Search

2513 Background: MDNA55 is an engineered IL-4 fused to pseudomonas exotoxin A being developed for GBM, an aggressive, universally fatal disease. No curative therapy exists and 75% of patients are not eligible for resection at recurrence. MDNA55 targets IL4R overexpressed in GBM, the immunosuppressive tumor microenvironment, and high expression is associated with poor survival outcomes in GBM. A Ph 2b trial of MDNA55 was completed in rGBM using convection-enhanced delivery to bypass the BBB. Here we report results from the Ph 2b trial and comparison against a matched Synthetic Control Arm (SCA). Methods: MDNA55-05 is an open-label, single-arm study of intratumoral delivery of ≤ 240 μg MDNA55 as a single treatment via ≤ 4 catheters in de novo GBM without IDH1/2 mutation at 1st or 2nd recurrence not eligible for resection, tumors ≤ 4 cm, KPS ≥ 70. IL4R expression in GBM tissues was determined by H-Score using a validated IHC assay. 1o endpoint is median overall survival (mOS); 2o endpoint includes the impact of IL4R status on mOS. An eligibility-matched SCA was identified retrospectively from patient registries at major neurosurgery centers with access to GBM tumor tissue banks under IRB-approved protocols. Results: 44 subjects comprise the MDNA55 per protocol analysis population: median age 56 (35 - 77); median dose 177 mg (range 18 – 240 mg), 50% had KPS ≤ 80. No systemic toxicities observed, drug-related AEs were primarily neurological and characteristic of GBM, no deaths attributed to MDNA55. Median OS was 11.6 months (95% CI 7.9 – 15.2). When stratified by IL4R expression, mOS in IL4R High (n = 21) was 15 vs. 8.4 months in IL4R Low (n = 19); p = 0.2175. OS12 is 57% vs. 33%. When compared to the SCA (n = 81), MDNA55 subjects survived significantly longer: mOS 12.4 vs. 7.7 months; p = 0.0077. When comparing IL4R High groups, mOS in MDNA55 (n = 21) was 15.8 vs. 6.2 months in the SCA (n = 17); p = 0.0626. Subgroup analysis in unmethylated MGMT subjects also show better survival with MDNA55 (n = 23) than the SCA (n = 31); mOS 12.3 vs. 7.7 months (p = 0.0268), indicating that MDNA55 may be beneficial in patients resistant to temozolomide. Conclusions: MDNA55 subjects represent a difficult to treat population ( de novo GBM, IDH wild-type, not eligible for surgery at recurrence). Single treatment with MDNA55 prolongs survival by nearly 10 months in a subset of rGBM expressing high levels of IL4R when compared to a matched SCA, providing an unprecedented outcome for this highly lethal disease. Clinical trial information: NCT02858895 .

e17607 Background: Metastatic castration resistant prostate cancer (mCRPC) is a fatal disease. Nonmetastatic, castration-resistant prostate cancer (nmCRPC) often predates mCRPC. Recently, three androgen receptor (AR) antagonists i.e. apalutamide, enzalutamide, and darolutamide have been approved for nmCRPC. Nonetheless, any new therapeutic approach poses new safety concerns. We conducted a systematic review and meta-analysis of the published phase 3 randomized controlled trials (RCTs) to determine the safety and tolerance of AR-antagonists in nmCRPC patients. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until November 2019. Published phase 3 RCTs using AR-antagonists in the study arm for nmCRPC were included in the analyses. We used Mantel-Haenszel (MH) method and random effects model to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) comprising 2687 patients in the AR-antagonist arm and 1417 patients in the control arm were included in the final analysis. AR-antagonists used in the study arms were following— ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy (ADT). Randomization was 2:1 in all studies. No publication bias was appreciated all three studies. The pooled RR of any-grade adverse events (AEs) is 1.08 (95% CI: 1.02 – 1.14, p = 0.01, I2 = 79%) which was statistically significant. The pooled RR of grade ≥ 3 AEs was also significant at 1.32 (95% CI: 1.19 – 1.46, p < 0.00001, I2 = 0%). The pooled RR of grade 5 event is 2.67 (95% CI: 0.79 – 9.02, p = 0.11, I2 = 70%) which was not statistically significant. The pooled RR for discontinuation of treatment regimen was also statistically significant at 1.31 (95% CI: 1.00 – 1.72, p = 0.05, I2 = 35%). Conclusions: In nmCRPC patients, AR-antagonists in combination with ADT is associated with a mild increase risk of any-grade AEs, grade ≥3 AEs, and treatment discontinuation secondary AEs. However, AR-antagonists were not associated with a significantly increased risk of death due to AEs. Careful clinical vigilance and timely intervention with appropriate supportive care are critical to prevent AEs related morbidities and prevent treatment discontinuation.

4 Background: Penile Squamous Cell Carcinoma (PSCC) is a rare but often fatal disease. In this study, we characterize the poorly understood immune microenvironment using multiplex immunofluorescence (mIF) and image analysis approaches in 54 patients with PSCC. Methods: Representative blocks of 54 PSCC patients were stained for six immune markers: CD3, CD8, CD68, PD-1, PD-L1, Pancytokeratin and DAPI. Two experienced pathologists using an image analysis system (InForm 2.2.4) divided them into the tumor and stroma compartment and assessed the different densities of cell phenotypes using R studio with results expressed as cells/mm2. The statistical correlations were performed using Fisher’s exact test, Pearson and Log-rank test for Kaplan Meyer plots. Results: 54 patients with confirmed diagnosis of PSCC had a median age of 62 (IQR 50-70). All samples were from the primary penile tumor with the majority of cases being HPV(–) (62%). We observed significantly higher stromal cytotoxic T cells in HPV(+) cases compared to HPV(–) ( P=0.04). Using the mean macrophage count as cutoff for positivity, high densities of total tumor macrophages CD68+ were associated with significantly improved estimated median cancer specific survival (CSS) (NA, P=0.04), median overall survival (OS) (68mos vs NA P=0.02) and lower risk of regional recurrence ( P=0.04). On the other hand, the high densities of stromal cytotoxic T cells antigen-experienced (CD3+CD8+PD-1+), was associated with significantly worse median OS (27 vs 102mos P=0.05) and median disease free survival (DFS) (18.2mos vs NA P= 0.07). Also, high densities of stromal T cells antigen-experienced (CD3+PDL-1+), were associated with significantly better CSS (NA, P=0.06) and better median OS (142.1 vs 68.8mos P=0.14). Conclusions: Using novel multiplex image analysis to assess the immune microenvironment in primary PSCC, we showed that high macrophage levels were associated with lower risk of recurrence and improved survival outcomes. Moreover, a low level of exhausted stromal cytotoxic PD-1+ T cells was associated with improved PSCC survival. Further characterization of T cell subsets in relation to tumor HPV status is ongoing.

e20070 Background: Malignant Pleural Mesothelioma (MPM) is a rare but fatal disease related to asbestos exposure, with historic survival in the order of 9 to 17 months. Chemotherapy is associated with only a modest benefit. The advent of immunotherapy has heralded significantly improved outcomes using checkpoint inhibitors in an as yet ill-defined cohort. We aim to identify predictive and prognostic biomarkers in a series of patients (pts) with MPM and describe survival data. Methods: A retrospective audit was undertaken of pts with MPM diagnosed between 2013 and 2017 at a single tertiary centre in Melbourne, Australia (Monash Health). Data relating to patient outcomes and clinicopathological features were obtained through medical reports. Further immunostains are being performed on archived tissue for PDL-1 status. Results: 65 pts were identified, of whom 52 (80.0%) were male. Median age was 73 years (range 44-90). 52 pts were noted to be ECOG 0-1. 42 pts (64.6%) were noted to have suspected asbestos exposure. Epithelioid MPM was the most common subtype, noted in 41 pts (63.1%) (table 1). 8 pts (12.3%) presented with stage IV disease. 16 pts (24.6%) received checkpoint inhibitor therapy, with 10 (63 %) in the second/third line setting. Median overall survival (OS) was 19.8 months (95% CI 13.3-26.3) in the whole cohort.Patient characteristics associated with poor OS were: presence of weight loss (P = 0.001), chest pain (p = 0.08) and ECOG 2 (p = 0.04). Pts with sarcomatoid histology who received immune checkpoint inhibitors in any line of treatment had significantly prolonged OS compared to other histologies. 3-year survival was 80% in this group while median OS was not reached (p = 0.04). This difference was not seen with other histologies. Conclusions: The evolving landscape of treatment in MPM appears to show promise in improving OS. In this unselected case series, our data is consistent with historic controls in terms of survival and prognostic factors. The finding of significantly improved survival with immune checkpoint inhibitors in the sarcomatoid histology is exciting and warrants further exploration. Further data on PDL1 status will be presented.

e17072Background: Small cell prostatic carcinoma (SCPC) is a rare but often fatal disease. SCPC is commonly seen after treatment with androgen deprivation therapy, however, primary de novo SCPC can...

494 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal disease inherently resistant to cytotoxic treatment. Despite the prevalence of liver and peritoneal metastases, subsets of patients also develop lung and bone metastases highlighting phenotypic heterogeneity. We reviewed the prognostic implications of metastatic sites on survival. Methods: This retrospective cohort study included all patients with PDAC who received surgical or oncological treatment at the University Health Network from September 2012 until December 2016. Clinical and pathological variables were obtained from patient electronic records. Radiological images and pathology reports were reviewed to ascertain sites of metastatic disease. The Kaplan-Meier method for survival and multivariable cox regression analysis identified prognostic factors. Results: 1153 patients were reviewed and 985 were included. 55% were male and the median age at diagnosis was 67 years. 287 (29%) completed curative surgery and 698 (71%) had locally advanced or metastatic disease; the median survival was 22 months and 9 months respectively. Lung and bone metastases were present in 18% (N = 180) and 6% (N = 58) of patients. In multivariable analysis increasing age and stage at diagnosis correlated with inferior survival (p < 0.0001) and the presence of any lung (HR 0.77; 95% CI 0.63-0.94, p = 0.01) or bone metastases (HR 0.74; 95% CI 0.54-1.0, p = 0.05) resulted in improved outcomes. Liver and peritoneal disease were not prognostic. Sex and family history of PDAC did not associate with survival. There was no association between site of metastases and sex however patients with bone metastases were significantly younger at first diagnosis (median age 63yrs, p < 0.01). Conclusions: Patients with advanced PDAC and metastases to lung or bone may represent distinct biological subtypes of PDAC. Molecular profiling of available tissue is ongoing.

165 Background: Gastric cancer is a highly morbid and fatal disease. While the clinical challenge with gastric cancer is widely described, little is known about the economic burden of the disease. Many guidelines outline the curative treatment for gastric cancer and in a universal healthcare system, equal access and uniform healthcare delivery is predicted. Yet, regional variation in practice exists and may result in increased healthcare costs. We therefore aimed to investigate of the costs of treating curative gastric cancer, explore regional variation in costs, and to identify the factors which drive these costs. Methods: We conducted a patient-level cost analysis of curative-intent stage I-III gastric cancer diagnosed between 2005 and 2008 from the perspective of a universal healthcare system, using a 26-month time horizon. Clinical and stage data were abstracted from a provincial chart review. Costs associated with physician billings, same day surgery, hospitalization, drug benefits, emergency department visits, continuing care, and long-term care were derived using administrative healthcare databases and compared among healthcare regions. Costs were inflated to 2017 United States dollars (USD). We used a linear regression model to identify factors predictive of these treatment costs. Results: A total of 722 patients with Stage I-III gastric cancer were identified. Mean costs per region ranged from $55,650 to $92,852 (USD) across 14 health regions. The lowest contributing cost sector was long-term care and the highest contributing proportion of costs was from hospital admissions. A laparoscopic surgical approach was predictive of lower costs while age over 70 years and death at one year from diagnosis was predictive of higher costs. Conclusions: Regional variation exists in the treatment costs for patients with curative gastric cancer despite guidelines directing appropriate care and healthcare delivery in a universal healthcare system. Governmental intervention to ensure quality care delivery is necessary for improved and sustainable curative gastric cancer care across regions.

e18504 Background: Adult ALL is a rare but progressive frequently fatal disease. For those who survive and respond to initial therapy, many experience relapse. For relapse ALL (rALL), stem cell transplant (SCT) is potentially curative. This retrospective observational study investigates the cost of care and the impact of SCT on total cost for rALL. Methods: A representative sample of German claims data covering approximately 7 million of the German population was used to identify patients 18 years and older with a new diagnosis of ALL (ICD-10-GM code: C91.0*) between Jan 2011 and Dec 2015 who had a relapse after remission to initial treatment. Mean health care cost per patient per quarter were determined by whether or not SCT was received after relapse. Costs were from the perspective of German statutory health insurance and included prescription, outpatient and inpatient treatment costs. Results: Of the total 116 incident adult ALL patients identified, 29 (25%) were determined to have had a relapse, 11 underwent SCT after the relapse (38%). Patients with a SCT appear to incur higher cost than those without SCT in each of the quarters after relapse was diagnosed (Table), with the highest in the first quarter, but decreasing in subsequent quarters. Inpatient cost accounted for the majority of the cost for the first three quarters for both SCT and non-SCT patients (64% in Q2 to 86% in Q1). The number of patients in the SCT cohort remained relatively stable, while the non-SCT cohort had only half the patients left by the third quarter post relapse. Conclusions: Current results inform the magnitude of cost in Germany associated with adult patients with rALL with or without a SCT after relapse. It would be important to determine the magnitude of benefit such as long-term survival associated with SCT as well. The cost estimates provide a benchmark against which new treatment options for rALL can be compared. [Table: see text]

e15616 Background: Cholangiocarcinoma (CCA) is a progressively fatal disease with an annual incidence of 1-2 cases per 100,000 people in the USA. Complete surgical resection is the only curative option for CCA. However, the majority of patients (pts) have advanced disease at diagnosis, and those undergoing resection often develop local or distant recurrence. Gemcitabine and Cisplatin remains the only standard chemotherapeutic regimen for advanced CCA. Alternative and improved therapies are critically needed. Gemcitabine/nab-Paclitaxel (GA) is a regimen that has become standard therapy in advanced pancreatic cancer (PDAC). Given the morphologic and histologic similarities between PDAC and CCA, this regimen has been used in advanced CCA, but no data exists regarding its efficacy in this disease. The goal of our study is to evaluate the Mayo Clinic experience with GA for the treatment of metastatic CCA. Methods: We retrospectively analyzed records from adult pts at Mayo Clinic with metastatic cholangiocarcinoma who received at least 2 cycles of GA. Our aims were to assess the progression-free survival (PFS), overall survival (OS) and disease response. Results: We analyzed 9 pts, 3 male and 6 female. The median age at diagnosis was 50 years (range 41-64). Six pts had metastatic disease at diagnosis while 3 underwent surgery with subsequent distant disease recurrence. Pts received a median of 2 lines (range 0-5) of systemic therapy prior to receiving GA, and a median of 2 cycles (range 2-15) of GA. At the time of our analysis, 4 of the 9 pts (44%) had died. The median OS from initiation of GA was 7.3 months (95% CI 1.7- 12.9) and median PFS from initiation of GA was 4.7 months (95% CI 0.48-8.9). The best overall responses using RECIST criteria were: partial response in 1 (11%), stable disease in 5 (55%) and disease progression in 3 (33%) pts. One pt remained on therapy 14.9 months after initiating GA. Conclusions: In our study, the combination of gemcitabine and nab-paclitaxel has demonstrated similar OS and PFS as other systemic therapies. To the best of our knowledge, this is the first report of this regimen in CCA. Ongoing, prospective trials are currently evaluating this regimen in advanced CCA.

e14552 Background: Metastatic melanoma remains a fatal disease as many patients fail to respond to novel therapies. Presently, we have an ongoing trial utilizing T cell receptor (TCR)-modified cells reactive to the melanoma antigen, tyrosinase, for treatment of metastatic melanoma (NCT01586403). Current protocols using viral vectors to generate cells for adoptive transfer require activation in the presence of IL-2. While IL-2 stimulates proliferation and production of mature effector cells, it also induces T cell exhaustion. We hypothesize that tyrosinase-reactive TCR-modified cells generated in the absence of activation have an increased potential for expansion, persistence, and anti-melanoma activity. In these studies, we investigate whether IL-7, a homeostatic regulator, facilitates the transfer of a tyrosinase-reactive TCR to lymphocytes without activation. Methods: Gene-modified cells were generated using a lentiviral vector including alpha and beta chains of a TCR reactive to tyrosinase and a truncated CD34 molecule as a transduction marker. Peripheral lymphocytes from normal human donors were transduced with lentivirus following no treatment, treatment with IL-7, or activation in the presence of IL-2. Transduced CD34 positive cells were isolated using magnetic activated cell sorting (MACS) and injected intravenously into NOD scid gamma (NSG) mice. Results: We found that IL-7 treatment improved transduction in non-activated cells and resulted in expression levels of CD34 and TCR variable beta chain 12 (vbeta12) comparable to cells activated in the presence of IL-2. When non-activated tyrosinase-reactive TCR-modified human T cells were adoptively transferred into NOD NSG mice, the cells were detectable in the peripheral blood of mice up to 7 days after transfer. Conclusions: These findings suggest that generating melanoma antigen TCR-modified cells in the absence of activation for adoptive transfer is feasible with IL-7 treatment. Ongoing studies in NSG mice transplanted with melanoma will help determine whether non-activated gene-modified cells will improve the efficacy and longevity of cell therapy for melanoma and other malignancies.

338 Background: Metastatic bladder cancer (mBC) is a fatal disease and novel therapies are urgently needed. Preclinical evidence suggests role of AR in BC progression. Enzalutamide (ENZ) is a novel AR antagonist that inhibits nuclear translocation of AR, DNA binding, and co activator recruitment. Our ongoing phase 1 trial is is assessing safety and tolerability of ENZ in combination with gemcitabine and cisplatin (GC) in mBC and explore novel correlatives in tumor tissues and CTCs. Methods: The study has 2 phases, dose escalation phase and dose expansion phase. The dose escalation phase had 2 cohorts testing ENZ at doses of 80 mg and 160 mg respectively with GC (gemcitabine 10000 mg/m2 on days 1 and 8 and cisplatin 70 mg/m2 on day 1 every 21 days). The dose escalation phase allowed both AR + and AR - mBC pts. Patients will be monitored for safety and tolerance with laboratory studies, clinical exam, and CT scans to assess response. Primary objective is safety and tolerability of ENZ and GC. Secondary objectives are objective tumor response, time to progression, and overall survival. Exploratory objectives include qualitative and quantitative evaluation of AR and pAKT expression with AQUA in tumor tissues and correlation with outcomes. CTCs are being evaluated at baseline and cycle 3, including AR expression in CTCs and correlation will be done with tumor AR expression and clinical outcomes. Key eligibility criteria are ECOG PS of 0-1, and no contraindications to study drugs. Results: In the dose expamnsion phase, 3 patients were enrolled in each cohort of 80 mg and 160 mg of ENZ respectively with GC and there were no DLTs or significant AEs related to the combination; the MTD of ENZ is 160 mg. Enrollment on dose expansion phase is ongoing. detectable CTCs were seen in 4/6 BC patients with 2 patients showing AR + CTCs at baseline. Further CTC analysis, including AR expression and tissue analysis for AR and pAKT analysis in tissues is ongoing. (Trial identifier: NCT02300610). Conclusions: This is a first of its kind clinical trial exploring the role of AR signaling in BC and targeting it with ENZ along with GC. The data gathered form this study will help us understand the clinical relevance of targeting AR in BC. Clinical trial information: NCT02300610.

During the last 25 years we have witnessed the remarkable transformation of cancer from an immediately fatal disease to one in which the majority of individuals receive highly effective treatments that result in long-term, diseasefree survivorship. 1 One need only think about the remarkable public achievements of cyclist Lance Armstrong to understand that life after cancer can permit continued high levels of physical and psychological performance. Although Armstrong’s achievements after cancer may not reflect the norm, they do represent one end of the spectrum for the quality of life after cancer treatment. More often, however, cancer patients are left with subtle and sometimes more overt sequelae from their cancer treatments that follow

56 Background: GBM is a uniformly fatal disease with average survival of < 3 years and universal cognitive problems, making advance care planning paramount. End of life (EOL) patterns of GBM care in the US have not been studied. We examined care in a cohort of GBM and brain tumor (BT) patients as part of a program to provide individual provider feedback about EOL care. Methods: We reviewed the care of all GBM patients over 3 years with a random sample of 100, and a 5-yr subset of 45 who received their care at Gilchrist Hospice (GH), our largest provider. We queried EPIC EMR for markers of quality. We also reviewed all 452 advanced cancer pts of the Sidney Kimmel Comprehensive Cancer Center (SKCCC) referred to GH from 7/1/13 to 3/31/15 to find the median length of stay (LOS) and %LOS < 7 days for each division and each physician; 29 BT patients (most GBM) are included. Results: Few patients had documented Advance Directives or code status. Of the 100 pts, 37% were hospitalized in the last 4 weeks of life, and 17% received chemotherapy. Hospice referral and use was 76%. Of those in GH, 64% died at home with hospice and 20% died in inpatient hospice. Variability among physicians in hospice LOS was high (cv = 124.30%) ranging from 6 to 158 days with a median of 33.5 days, exceeding national averages, and 3 of 6 practitioners were below average LOS. Conclusions: In this snapshot of GBM EOL care in the US, improvements can be made in the use of advance care planning, code status, chemotherapy near death, and hospitalization rates. Hospice LOS is above national averages but varies by physician. [Table: see text]

e18033 Background: PML is a rare, fatal disease that results from reactivation of the JC virus during immunosuppressed states. Previously we reported that rituximab is associated with a 5-fold incr...

e18000 Background: HLH is a rare yet fatal disease, with multiple etiologies. Post-HSCT is poorly described. Role of Allogeneic (AlHSCT) vs Autologous (AuHSCT) in its development is yet to be exami...

e15587 Background: Renal Cell Carcinoma (RCC) accounts for 2% of all adult malignancies, its remains a very aggressive and often fatal disease, and is increasingly being recognized as a metabolic d...

e19540 Background: Progressive multifocal leukoencephalopathy (PML) is a rare, fatal disease that results from activation of a highly prevalent, dormant JC virus during immunosuppressed states. Rit...

9101 Background: Stage I melanoma has excellent prognosis, yet it remains a treacherous entity leading to fatal disease progression in a small and ill-defined population of patients. Role of complete lymphadenectomy in early melanoma is not determined. Methods: We used the Surveillance Epidemiology and End Results (SEER) database from 2004 to 2009 to identify patients who underwent wide local excision (WLE) with or without nodal surgery for management of AJCC Stage I primary cutaneous melanoma. Patients with complete data on age, race, sex, and primary tumor histology and anatomic site were categorized by type of surgical treatment into WLE, WLE+sentinel node biopsy (SNB), or WLE+complete lymphadenectomy (CLND) groups. Five-year disease-specific survival (DSS) was determined by treatment group and by sentinel node status. Specific risk factors were identified using multivariate analysis. Results: During the selected time period, 51,573 patients were diagnosed with AJCC Stage I cutaneous melanoma. Rate of SNB was 22%, and out of this group, 2% of patients had metastases to the regional lymph nodes. Five-year DSS was decreased in the node-positive group compared to the patients who had a negative SNB or WLE only (HR=4.95). Rate of CLND was 67%, and it did not improve survival of the patients with positive SNB (5-year DSS 83% vs. 79%, p=0.29). Performance of CLND did not correlate with age, histological type, presence of ulceration, or Breslow depth. Conclusions: SEER database suggests that a clinical equipoise regarding the utility of CLND in patients with positive SLN remains. These findings justify ongoing MSLT II.

8578 Background: Metastatic melanoma remains an almost certainly fatal disease. Current therapies fail to improve survival rates; therefore it is critical to identify alternate therapies for this d...

e15191 Background: CRPC remains a fatal disease but with improved survival based on the development of novel agents. These developments now allow for sequential therapies. We treated 20 patients in...

3537 Background: Colorectal cancer (CRC) diagnosed before age 30 is a rare and often fatal disease whose biology remains poorly understood. To better understand its pathogenesis, we compared tumor ...

e15022 Background: AMSCC of the penis is a rare but fatal disease. Combination chemotherapy is effective; but responses are brief in duration with few long term survivors. Targeted therapy directed...

We thank Drs Khakoo and Marghoob for their interest in our article. We would like to take the opportunity to respond to the comments brought forward by them. Khakoo and Marghoob criticized that our article might mislead readers to believe that neurocutaneous melanosis (NCM) is a generally fatal disease. This is certainly not our intention, and we are fully aware of the heterogenous nature of this disease. Our article—and this is indicated in the title—describes only a case report of a child with a symptomatic NCM and correlating Dandy-Walker malformation leading to death. Children with this rare defect do have a poor life expectancy, as already demonstrated by several other case reports. In our article, we differentiate between symptomatic and asymptomatic NCM and clearly cite that “asymptomatic cerebral melanosis is assumed to occur in as many as 25% of infants with giant nevi,” which is concordant with the figures contemplated by Khakoo and Marghoob. Khakoo and Marghoob also comment that small melanin deposits in the brain may be missed on magnetic resonance imaging scans. This can certainly occur; however, it is unclear whether these small deposits will become symptomatic and whether the detection of these small deposits is leading to any therapeutic consequences. Lastly, we absolutely agree that for the best management of patients with NCM, “a multidisciplinary team approach” is necessary. We therefore concluded our article, which was written by an interdisciplinary board of dermatologists, pediatricians, neurosurgeons, and neuropathologists, by saying that “interdisciplinary care of patients with symptomatic NCM by pediatricians, dermatologists, and neurosurgeons is essential.”

4500 Background: Hereditary diffuse gastric cancer (HDGC) is a potentially fatal disease that occurs due to mutations in the E- cadherin (CDH1) gene, as discovered in 1998. Its penetrance ranges between 70–80%. Its morbidity and mortality can be altered favorably through genetic counseling, germline mutation testing, and highly-targeted management that includes prophylactic total gastrectomy. Lobular breast cancer has been identified as an integral lesion in HDGC. Methods: This international collaborative group on HDGC is comprised of 56 mutation-positive families, which is the world’s largest resource of such families. Cancer diagnoses were verified with pathology slides/tissue block review when possible, or reports. Genetic counseling covering the pros and cons of mutation testing, screening and its limitations, and the option of prophylactic total gastrectomy was provided. Results: Findings on 56 HDGC mutation-positive families show carrier testing to have been performed on 267 individuals, of which 123 were CDH1 mutation positive. Prophylactic gastrectomies were performed on 14 families involving 50 individuals. Occult cancer was diagnosed in 31 (31/39=79.5%; results are pending on the remaining 11), based upon pathology and verbal reports. Five individuals underwent prophylactic gastrectomy prior to genetic counseling, 3 of whom later tested negative for mutations. In one of these remarkable HDGC families, 11 first cousins who tested positive for the CDH1 mutation underwent prophylactic total gastrectomy. On a post-surgery questionnaire, they each stated that the decision for the prophylactic procedure was the “right one” for them. In each case, a parent had died of HDGC sequelae, adding to the cousins’ acceptance of DNA testing and surgery. They considered their post-operative nutritional programs to have been acceptable. Conclusion: HDGC and its life-threatening sequelae were significantly ameliorated in CDH1 mutation carriers through total prophylactic gastrectomy in patients at enormous lifetime risk for HDGC. Decision for mutation testing and surgery may be more acceptable through intensive education in concert with a compassionate management team. No significant financial relationships to disclose.

13150 Background: AI CaP is an invariably fatal disease. While treatment with Doc, a microtubule-stabilizing taxane, improves survival, patient outcomes remain suboptimal. PS-341 inhibits degradation of cell cycle and tumor suppressor proteins resulting in cycle arrest and apoptosis. We hypothesized that the combination of Doc with PS-341 would abrogate the abnormal survival response seen in AI CaP and lead to improved tumor cell kill, but that results would be dependent on administration schedule due to interactive cell cycle kinetics. Methods: The PC3 cell line model of AI CaP was evaluated in vitro and in vivo to determine response to Doc or PS-341 alone, and in combination in sequences of PS-341→Doc, Doc→PS-341, and simultaneous (PS-341 + Doc). Cell cycle and protein analyses were performed by flow cytometry and Western blotting, respectively. For nu/nu mouse xenografts, 5 × 106 cells were injected subcutaneously into each flank. The agents were administered either together or 24hr apart, with all regimens given weekly [IP doses: Doc: 10 mg/kg; PS-341: 0.5 mg/kg]. Results: in vitro: Each combination showed an increased apoptotic sub-G1 population versus untreated cells, in addition to altered cell cycling in a sequence-specific manner. Of the combinations, PS-341 + Doc showed the largest sub-G1 while Doc→PS-341 had the lowest sub-G1 but the largest S-phase content; in vivo: PS-341 + Doc showed a cytotoxic effect (reduction in tumor volume) while the combinations of Doc→PS-341 and PS-341→Doc both showed growth inhibition (stabilization of tumor growth) as best response. Conclusions: Combinations of PS-341 and Doc have sequence specific cell cycle effects leading to increases in apoptosis (PS-341 + Doc) or cell cycle arrest (Doc→PS-341). Clinical validation of these findings is warranted. (ACS: CRTG-0019701-CCE) No significant financial relationships to disclose.