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PDF file - 151K, Supplemental Table 1. mutations found in NYU cohort and previously discovered by Hodis et al; and Krauthammer et al; Supplemental Table 2. Breslow-Day test of homogeneity for association between PP6C, BRAF, or NRAS mutations in Primary and Metastatic patients respectively. Supplemental Table 3. Bbaseline characteristics and prognostic factors by PP6C mutation status in primary and metastatic patients. Supplemental Table 4: PP6C, BRAF and NRAS mutation allele:wild-type allele ratios. Supplemental Table 5. Correlation of PP6R binding and Aurora A Kinase phosphorylation(primary patients only).

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XLS file, 17K, Patient demographics, tumor characteristics, treatment, occurrence and severity of local and systemic adverse events and anti-tumor response per patient (n=10).

PDF file, 282K, A (non-responder 1): In situ TILs analysis by IHC in a patient with minimal T cell infiltrate before treatment (H&E stain and IHC for CD3, CD4, CD8 and FoxP3, 200x). B: (non-responder 2): In situ TILs analysis by IHC in a patient with moderate T cell infiltrate before imiquimod treatment. (H&E stain and IHC for CD3, CD4, CD8 and FoxP3, 200x).

p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients. Cancer Res; 70(21); 8446–56. ©2010 AACR.

Supplementary Figures 1-8, Tables 1-7 from High Levels of Hsp90 Cochaperone p23 Promote Tumor Progression and Poor Prognosis in Breast Cancer by Increasing Lymph Node Metastases and Drug Resistance

Hypofractionated whole-breast radiation therapy (RT) has proved to be equivalent to conventionally fractionated RT in multiple randomized trials. There is controversy regarding its use in younger women because of their underrepresentation in trials and the concern for late toxicity. We evaluated disease control and cosmetic outcomes in patients aged50 years treated with hypofractionated RT in 4 prospective single-institutional trials.From 2003 to 2015, 1313 patients were enrolled in 4 prospective protocols investigating the use of adjuvant hypofractionated RT after breast-conserving surgery with a daily or weekly concomitant boost. We identified the records of 348 patients aged50 years at consultation for this analysis. Overall survival, disease-free survival, and local recurrence-free survival were estimated using the Kaplan-Meier method by study and across studies using meta-analytic methods. The late effects of RT, clinician-rated cosmesis, and patient-rated cosmesis were also evaluated.With a median follow-up period of 66.9 months, the overall survival rate was 99.6%, the disease-free survival rate was 96.3%, and the local recurrence-free survival rate was 97.7% at 3 years. Clinician-rated cosmesis (n = 242) was excellent or good in 93.4% of cases and fair or poor in 6.6%. Patient-rated cosmesis (n = 259) was excellent or good in 86.1% and fair or poor in 13.9%. When patients rated themselves differently than their physicians, patients more often rated themselves poorly compared with their physicians (P = .0044, Cochran-Mantel-Haenszel test).At a median follow-up of 5 years, an analysis of patients aged 50 years demonstrated that hypofractionated RT was safe and effective, with good to excellent cosmesis as assessed by both clinicians and patients.

Introduction. Prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (AHCT) remains a major challenge. The combination of methotrexate (MTX) and a calcineurin inhibitor has been the standard regimen for prophylaxis in patients receiving matched sibling donor (MSD) or matched unrelated donor (MUD) transplants for the past few decades. However, over 50% of patients undergoing AHCT still develop acute or chronic GvHD or even both, causing high rates of morbidity and mortality. Moreover, calcineurin inhibitors also have untoward toxic side effects. High dose post-transplant cyclophosphamide (PTCy), initially introduced for GvHD prevention in the setting of haploidentical transplantation, has now been studied in MSD and MUD transplants. We adopted a novel approach to prevent GvHD using a short course of PTCy and bortezomib. We hypothesized that such combination is safe and effective and omits the need for calcineurin or m-TOR inhibitors. Study Design. We report the outcomes of a prospective cohort of patients who received PTCy and bortezomib for GvHD prevention following MSD or MUD transplants. Twenty-eight patients were treated in a phase I-II trial and their clinical outcomes were previously reported (al-Homsi AS et al, BBMT 2019). Most of the remaining patients were treated on an extension trial. GvHD prevention consisted of PTCy 50 mg/kg IV on day +3 and +4, and bortezomib 1.3mg/m 2 IV 6 hours after transplant and again 72 hours after. Patients receiving MUD transplants also received rabbit ATG (thymoglobulin®) 5mg/kg total IV fractionated on day -4 to -2. All patients received peripheral blood grafts and standard supportive care as per Institutional policy. G-CSF was administered routinely until neutrophil engraftment. Results. Fifty-eight patients are included in this analysis. Median age was 60 (range 22-78) years. Fifty-three percent of patients were male. Underlying malignancies consisted of myeloid and lymphoid malignancies in 79.3% and 20.6%, respectively. Acute myeloid leukemia (50%) and myelodysplastic syndromes (24.1%) were the most common diseases. At transplant, disease risk index was low, intermediate, high and very high in 19.0%, 48.3%, 31.0% and 1.7% of patients, respectively. Median Pretransplant Assessment of Mortality Score (PAM) was 16.7 (5.4-29.4). Grafts were from MSD in 24.1% or MUD in 75.9% of patients. Recipient (R)/Donor (D) CMV status at transplant was as follows: R+/D+: 43%; R+/D-: 21%; R-/D+: 14% and R-/D-: 22%. Conditioning regimens consisted of reduced intensity fludarabine and busulfan in all but 2 patients who were conditioned with myeloablative fludarabine and busulfan. Overall, the regimen was remarkably well tolerated. Median times to neutrophil and platelet engraftment were 16 (13-28) and 26 (15-57) days respectively. No patient experienced primary graft failure. CMV and EBV reactivation rates were 46.6% and 24%. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35% (95% CI: 22%-47%) and 15% (95% CI: 7%-25%) at day +120, respectively. Cumulative incidence of chronic GvHD was 14% at 1 year . Overall, 34% of patients required immunosuppression with systemic steroids after day +4 either for grade III-IV acute or chronic GvHD. Disease relapse rate was 26%. One-year cumulative incidence of transplant-related mortality was 14% (95% CI: 6%-25%). Median overall survival was 30.7 (95% CI: 15.7-not yet reached) months. One-year overall survival was 72% (95% CI: 57%-82%). One-year composite GvHD (acute and chronic) free and relapse free survival (GRFS) was 41.6% (95% CI: 28.9%-54%). Conclusion. PTCy and bortezomib combination for GvHD prophylaxis following MSD and MUD transplants is well tolerated and effective. It offers an alternative regimen to calcineurin and m-TOR inhibitor-containing regimens and may be preferred in certain settings including patients with limited resources, poor medication compliance, and with impaired renal function. A comparison of this cohort to a matched control group of patients receiving methotrexate and cyclosporine for GvHD prevention is ongoing. Disclosures Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Other: Advisory Board, Speakers Bureau; Jazz: Other: Advisory Board, Speakers Bureau; Abbvie: Consultancy; Takeda: Speakers Bureau. Al-Homsi: Celyad: Other: Advisory Board; Daichii Sanyko: Consultancy. OffLabel Disclosure: Cyclophosphamide and Bortezomib are used for GvHD prevention

Prior studies of timeliness of adjuvant chemotherapy (AC) initiation in stage III colon cancer have suggested longer time to AC at public compared with private hospitals. Few studies have explored differences in AC completion. We investigated whether timely initiation and completion of AC differed between a public and private hospital, affiliated with the same academic institution in a large, urban setting. We conducted a retrospective cohort study of stage III colon cancer patients who had surgery and AC at the same medical center between 2008 and 2015, either at its affiliated public hospital (n = 43) or private hospital (n = 79). We defined timely initiation as receiving AC within 60 days postoperatively, and completion as receiving ≥ 75% of planned AC. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with AC delivery. Median number of days to AC was significantly greater among patients at the public (53, range 31–231) compared with the private hospital (43, range 25–105; p = 0.002). However, the percentage of patients with timely AC initiation did not differ substantially by hospital (74 vs 81%, p = 0.40). In multivariable analysis, age (OR 0.95/year, 95% CI 0.91–0.99) and laparoscopic versus open surgery (OR 5.65, 95% CI 1.92–16.62) were significant factors associated with timely AC initiation. Moreover, AC completion did not differ significantly between public (83.7%) and private (89.9%) hospital patients (p = 0.32). The proportions of patients with timely initiation and completion of AC were similar at a public and private hospital affiliated with a large, urban medical center. Future research should investigate how specific system-level factors help alleviate this expected difference in timely care delivery.

The LUCINDA Trial (Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer’s) is a 52 week, randomized, placebo-controlled trial of leuprolide acetate (Eligard) in women with Alzheimer’s disease (AD). Leuprolide acetate is a gonadotropin analogue commonly used for hormone-sensitive conditions such as prostate cancer and endometriosis. This repurposed drug demonstrated efficacy in a previous Phase II clinical trial in those women with AD who also received a stable dose of the acetylcholinesterase inhibitor donepezil (Bowen et al., 2015). Basic biological, epidemiological and clinical trial data suggest leuprolide acetate mediates improvement and stabilization of neuropathology and cognitive performance via the modulation of gonadotropin and/or gonadotropin-releasing hormone signaling. LUCINDA will enroll 150 women with mild-moderate AD who are receiving a stable dose of donepezil from three study sites in the United States. Cognition and function are the primary outcome measures as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale. Blood and MRI biomarkers are also measured to assess hormonal, inflammatory and AD biomarker changes. We present the protocol for LUCINDA and discuss trial innovations and challenges including changes necessitated by the covid-19 pandemic and study drug procurement issues.

4504 Background: Trimodality bladder preservation therapy (TMT) is a standard treatment option for clinically localized MIBC with curative intent. Pembro has shown activity in MIBC in the neoadjuvant setting and may combine well with TMT to improve outcomes. This trial evaluated the safety and efficacy of pembro added to TMT in MIBC. Methods: This multicenter phase 2 trial included pts with cT2 – T4aN0M0 MIBC who declined or were ineligible for cystectomy (RC), ECOG PS 0/1, eGFR > 30 cc/min, and no contraindications to pelvic RT or pembro. No perioperative chemotx for MIBC was permitted. Pts received pembro 200 mg x 1 followed 2-3 weeks by maximal TURBT and then whole bladder RT (52 Gy/20 fx; IMRT preferred) with twice wkly gem 27 mg/m2 and pembro Q3 wks x 3 treatments. 12 wks post-RT, CT/MR AP, TUR of tumor bed and cytology were performed to document response. Up to 6 pts were enrolled to a safety cohort (SC) followed by 48 pts in efficacy cohort (EC). The primary endpt is 2-yr bladder-intact disease-free survival (BIDFS: first of MIBC or regional nodal recurrence, distant metastases, or death) assessed by serial cysto/cytology and CT/MRI. EC had 85% power to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate (RTOG Pooled analysis; Mak JCO 2014). Key secondary endpts were safety, 12 wks CR rate, metastases-free survival and overall survival. Tumor tissue was collected at study entry, maximal TURBT and post-treatment TUR of tumor bed with serial PBMCs for correlative analyses. Results: From 5/2016 to 10/2020, 54 pts (6 SC, 48 EC; 72% M) enrolled at 5 centers; Median age 67 (65-89) for SC and 74 (51-97) for EC. C-stage (74% cT2, 22% cT3, and 4% cT4). 39 (72%) declined RC. All 6 pts in SC and 42/48 (88%) of EC pts completed all study therapy; 1/48 (2%), 2/48 (4%), and 4/48 (8%) discontinued RT/Gem, Gem or Pembro, respectively, most often due to toxicity. As of 1/2021 (median F/U 40.9 mos (38.6-50.8) SC and 11.7 mos (0.6 – 32.2) EC), no recurrences in SC, and 12/48 EC pts had any recurrence (6 NMIBC, 0 MIBC, 2 regional and 4 distant). The estimated 1 yr BIDFS rate is 77% (95% CI: 0.60-0.87). 12 wks CR rate was 100% in SC and 83% for EC (1 PR, 3 NR, 1 Progression, 11 NE; 2 still on active study). In the EC, 35% of pts had a Gr ≥3 TEAE (Gr 3 events included UTI 8%, diarrhea 4%, colitis 4%, bladder pain/obstruction 4%, neutropenia 2%, thrombocytopenia 2%). Notable Pembro Gr ≥3 TRAE included 3 pts (6%) Gr 3 GI toxicity and 1 pt Gr 4 colonic perforation. 1 patient died due to fungemia, unrelated to study therapy. Conclusions: Pembro added to hypofractionated RT and twice weekly gem was well-tolerated with promising efficacy in this early analysis. Pembro-related toxicity was consistent with prior monotherapy trials. Selected correlative analyses from serially collected blood and tissue specimens will be presented. Clinical trial information: NCT02621151.

Purpose:Neoadjuvant therapy has been widely integrated in the treatment of locally advanced breast cancer. Over time, this strategy has been extended to include patients with earlier stage disease to allow for assessment of in vivo response to treatment. The aim of this study was to describe the national trends in neoadjuvant therapy for all invasive breast cancers with a particular focus on triple negative disease and HER2 status. Methods: The National Cancer Database (NCDB), an oncology outcomes database that collects data from more than 1500 Commission on Cancer (CoC) accredited cancer programs, was queried for all women diagnosed with invasive breast cancer from 2006-2013. Patients with unknown systemic therapy sequence were excluded. Women were classified by whether or not they received neoadjuvant systemic, chemo and/or endocrine, therapy. Results: We identified 1,221,976 cases that were eligible for this analysis. Of these, 29.7% were HER2 negative, 18.4% were classified as triple negative, and 8.9% received neoadjuvant systemic therapy. The percentage of patients receiving neoadjuvant therapy increased from 7.5% in 2006 to 9.8% in 2012 with a slight decrease to 9.5% in 2013. This increase in the use of neoadjuvant therapy over the time period was statistically significant (p Number and percent of patients who received/did not receive neoadjuvant therapy by year2006 (N=136117)2007 (N=143033)2008 (N=148888)2009 (N=154713)2010 (N=154040)2011 (N=162333)2012 (N=163395)2013 (N=159457)No Neoadjuvant Therapy | 125908 (92.5)131559 (91.98)136593 (91.74)141364 (91.37)139459 (90.53)146500 (90.25)147401 (90.21)144306 (90.5)Neoadjuvant Therapy | 10209 (7.5)11474 (8.02)12295 (8.26)13349 (8.63)14581 (9.47)15833 (9.75)15994 (9.79)15151 (9.5) Conclusions: Over the time period from 2006-2013, there has been an apparent increase in the percentage of patients who received neoadjuvant therapy. This trend is accompanied by increases in the percentage of TNBC patients and in Her2 positive patients who received neoadjuvant therapy. Other factors and the joint effects of these factors on the observed increase in the use of neoadjuvant therapy are under evaluation to elucidate the basis for this observation in the NCDB data. Citation Format: Schnabel F, Schwartz S, Hochman T, Chun J, Goldberg J. National trends in neoadjuvant therapy for breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-26.

Patients with multifocal breast cancers (MBCs) have a poorer prognosis than patients with unifocal breast cancers. Studies have attributed this to tumor size underestimation in MBC. An alternative hypothesis is that some MBCs behave in a fashion analogous to the “satellite” and “in-transit metastasis” observed in melanoma and, thereby, are more clinically aggressive. We identified 79 cases of MBC, which we classified into 2 groups: study cases defined as ≥2 morphologically similar tumor foci with ≥1 focus without in situ carcinoma (n = 21); and a control group defined as ≥2 morphologically similar or dissimilar foci with associated in situ carcinoma in all foci (n = 58). The odds of being a study case is 1.86 (95% confidence interval [CI] 1.26-2.74) times greater per unit increase in number of tumor foci (median of 4 tumor foci; P = .002). Study cases were 73.33 (95% CI = 8.91-603.16) times more likely to have lymphovascular invasion (LVI) and 14.72 (95% CI = 4.37-49.61) times more likely to have nodal metastases. Grade I/II tumors were 0.20 (95% CI = 0.07-0.59) times less likely to be study cases. There was a significant positive interaction ( P < 0.001) indicated by the relationship of LVI status and nodal status with the study case and control group. We conclude that there is a subset of MBC that presents with more numerous tumor foci and a higher rate of nodal metastasis. The aggressive behavior of these cases may be attributed to their proclivity for LVI.

INTRODUCTION Vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT represent clinically and/or preclinically validated molecular targets in vestibular schwannomas. We conducted a single institution, prospective, open-label, two-stage phase II study (ClinicalTrials.gov identifier NCT02129647) to estimate the response rate to axitinib, an oral multi-receptor tyrosine kinase inhibitor targeting VEGFR, PDGFR and c-KIT, in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannomas (VS). METHODS NF2 patients older than 5 years with at least one volumetrically measurable, progressive VS were eligible. The primary endpoint was to estimate the objective volumetric response rates to axitinib. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Response was assessed every 3 months with MRI using 3-D volumetric tumor analysis and audiograms. Volumetric response and progression were defined as ≥20% decrease or increase in VS volume, respectively. RESULTS Twelve eligible patients (ages: 14–56 years) were enrolled on this study. Seven of twelve patients completed 12 cycles (range: 2 to 12 cycles). We observed two imaging and three hearing responses. Best volumetric response was -53.9% after nine months on axitinib. All patients experienced drug-related toxicities, the most common adverse events were diarrhea, hematuria and skin toxicity, not exceeding grade 2 and hypertension, not exceeding grade 3. CONCLUSIONS While axitinib has modest anti-tumor activity in NF2 patients, it is more toxic and appears to be less effective compared to bevacizumab. Based on these findings, further clinical development of axitinib for this indication does not appear warranted.

Physical activity (PA) and health were compared in younger (YA; 18-44 years), middle-aged (MA; 45-64 years), and older (OA; ≥65 years) adults with disability (PWD), functional limitation (PFL), or without disability (PWoD). Disability occurred in YA (PWD: 2.3%; PFL: 14.3%), MA (PWD: 8.5%; PFL: 23.8%), and OA (PWD: 14.9%; PFL: 26.6%). Not meeting aerobic/muscle-strengthening PA recommendations was frequent in YA (PWD: 50.7%; PFL: 42.5%; PWoD: 35.8%), MA (PWD: 56.7%; PFL: 44.0%; PWoD: 35.6%), and OA (PWD: 57.8%; PFL: 44.1%; PWoD: 33.1%). Among PWD, YA and MA met muscle, strengthening recommendations more frequently than did OA; PFL did more aerobic PA than PWD. The presence of chronic diseases, female gender, White race, lower education, and less income were associated with being PWD or PFL. Those with greater PA were less likely to be PWD or PFL. Results suggest increasing public health efforts to promote healthy lifestyles in MA and OA.

BACKGROUND There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a “hypermutator phenotype”. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily transformed IDH-mutant GBMs. Safety-lead-in results will be presented. METHODS This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE. RESULTS Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5–54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade ≥ 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade ≤ 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4–5.7). Median OS was 10.1 (range 6.8–21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual. CONCLUSIONS Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen.

Background: The treatment paradigm of adult patients with acute lymphoblastic leukemia (ALL) is primarily derived from successful pediatric chemotherapy regimens. Pegasparagase (PEG) is a key component of pediatric therapy and is the backbone of cytotoxic ALL regimens. However, among the adult population the use of PEG has been limited by the difficulty in tolerating prolonged asparagine depletion. Hepatotoxicity is among the most common adverse events reported with the use of PEG, with grade 3/4 hepatotoxicity seen in 20% of young adults compared to 40-60% of older adults. Incorporating PEG into the treatment of ALL patients under 40 remains an accepted practice despite some studies that report up to 75% of patients have grade 3/4 adverse events as a result of asparagine depletion. In a study of 85 patients with ALL, 3-year overall survival (OS) was significantly different between patients older and younger than 35 (52% vs 83% p = 0.003). Whether this difference is due to PEG toxicity or to other factors remains to be determined. At NYU hospitals, PEG-containing protocols are frequently deployed to treat adult ALL. In our study, we sought to look at the difference in PEG toxicity and response rate (RR) in patients older and younger than 35 and whether these toxicities contributed to a delay in subsequent treatments and to a worse outcome. Methods: We conducted a retrospective chart review of patients older than 18 diagnosed with ALL or lymphoblastic lymphoma, who received at least 1 dose of PEG at our institution between 2014 and 2018. All patients received PEG as part of their first line treatment protocol. Our main objective was to compare the tolerability and toxicity profile of intravenous PEG in patients ≥35 years old versus Results: Out of a total of 50 patients, 23 were age ≥ 35 (46%). Mean age was 34.4 (Range: 18.9-63.1). The 2 groups shared similar distributions in gender, race, and Philadelphia chromosome (Ph) subtypes (Table 1). The older group received significantly less PEG, 5114.8 vs. 25353.7 units (p=0.0007) and 1.65 vs. 3.59 doses (p Conclusions: Patients aged ≥ 35 received significantly less PEG during their treatments but were more likely to develop severe grade 3-4 hepatotoxicity compared to their younger counterparts. The response rates were similar with comparable MRD negativity rates after induction regardless of total amount of PEG administered. However, relapse occurred more frequently in the older group, possibly resulting from more frequent delays in administering other chemotherapy agents due to PEG toxicity. Incorporation of PEG is important in the treatment of ALL but should be used with caution in patients ≥35 years old, and will likely require dose and schedule modifications. A larger prospective trial investigating adequate dosing and scheduling of PEG in this age group is warranted, specifically comparing delays in chemotherapy, relapse, and survival rates in regimens with and without PEG. Disclosures No relevant conflicts of interest to declare.

Recent whole genome melanoma sequencing studies have identified recurrent mutations in the gene encoding the catalytic subunit of serine/threonine phosphatase 6 (PPP6C/PP6C). However, the biochemical, functional, and clinical ramifications of these mutations are unknown. Sequencing PP6C from patients with melanoma (233 primary and 77 metastatic specimens) with extended prospective clinical outcome revealed a large number of hotspot mutations in patients with both primary and metastatic melanoma. Despite minimal association between stage and presence of PP6C mutations in patients with primary melanoma, a subpopulation of cells within each tumor did contain PP6C mutations, suggesting PP6C mutation is an early, but non–tumor-initiating event in melanoma. Among patients with primary melanoma with PP6C mutations, patients with stop mutations had significantly shorter recurrence-free survival compared with patients without stop mutations. In addition, PP6C mutations were independent of commonly observed BRAF and NRAS mutations. Biochemically, PP6C mutations could be classified as those that interact with PP6C regulatory subunits and those that do not. Mutations that did not bind to PP6C regulatory subunits were associated with increased phosphorylation of Aurora kinase, a PP6C substrate, and mitotic defects. However, both classes of PP6C mutations led to increased sensitivity to Aurora kinase inhibition. Together, these data support for the first time that PP6C mutations are molecularly, biochemically, and clinically heterogeneous. Implications: PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors. Mol Cancer Res; 12(3); 433–9. ©2013 AACR.

Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers.We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients.None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules.Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.

Myelofibrosis is a chronic and progressive myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating symptoms and leukemic transformation. Ruxolitinib, an oral JAK1/2 inhibitor, is highly effective in ameliorating systemic symptoms and reducing splenomegaly. Current clinical research is focused on the evaluation of agents based on pre-clinical rationale that can result in disease course modification. Panobinostat is a pan-histone deacetylase inhibitor that has demonstrated clinical activity as a single agent in early phase trials of myelofibrosis. We previously conducted a phase I trial of panobinostat monotherapy in patients with myelofibrosis and determined 25mg thrice weekly as the recommended phase II dose. We then completed an investigator initiated, Simon 2-stage, phase II trial of 22 myelofibrosis patients at our single institution. After 6 cycles of therapy, the overall response rate by IWG-MRT criteria was 36% (8/22; 95% CI: 16-56%). The median percent reduction in spleen volume was 34% (range, 1.6%-73%) in eight evaluable patients. The average reduction in JAK2V617F allele burden was 6.8% (Range; -4.0% to 20.2%) and one patient obtained a complete molecular response. Six patients remained on therapy in the extension phase for a median of 18 months (range, 7-44). Treatment discontinuation was frequent due to patient/physician perception of therapy ineffectiveness. The optimal dosing of panobinostat for the treatment of MF remains somewhat ill-defined but appears to be most effective and better tolerated when administered at lower doses over a prolonged duration of therapy.

This single-institution phase II study was performed to estimate the response rate to lapatinib in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Twenty-one eligible patients were enrolled. Brain and spine MRIs, including 3-dimensional volumetric tumor analysis, and audiograms were performed once at baseline and again every 12 weeks. The primary response end point was evaluable in 17 patients and defined as ≥15% decrease in VS volume. Hearing was evaluable as a secondary end point in 13 patients, with responses defined as an improvement in the pure tone average of at least 10 dB or a statistically significant increase in word recognition scores. Four of 17 evaluable patients experienced an objective volumetric response (23.5%; 95% confidence interval [CI], 10%–47%), with median time to response of 4.5 months (range, 3–12). In responders, reduction in VS volumes ranged from −15.7% to −23.9%. Four of 13 patients evaluable for hearing met hearing criteria for response (30.8%; 95% CI, 13%–58%). One sustained response exceeded 9 months in duration. Median time to overall progression (ie, volumetric progression or hearing loss) was 14 months. The estimated overall progression-free survival and volumetric progression-free survival at 12 months were 64.2% (95% CI, 36.9%–82.1%) and 70.6% (95% CI, 43.1%–86.6%), respectively. Toxicity was generally minor, and no permanent dose modifications were required. Lapatinib carries minor toxicity and has objective activity in NF2 patients with progressive VS, including volumetric and hearing responses. Future studies could explore combination therapy with other molecular targeted agents such as bevacizumab.

Healthcare disparities associated with insurance and socioeconomic status have been well characterized for several malignancies, such as lung cancer. To assess whether there are healthcare disparities in thyroid cancer, this study evaluated the stage on initial presentation of patients with differentiated thyroid cancer (DTC) in a public versus university teaching hospital.A retrospective chart review was performed to identify patients with a new diagnosis of DTC from January 1, 2007, to January 1, 2010, in a large public and adjoining university teaching hospital at a single academic medical center. Medical records were reviewed for demographics, pathology, and American Joint Committee on Cancer tumor-node-metastasis stage at initial presentation.There were 49 cases of well-DTC (96% papillary and 4% Hürthle) in the public hospital and 370 cases (95% papillary, 2% Hürthle, and 3% follicular) in the university teaching hospital. Median age (years) at presentation was 50 in the public versus 48 in the university teaching hospital (p=0.39). Ninety-six percent of public hospital patients were from ethnic minorities compared with 16% of university teaching hospital patients (p0.0001). Only 1 (2%) public hospital patient had private insurance compared with 85% of university teaching hospital patients. Tumor status (p=0.002) and stage (p=0.03) were more advanced and extrathyroidal extension (p=0.02) was more prevalent among public hospital patients compared with university teaching hospital patients. In a multivariable analysis, public hospital, male gender, increasing age, advanced tumor status, and the presence of lymphovascular invasion were the best predictors of more advanced disease stage. Public hospital patients were 3.4 times more likely to present with advanced DTC than university teaching hospital patients of the same age, gender, tumor status, and lymphovascular invasion status (95% confidence interval 1.29-8.95).In a public hospital, where the patient population is defined primarily by insurance status, patients were more likely to present with advanced-stage DTC than patients presenting to an adjacent university teaching hospital. These results suggest a disparity in the stage on initial presentation of DTC, possibly resulting in a delayed diagnosis of cancer.

Background There are well established risk factors for breast cancer, including elements of personal and family history. Ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) have long been viewed as representing two points on the spectrum of one disease. There is limited and conflicting information in the literature regarding risk factor profiles for DCIS as compared with IDC. The purpose of this study was to investigate the relationship of established risk factors in a population of women newly diagnosed with pure DCIS and IDC. Methods The Breast Cancer Database at NYU Langone Medical Center was queried for women who were diagnosed with pure DCIS and IDC from 1/2010-3/2011. Variables of interest included: age, family history of breast cancer (FHBC), BRCA1/2 status, age at menarche and menopause, parity, age at first birth, breast feeding, body mass index (BMI), history of atypical hyperplasia or lobular carcinoma in situ (ADH, ALH, LCIS), stage, ER/PR status, and method of presentation. Wilcoxon non-parametric tests, Chi-Square tests, and Fisher's Exact Tests were used to evaluate differences among DCIS and IDC patients. Results Of the 593 women identified in this study, 140 (24%) had pure DCIS and 453 (76%) had IDC. The median age at diagnosis was 59 years. There were 9 (1.5%) BRCA1/2 mutation carriers. Of these, 7 had IDC and 2 had DCIS. The majority of patients with IDC were stage I (67%) and ER/PR+ (73%). The majority of patients with DCIS were also ER/PR+ (71%). In our cohort, the majority of DCIS (83%) was mammographically detected versus 47% of IDC cases. There were no statistically significant differences in breast cancer risk factors between the two groups. Conclusions In contrast to some previously published work, the risk factor profile in our cohort was similar for patients with IDC and DCIS. In this population, the majority of cases of DCIS were detected mammographically, underscoring the importance of mammography in early detection of breast cancer. There is increasing interest in identifying a population of women with DCIS who might never progress to invasive disease. Our data suggests that this population is unlikely to be distinguished by its risk factor profile. Genetic and molecular characteristics are more likely to provide the criteria by which this subgroup of patients is identified. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-10-08.

Prostate-specific antigen (PSA) is the only independent predictor of biochemical recurrence (BCR) following radical prostatectomy (RP) subject to change over time.To determine whether an ultrasensitive PSA measured at 3 yr following RP is a predictor of subsequent BCR.There were 1197 consecutive men with clinically localized prostate cancer who underwent an open radical retropubic prostatectomy (ORRP) at a tertiary referral academic medical center. Exclusions included 107 men (8.9%) who developed a PSA level ≥ 0.2 ng/ml or underwent hormone therapy or radiation therapy (RT) within the first 3 r after surgery, 191 men (16%) who did not undergo a 3-yr ultrasensitive PSA assay, and 98 men (8.2%) who had PSA levels ≥ 0.1 and0.2 at 3 yr. The remaining 801 men were stratified into two groups based on their ultrasensitive PSA level at 3 yr postoperatively: group 1, which consisted of patients whose PSA was ≤ 0.04 (n = 765), and group 2, which consisted of patients whose PSA was0.04 and0.10 (n = 36).Delayed BCR was the primary end point and represented those men in this cohort who developed a PSA level ≥ 0.2 or underwent salvage RT for a persistently rising PSA level after 3 yr of follow-up.The 7-yr cumulative BCR-free survival rate for groups 1 and 2 was 0.957 (95% confidence interval [CI], 0.920-0.978) and 0.654 (95% CI, 0.318-0.855), respectively. In multivariable Cox proportional hazards models, ultrasensitive PSA level at 3 yr remained the only significant predictor of delayed BCR (likelihood ratio χ(2) for full model: 27.03; df = 1; p0.001). A limitation of the study is that no uniform PSA assay was obtained.Our findings provide compelling evidence that an ultrasensitive PSA at 3 yr following RP provides useful insights into delayed BCR and is a source of reassurance for the overwhelming majority of men being followed for delayed recurrences.

p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients. Cancer Res; 70(21); 8446–56. ©2010 AACR.

Translational regulation is critical in cancer development and progression. Translation sustains tumor growth and development of a tumor vasculature, a process known as angiogenesis, which is activated by hypoxia. Here we first demonstrate that a majority of large advanced breast cancers overexpress translation regulatory protein 4E-BP1 and initiation factor eIF4G. Using model animal and cell studies, we then show that overexpressed 4E-BP1 and eIF4G orchestrate a hypoxia-activated switch from cap-dependent to cap-independent mRNA translation that promotes increased tumor angiogenesis and growth at the level of selective mRNA translation. Elevated levels of 4E-BP1 trigger hypoxia inhibition of cap-dependent mRNA translation at high-oxygen levels and, with eIF4G, increase selective translation of mRNAs containing internal ribosome entry sites (IRESs) that include key proangiogenic, hypoxia, and survival mRNAs. The switch from cap-dependent to cap-independent mRNA translation facilitates tumor angiogenesis and hypoxia responses in animal models.

Many organisms accumulate a pool of germline stem cells during development that is maintained in later life. The dynamics of establishment, expansion and homeostatic maintenance of this pool are subject to both developmental and physiological influences including the availability of a suitable niche microenvironment, nutritional status, and age. Here, we investigated the dynamics of germline proliferation during stages of expansion and homeostasis, using the C. elegans germ line as a model. The vast majority of germ cells in the proliferative zone are in interphase stages of mitosis (G1, S, G2) rather than in the active mitotic (M) phase. We examined mitotic index and DNA content, comparing different life stages, mutants, and physiological conditions. We found that germ cells in larval stages cycle faster than in adult stages, but that this difference could not be attributed to sexual fate of the germ cells. We also found that larval germ cells exhibit a lower average DNA content compared to adult germ cells. We extended our analysis to consider the effects of distance from the niche and further found that the spatial pattern of DNA content differs between larval and adult stages in the wild type and among mutants in pathways that interfere with cell cycle progression, cell fate, or both. Finally, we characterized expansion of the proliferative pool of germ cells during adulthood, using a regeneration paradigm (ARD recovery) in which animals are starved and re-fed. We compared adult stage regeneration and larval stage expansion, and found that the adult germ line is capable of rapid accumulation but does not sustain a larval-level mitotic index nor does it recapitulate the larval pattern of DNA content. The regenerated germ line does not reach the number of proliferative zone nuclei seen in the continuously fed adult. Taken together, our results suggest that cell cycle dynamics are under multiple influences including distance from the niche, age and/or maturation of the germ line, nutrition and, possibly, latitude for physical expansion.

Beta-blockers reduce mortality in patients with systolic chronic heart failure (CHF), yet prescription rates have remained low among primary care providers.To determine the beta-blocker prescription rate among patients with systolic CHF at primary care Veterans Affairs (VA) clinics, its change over time; and to determine factors associated with nonprescription.Retrospective chart review.Seven hundred and forty-five patients with diagnostic codes for CHF followed in primary care clinics at 3 urban VA Medical Centers.Rate of beta-blocker prescription and comparison of patient characteristics between those prescribed versus those not prescribed beta-blockers.Only 368 (49%) had documented systolic CHF. Eighty-two percent (303/368) of these patients were prescribed a beta-blocker. The prescription rate rose steadily over 3 consecutive 2-year time periods. Patients with more severely depressed ejection fractions were more likely to be on a beta-blocker than patients with less severe disease. Independent predictors of nonprescription included chronic obstructive pulmonary disease, asthma, depression, and age. Patients under 65 years old were 12 times more likely to receive beta-blockers than those over 85.Primary care providers at VA Medical Centers achieved high rates of beta-blocker prescription for CHF patients. Subgroups with relative contraindications had lower prescription rates and should be targeted for quality improvement initiatives.

To compare per diem total direct, ancillary (laboratory and radiology) and pharmacy costs of palliative care (PC) compared to usual care (UC) patients during a terminal hospitalization; to examine the association between PC and ICU admission.Retrospective, observational cost analysis using a VA (payer) perspective.Two urban VA medical centers.Demographic and health characteristics of 314 veterans admitted during two years were obtained from VA administrative data. Hospital costs came from the VA cost accounting system.Generalized linear models (GLM) were estimated for total direct, ancillary and pharmacy costs. Predictors included patient age, principal diagnosis, comorbidity, whether patient stay was medical or surgical, site and whether the patient was seen by the palliative care consultation team. A probit regression was used to analyze probability of ICU admission. Propensity score matching was used to improve balance in observed covariates.PC patients were 42 percentage points (95% CI, -56% [corrected] to -31%) less likely to be admitted to ICU. Total direct costs per day were $239 (95% CI, -387 to -122) lower and ancillary costs were $98 (95% CI, -133 to -57) lower than costs for UC patients. There was no difference in pharmacy costs. The results were similar using propensity score matching.PC was associated with significantly lower likelihood of ICU use and lower inpatient costs compared to UC. Our findings coupled with those indicating better patient and family outcomes with PC suggest both a cost and quality incentive for hospitals to develop PC programs.

Background: Although the optimal timing of adjuvant chemotherapy (AC) for stage III colon cancer patients has been debated, most studies recommend initiating AC within approximately 60 days of surgery. Significant disparities in timeliness of AC initiation in colon cancer have been reported in public versus private hospitals, with longer time to AC at public hospitals. We evaluated whether timeliness of AC differed between a public and a private hospital, both affiliated with the same major academic institution in New York City. Methods: We conducted a retrospective cohort study of Stage III colon cancer patients who underwent surgery and received AC at the same institution from 2008-2015 at NYU Langone Medical Center’s affiliated public hospital (Bellevue) or its private hospital (Tisch). Patient data were obtained through review of hospital tumor registry and electronic medical records. Patient characteristics were compared by hospital. We defined timeliness as receipt of AC within 60 days postoperatively. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with timely AC. Results: Forty three patients at Bellevue Hospital and 79 patients at Tisch Hospital who underwent surgery and received AC at the same institution were included. Median number of days to AC was significantly greater among patients receiving care at Bellevue (53, range 31-231) compared to Tisch (43, range 25-105; p=0.002). However, the percentage of patients who received timely AC did not differ substantially at Bellevue and Tisch (74% vs 81%, p=0.40). Individual characteristics significantly associated with timely initiation of AC were non-Hispanic ethnicity (OR: 2.71, 95% CI: 1.06-6.95), married (OR: 2.89, 95%CI: 1.15-7.30), and laparoscopic (vs open) surgery (OR: 4.30, 95%CI: 1.64-11.25). The odds of receiving timely AC at Bellevue compared to Tisch was not significant (OR: 0.68, 95% CI: 0.28-1.65). When hospital and other factors were examined jointly, only age (OR: 0.95/year, 95% CI: 0.91-0.99) and laparoscopic (vs open) surgery (OR: 5.65, 95% CI: 1.92-16.62) remained as important factors associated with receiving timely AC (Likelihood Ratio Chi-Square=14.95, p=0.0019). When hospital was omitted from multivariable analysis, age and surgery type still remained the only significant factors associated with timely AC (OR’s unchanged, Likelihood Ratio Chi-Square=14.81, p-value=0.0006). Conclusions: The proportion of patients receiving timely AC within 60 days of surgery was similar at both an affiliated public and private hospital at NYU Langone Medical Center. Age and type of surgery were significant predictors of timeliness in our population. Further research should be conducted to understand how system-level factors may promote timely receipt of care. Citation Format: Daniel Lin, Benjamin Levinson, Judith D. Goldberg, Tsivia Hochman, Lawrence P. Leichman, Heather T. Gold. Comparison of a public versus private hospital in New York City in delivering timely adjuvant chemotherapy among stage III colon cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5282. doi:10.1158/1538-7445.AM2017-5282

Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34+ cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment.

Tumor grade plays a critical role in the management of papillary non-invasive urothelial carcinoma (UC). Since grading of UC relies on morphologic criteria, variability in interpretation exists among pathologists. The objective of this study was to examine inter-observer variability in the grading of papillary non-invasive UC at a single academic medical center.One general pathologist and two genitourinary pathologists were blinded to patient identity and graded 98 consecutive UC specimens using the 1973 and 2004 classification systems. Kappa statistics (κ) were used to measure inter-observer reproducibility to account for agreement expected purely by chance. By convention, ϰ values from 0.21-0.4 represent "fair", from 0.41-0.6 represent "moderate", and0.6 represent "substantial" agreement.Raw percentage agreement among all three pathologists was only 26% using the 1973 system and 47% using the 2004 system. When measured by kappa, overall agreement was only "fair" for both systems and while higher for the 2004 system than the 1973, this was not significant (: 0.38 versus 0.26, respectively). There were no significant differences in agreement when comparing the specialists agreement between themselves with agreement between each specialist and the generalist (ϰ: 0.31-0.37 versus ϰ: 0.18-0.46).The current grading system continues to demonstrate challenges in reproducibility among general and specialized pathologists. The degree of variability has significant implications on management decisions for non-invasive UC. Our findings underscore the need to identify molecular markers that can provide a more objective and reliable risk stratification system to guide patient management.

Recurrent pediatric low-grade astrocytoma (PLGA) represents a major clinical problem in neuro-oncology, and novel, less toxic and more effective therapies are needed.1 Recently, our increased understanding of the key molecular pathways driving PLGA growth and the increasing availability of targeted therapies for those pathways have led to great interest in exploring molecular targeted therapies for PLGA. Pilocytic astrocytoma (PA) is the most common histological subtype of PLGA. Patients with neurofibromatosis type 1 (NF1) are predisposed to developing PAs, predominantly in the optic tract (ie, optic pathway gliomas [OPGs]).2 NF1 is characterized by the loss of the NF1 gene product neurofibromin, resulting in activation of the RAS/RAF/MEK/ERK signaling pathway.3 The majority of sporadic PAs harbor a unique tandem duplication at chromosome 7q34, which produces a fusion gene between KIAA1549 and the kinase domain of BRAF that result in constitutive BRAF and ultimately MAPK activation. In recent genomic studies, almost all PAs that do not harbor KIAA-BRAF have been shown to harbor other genetic lesions that also result in constitutive MAPK pathway activation, such as activating genetic hits in FGFR1, NTRK2, and RAF1.4,5 PLGAs express pro-angiogenic factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF]), and their receptors (VEGFR and PDGFR).6–8 Bevacizumab, a VEGF inhibitor, has recently shown very encouraging activity in PLGA.9,10 Sorafenib is an oral, small-molecule multikinase inhibitor with potent in vitro activity against both wild-type and mutant (V600E) BRAF.11 Recent preclinical data showed that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with sorafenib.12 Sorafenib also exerts anti-angiogenic activity via inhibition of VEGFR-1/2/3, PDGFRβ, Flt-3, and c-kit, which has been studied in a variety of preclinical models13,14 as well as in clinical studies using dynamic, contrast-enhanced MRI.15 Because sorafenib is a potent inhibitor of several key molecular pathways that are relevant in PLGAs and encouraging preclinical data,12 we conducted this prospective phase II clinical trial to assess the objective response rate to sorafenib in patients with PLGA.

Summary Objectives Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5–20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC. Methods Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance). Results Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26–2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention-deficit/hyperactive disorder, or major depressive disorder. Significance The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Introduction Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data showed strong activation of the phosphatidylinositide-3-kinase/mammalian target of rapamycin (mTOR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, and expression of inflammatory cytokines and tumor-associated macrophages (TAMs). Patients and Methods Archival tumor tissue from 3 disease types (IBC treated with neoadjuvant chemotherapy [NAC], n = 45; invasive ductal carcinoma [IDC] treated with NAC [n = 24; ‘treated IDC'; and untreated IDC [n = 27; ‘untreated IDC']) was analyzed for the expression of biomarkers phospho-S6 (pS6) (mTOR), phospho-JAK2 (pJAK2), pSTAT3, interleukin (IL)-6, CD68 (monocytes, macrophages), and CD163 (TAMs). Surrounding nontumor tissue was also analyzed. Results Biomarker levels and surrogate activity according to site-specific phosphorylation were shown in the tumor tissue of all 3 disease types but were greatest in IBC and treated IDC and least in untreated IDC for pS6, pJAK2, pSTAT3, and IL-6. Of 37 IBC patients with complete biomarker data available, 100% were pS6-positive and 95% were pJAK2-positive. In nontumor tissue, biomarker levels were observed in all groups but were generally greatest in untreated IDC and least in IBC, except for JAK2 . Conclusion IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, which suggests a potential mechanism of resistance after NAC. Biomarker levels in surrounding nontumor tissue suggested that the stroma might be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of pS6 and pJAK2 in IBC might support dual targeting of the mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combined targeted therapies in IBC.

Panobinostat (LBH589), a novel histone deacetylase inhibitor (HDACi), was evaluated in a phase I study of patients with primary myelofibrosis (PMF) and post-essential thrombocythaemia/polycythaemia vera-related myelofibrosis (Post-ET/PV MF). Eighteen patients (PMF 56%; Post-PV MF 28%; Post-ET MF 17%) were treated in three cohorts at oral doses of (i) 20, (ii) 30, and (iii) 25 mg three times weekly consecutively. Reversible thrombocytopenia was the dose-limiting toxicity. Five patients (two in Dose Cohort 1, one in Dose Cohort 2 and two in Dose Cohort 3) received six or more cycles and were evaluable for response assessment. After the sixth cycle, three of these five patients achieved clinical improvement (CI) with 100% reduction in palpable splenomegaly from baseline, and two patients experienced stable disease. Panobinostat therapy was also associated with improvement in the degree of anaemia in two of the five patients. Of the three patients who achieved CI after six cycles, one patient achieved a near complete remission after 15 cycles of treatment and another patient had resolution of marrow fibrosis after 16 cycles. We conclude that panobinostat is a well-tolerated, clinically active treatment for MF patients, regardless of JAK2 V617F status, and most effective when given at low doses over long periods of time.

Purpose: Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local antitumor immunity and induces the regression of breast cancer skin metastases. Experimental Design: A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 d/wk for 8 weeks. Safety and immunologic correlates were secondary objectives. Results: Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1 to 2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response [20%; 95% confidence interval (CI), 3%–56%]. Responders showed histologic tumor regression with evidence of an immune-mediated response, showed by changes in the tumor lymphocytic infiltrate and locally produced cytokines. Conclusion: Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a proimmunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve antitumor immune and clinical responses. Clin Cancer Res; 18(24); 6748–57. ©2012 AACR.

INTRODUCTION AND OBJECTIVES: Pathological grade is the most important prognostic indicator used to risk stratify and select treatment for non-invasive urothelial carcinoma (UC). The 1973 World Health Organization (WHO) grading classification has been most widely used, but suffers from unacceptably high interobserver variability. The 2004 WHO/International Society of Urological Pathology (ISUP) revision was developed to reduce variability by providing welldefined histological criteria for each grade. We compared interobserver reproducibility between the 1973 and 2004 systems and between general versus expert genitourinary pathologists. METHODS: 1 general pathologist (GP) and 2 genitourinary pathology specialists (GU1 and GU2) were blinded to patient identity and graded 98 consecutive UC specimens retrospectively using the 1973 and 2004 classifications. Kappa statistics ( ) were used to measure interobserver reproducibility. By convention, values from 0.21 – 0.4 represent “fair” agreement, from 0.41 0.6 represent “moderate” agreement, and 0.6 represent “substantial” agreement. As an example, values for prostate cancer Gleason score among genitourinary pathologists have been reported to be 0.6. RESULTS: Overall agreement was only fair for both systems and while higher for the 2004 system than the 1973, this was not significant ( : 0.38 versus 0.26, respectively). Agreement between the two specialists versus agreement between each specialist and the generalist was higher using the 1973 system ( : 0.37 vs 0.33 and 0.18) but lower using the 2004 system ( : 0.31 vs 0.46 and 0.39). The generalist had better agreement with both specialists using the 2004 system versus the 1973 system ( : 0.46 and 0.39 versus 0.33 and 0.18). These findings were not statistically significant. CONCLUSIONS: Reproducibility is not improved by the 2004 WHO/ISUP revision to the 1973 WHO grading system, even among expert genitourinary pathologists. Since management of non-invasive UC is primarily determined by its grade, this limits a clinician’s ability to risk stratify tumor and potentially alters treatment. Our findings underscore the need to identify molecular markers that can provide a more reliable risk stratification system.

Purpose Damage to heart and lung from breast radiotherapy is associated with increased cardiovascular mortality and lung cancer development. We conducted a prospective study to evaluate which position is best to spare lung and heart from radiotherapy exposure. Methods and Materials One hundred consecutive Stage 0–IIA breast cancer patients consented to participate in a research trial that required two computed tomography simulation scans for planning both supine and prone positions. The optimal position was defined as that which best covered the contoured breast and tumor bed while it minimized critical organ irradiation, as quantified by the in-field heart and lung volume. The trial was designed to plan the first 100 patients in each position to study correlations between in-field volumes of organs at risk and dose. Results Fifty-three left and 47 right breast cancer patients were consecutively accrued to the trial. In all patients, the prone position was optimal for sparing lung volume compared to the supine setup (mean lung volume reduction was 93.5 cc for right and 103.6 cc for left breast cancer patients). In 46/53 (87%) left breast cancer patients best treated prone, in-field heart volume was reduced by a mean of 12 cc and by 1.8 cc for the other 7/53 (13%) patients best treated supine. As predicted, supine-prone differences in in-field volume and mean dose of heart and lung were highly correlated (Spearman's correlation coefficient for left breast cancer patients was 0.90 for heart and 0.94 for lung and 0.92 for right breast cancer patients for lung). Conclusions Prone setup reduced the amount of irradiated lung in all patients and reduced the amount of heart volume irradiated in 87% of left breast cancer patients. In-field organ volume is a valid surrogate for predicting dose; the trial continued to the planned target of 400.

We report a comparison of the dosimetry and toxicity of three-dimensional conformal radiotherapy (3D-CRT) vs. intensity-modulated radiotherapy (IMRT) among patients treated in the prone position with the same fractionation and target of the hypofractionation arm of the Canadian/Whelan trial.An institutional review board-approved protocol identified a consecutive series of early-stage breast cancer patients treated according to the Canadian hypofractionation regimen but in the prone position. Patients underwent IMRT treatment planning and treatment if the insurance carrier approved reimbursement for IMRT; in case of refusal, a 3D-CRT plan was used. A comparison of the dosimetric and toxicity outcomes during the acute, subacute, and long-term follow-up of the two treatment groups is reported.We included 97 consecutive patients with 100 treatment plans in this study (3 patients with bilateral breast cancer); 40 patients were treated with 3D-CRT and 57 with IMRT. IMRT significantly reduced the maximum dose (Dmax median, 109.96% for 3D-CRT vs. 107.28% for IMRT; p0.0001, Wilcoxon test) and improved median dose homogeneity (median, 1.15 for 3D-CRT vs. 1.05 for IMRT; p0.0001, Wilcoxon test) when compared with 3D-CRT. Acute toxicity consisted primarily of Grade 1 to 2 dermatitis and occurred in 92% of patients. Grade 2 dermatitis occurred in 13% of patients in the 3D-CRT group and 2% in the IMRT group. IMRT moderately decreased rates of acute pruritus (p = 0.03, chi-square test) and Grade 2 to 3 subacute hyperpigmentation (p = 0.01, Fisher exact test). With a minimum of 6 months' follow-up, the treatment was similarly well tolerated in either group, including among women with large breast volumes.Hypofractionated breast radiotherapy is well tolerated when treating patients in the prone position, even among those with large breast volumes. Breast IMRT significantly improves dosimetry but yields only a modest but confirmed benefit in terms of toxicities. If a concurrent boost to the tumor bed is not required, a conformal 3D-CRT approach can adequately deliver prone whole-breast hypofractionation radiotherapy.

International audience; Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and overexpressed by many tumors. Here, we documented the presence of MMP-2-specific CD4(+) T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4(+) T cells displayed an inflammatory T(H)2 profile, i.e., mainly secreting TNF-α, IL-4, and IL-13 and expressing GATA-3. Furthermore, MMP-2-conditioned dendritic cells (DCs) primed naïve CD4(+) T cells to differentiate into an inflammatory T(H)2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 degrades the type I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type 2 "conditioner" and may play a role in the observed prevalence of detrimental type 2 responses in melanoma.

We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m2 intravenously twice a week) for 10–12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2–7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of

Inflammatory breast cancer (IBC) is the most lethal form of primary breast cancer. IBC lethality derives from generation of tumour emboli, which are non-adherent cell clusters that rapidly spread by a form of continuous invasion known as passive metastasis. In most cancers, expression of E-cadherin, an epithelial marker, is indicative of low metastatic potential. In IBC, E-cadherin is overexpressed and supports formation of tumour emboli by promoting tumour cell interactions rather than adherence to stroma. E-cadherin, a surface component of adherens junctions, is anchored by interaction with p120 catenin (p120). We show that the unique pathogenic properties of IBC result in part from overexpression of the translation initiation factor eIF4GI in most IBCs. eIF4GI reprograms the protein synthetic machinery for increased translation of mRNAs with internal ribosome entry sites (IRESs) that promote IBC tumour cell survival and formation of tumour emboli. Overexpression of eIF4GI promotes formation of IBC tumour emboli by enhancing translation of IRES-containing p120 mRNAs. These findings provide a new understanding of translational control in the development of advanced breast cancer.

Study Objective: To characterize and compare acceptability of human papillomavirus (HPV) vaccination by Latino parents at an urban medical center in the United States and a community hospital in El Salvador. Design: After reading an information sheet on HPV, 148 subjects at Bellevue Hospital in New York City and 160 subjects at Hospital Nacional de Santa Gertrudis in San Vicente, El Salvador, completed a survey. Results were analyzed using chi-square, Fisher's exact test, and Student's t-tests. Results and Conclusions: Parental acceptance of HPV vaccination was higher in a sample of Salvadoran subjects than in a sample of U.S. Latinas (P! 0.001 for daughters and sons). Reasons for objecting to HPV vaccination differ in the two locations. There are important differences between Salvadoran and U.S. subjects. Salvadorans are more accept- ing of HPV vaccination, and parental acceptance is unlikely to be a barrier to widespread vaccination in El Salvador. Tar- geted educational materials are needed in both locations.

To determine whether low-income seniors and those without prescription drug coverage are more likely to use generic cardiovascular drugs than more affluent and better insured adults.Cross-sectional analysis.We used data from the 2001 Medicare Current Beneficiary Survey. Analyses included noninstitutionalized survey respondents over age 65 years with hypertension who usedor =1 multisource cardiovascular drugs (N = 1710). We examined the association of income and prescription coverage with use of generic versions of multisource drugs from 5 classes: angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic receptor antagonists (beta-blockers), calcium channel blockers, alpha1-adrenergic receptor antagonists (alpha-blockers), and thiazide diuretics.Rates of generic medication use were 88.5% (beta-blockers); 92.8% (thiazides); 58.7% (calcium channel blockers); 60.7% (ACE inhibitors); and 52.6% (alpha-blockers). In multivariate analysis of generic medication use aggregated across the 5 drug classes, individuals with incomes below 200% of the federal poverty level were modestly more likely to use generic medications compared with seniors with incomes above 300% of the poverty level. Seniors who lacked prescription coverage were more likely to use generics than those who had employer-sponsored coverage, although the association was of marginal statistical significance (relative risk = 1.29, 95% confidence interval = 1.00, 1.60).Seniors with low incomes or no prescription coverage were only somewhat more likely to use generic cardiovascular drugs than more affluent and insured seniors. These findings suggest that physicians and policy makers may be missing opportunities to reduce costs for Medicare and its economically disadvantaged beneficiaries.

Limited information is available on preoperative status and risks for complications for older patients having surgery for hip fracture. Our objective was to identify potentially modifiable clinical findings that should be considered in decisions about the timing of surgery.We conducted a prospective cohort study with data obtained from medical records and through structured interviews with patients. A total of 571 adults with hip fracture who were admitted to 4 metropolitan hospitals were included.Multiple logistic regression was used to identify risk factors (including 11 categories of physical and laboratory findings, classified as mild and severe abnormalities) for in-hospital complications. The presence of more than 1 (odds ratio [OR] 9.7, 95% confidence interval [CI] 2.8 to 33.0) major abnormality before surgery or the presence of major abnormalities on admission that were not corrected prior to surgery (OR 2.8, 95% CI 1.2 to 6.4) was independently associated with the development of postoperative complications. We also found that minor abnormalities, while warranting correction, did not increase risk (OR 0.70, 95% CI 0.28 to 1.73).In this study of older adults undergoing urgent surgery, potentially reversible abnormalities in laboratory and physical examination occurred frequently and significantly increased the risk of postoperative complications. Major clinical abnormalities should be corrected prior to surgery, but patients with minor abnormalities may proceed to surgery with attention to these medical problems perioperatively.