seen. Pemetrexed distributed from the plasma to the CSF within 1-4 h with the resulting CSF concentrations < 5 % of plasma. Pemetrexed was tolerated in solid tumor patients with CNS metastases. Limited anti-tumor activity was seen, which might have been due to low CSF concentrations, although some patients displayed prolonged benefit. [ABSTRACT FROM AUTHOR]

The objective of this study is to evaluate the patterns of relapse and survival trends in patients with single brain metastases treated with post-operative adjuvant Gamma knife stereotactic radiosurgery (GKS) without whole brain radiotherapy (WBRT). Retrospective analysis of all consecutive patients who underwent GKS to the tumor cavity following resection of solitary brain metastasis was performed at a single institution. Between March 2001 and June 2010, 56 patients underwent GKS to the resection cavity following resection of intracranial metastases; no patient received pre- or post-operative WBRT as an adjuvant (salvage WBRT was permissible). The mean marginal dose was 17.1 Gy (range 14-20 Gy). The mean follow-up period was 24 months (range 3-99 months). Five patients (8.9%) had local recurrence in the immediate vicinity of the resection cavity, qualifying as 'local failures', and 21 (37.5%) recurred at distant intracranial sites. Median intracranial recurrence free survival was 13 months. Median overall survival was 20.5 months. Salvage interventions were required in 26 patients, and included repeat radiosurgery in 17 patients, further surgery in two patients, and salvage WBRT in eight (14.3%; two of whom had also been locally salvaged with repeat radiosurgery) patients. As expected, avoidance of WBRT results in a high rate of intracranial failure (26/56 patients, 46%), even in well-selected patients with only single brain metastases. As anticipated, the majority of failures (21, 37.5%) are 'distant intracranial', and in this well-selected cohort the local failure rate is low (5/56 patients, <9%). All patients failing intracranially (46%) are potential candidates for salvage therapies, but WBRT as salvage was utilized in only 14.3% of patients. The median intracranial relapse-free was 13 months and overall survival was 20.5 months. [ABSTRACT FROM AUTHOR]

Extracranial metastases from glioblastoma (GBM) are uncommon with an estimated incidence of less than 2%. We report two cases of metastatic GBM seen within an 8-week period followed by a literature review. We attempted to identify common factors or a causative mechanism. Factors that predominated among the reviewed cases included male gender, tumor location, and younger age. Causative mechanisms were not apparent. While metastatic disease remains rare, it might be occurring with increasing frequency. This trend might be due to increased diagnosis, better imaging, a more extensive physician workup, or an increase in survival. Metastatic GBM can present and progress quite rapidly, and repeat evaluations of persistent or worsening complaints among GBM patients are warranted. Early diagnosis of metastatic disease spread can help to expedite alleviation of patients' discomfort, in an already aggressive disease process. [ABSTRACT FROM AUTHOR]

The utility of archived paraffin-embedded breast tissue for risk-related research is often limited by missing menopausal status data. We tested the hypothesis that breast tissue gene expression patterns can improve menopausal stratification. Healthy high-risk participants in a clinical trial underwent breast random fine-needle aspiration (rFNA); 100 ng of RNA extracted from rFNA samples was reverse-transcribed; the expression of 28 estrogen-responsive genes was evaluated by real-time PCR. True menopausal status (TMS) was determined by measurement of plasma hormones and age. Differentially expressed genes and age were analyzed by logistic regression. The accuracy of the menopause prediction was assessed using receiver-operator characteristic (ROC) analysis, and validated in a second independent set of 44 women. In the test set, postmenopausal women demonstrated significantly lower expression of five estrogen-responsive genes: GREB1, PGR, TFF1, PRLR, and CCND1 (adjusted P < 0.03 for all). In the validation set, three of these genes were expressed at lower levels in postmenopausal women (GREB1, PGR, TFF1) (adjusted P < 0.06 for all). In the test set, the modeled area under the curve (AUC) for age and three genes was higher than for age >50 alone (AUC 96.1% vs. 87.2%, P = 0.002), and remained better than for age alone in the validation set (99.0% vs. 95.5%, P = 0.16). Estrogen-related gene expression in breast specimens can be used to improve menopausal classification, reducing the biological noise related to menopause in studies that seek to identify RNA or protein risk biomarkers in archived breast samples. [ABSTRACT FROM AUTHOR]

Background: Hypertriglyceridemia subjects with metabolic syndrome exhibit variable postprandial triglyceride responses. We investigate the effects of fenofibrate therapy on postprandial triglyceride-containing lipoproteins in subjects with early (3.5 h) versus late (8 h) postprandial triglyceride responses. Methods: Fifty-five subjects with fasting hypertriglyceridemia (≥1.7 mmol/L (150 mg/ dL) and <5.8 mmol/L (500 mg/dL)) and ≥2 Adult Treatment Panel III criteria of the metabolic syndrome were randomized to daily fenofibrate (160 mg/d) or placebo for 12 weeks in a double-blind controlled clinical trial. A standardized fat load (50 g/m) was given orally after a 12 h fast. Blood specimens were obtained at 0 h (fasting), 3.5 h, and 8 h after the test meal. Analysis is confined to the 53 subjects with clearly identifiable early or late triglyceride peaks prior to therapy. Results: Fenofibrate was more effective in late peakers ( n = 8) when compared to early peakers ( n = 15) with respect to reducing postprandial triglyceride concentrations (−67% vs. −34%, p = 0.0024) and large VLDL (−76% vs. −31%, p = 0.0016), and increasing total HDL particles (20% vs. 11%, p = 0.008) and large HDL particles (185% vs. 88%, p = 0.003). On fenofibrate therapy, 100% of those initially designated as late peakers were reclassified as early peakers; 47% of late peakers assigned to placebo were reclassified as early peakers. Conclusions: Late postprandial triglyceride responders have attenuated clearance of large VLDL particles, but they were more responsive to fenofibrate. [ABSTRACT FROM AUTHOR]