bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized phase II study of individualized stereotactic body radiation therapy (SBRT) versus transarterial chemoembolization (TACE) as a bridge to transplant in hepatocellular carcinoma (HCC).
Authors: Nugent Francis Warren , Gunturu Krishna , Stuart Keith E. , Flacke Sebastian , Molgaard Chris , Hunter Klaudia , Qamar Amir , Iqbal Shams , Gordon Frederick , Galuski Kari , Hartnett Erin
Published: September 2018

e15677

Background: For HCC pts undergoing LT, local treatment as a "bridge" is standard to decrease likelihood of tumor progression. The most common treatment is TACE, but the safest and most effective bridging modality is unclear. Recently, SBRT has been shown to be both safe and effective when used in pts with locally advanced HCC. We prospectively compare SBRT to TACE as a bridge for HCC pts undergoing LT. Methods: 60 pts are planned for accrual. Pts with C-P < 9 and HCC within Milan Criteria were randomized between two arms. TACE pts received 2 treatments one month apart using DEBDOX beads. TACE pts were hospitalized after each treatment. Pts randomized to SBRT, after fiducial placement, received a median total dose of 45 Gy delivered over 5 fractions. Mean liver dose, Veff, and NTCP were utilized to determine the prescription dose. Pts were assessed by imaging using mRECIST criteria at 2 months and every 3 months thereafter until LT or death. Toxicity and quality of life (QOL) were assessed before treatment, during treatment, 2 weeks post-treatment, and then every 3 months using the PIQ-6 Pain Impact Questionnaire and the SF-36v2 Health Survey. Primary endpoint was need for retreatment of the previously treated lesion(s). Secondary endpoints include toxicity, pathologic response, radiologic response, QOL, and cost. Results: From 9/2014-1/17, 33 pts within Milan Criteria with C-P Class A/B cirrhosis were randomized to TACE (n = 18) vs. SBRT (15). Data on evaluable pts is summarized in the table below. Conclusions: For HCC patients with C-P Class A/B liver cirrhosis, SBRT appears at least equally effective as TACE as a bridge to liver transplantation. SBRT may engender less toxicity, better maintain QOL, and eliminate the need for hospitalization. An update along with a full cost analysis will be presented in June. Clinical trial information: nct02182687. [Table: see text]
IL-8 as PD biomarker for TGF-b antisense (OT-101) therapy: Results of a phase II trial.
Authors: Trieu Vuong N. , Wang Wen , Qazi Sanjive , Ng Kevin , D'Cruz Osmond , Nam David , Hwang Larn
Published: September 2018

e15742

Background: Trabedersen (OT-101) is a phosphorothioate antisense specific for human TGF-β2 mRNA. In a Phase I/II study of OT-101 in patients with advanced pancreatic cancer (PAC) treated second line and beyond, improved Overall Survival (OS) was observed when OT-101 was followed with chemotherapy. Here, we examined the association between plasma levels of cyto-/chemokines and OS outcomes and identified IL-8 as a biomarker for improved OS. Methods: 37 patients with PAC were treated with OT-101 by IV infusion in escalating doses of 2 treatment schedules (7-days on, 7-days off and 4-days on, 10-days off). Plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of OT-101 therapy (140 mg/m2/day on a 4-days on, 10-days off cycle). IL-8 levels were measured in 12 patients before and during 3 cycles of treatment on Days 2 and 5. Maximum levels of IL-8 on Day 2 were subtracted from levels on Day 5 and these standardized scores were correlated with log10 transformed OS values. Feedback interactions with PK parameters were also investigated utilizing an ANCOVA model. Results: We observed OS of 14.5 months and 2.6 months for those treated with and without subsequent chemotherapies, respectively (p = 0.0009). Peak IL-8 levels were apparent after 2 days of OT-101 treatment. A significant regression and 95% CI was evident, whereby increasing difference of IL-8 following Day 2 vs Day 5 was positively correlated with OS (R2 = 0.58, F1,9 = 12.32, P = 0.0066). R- squared increased from 0.4955, p < 0.0001, for all patients to 0.8524, p < 0.0001, for patients without subsequent chemo and 0.9744, p < 0.0001, for patients with subsequent chemo. The ANCOVA model for two PK parameters exhibited significant model fits (F3,7 = 7.89, P = 0.012 for Simulated Vz Mean; F3,7 = 8.18, P = 0.011 for Simulated Cl Mean) and the interaction effects resulted in lower p-values for the correlation of OS vs IL-8 levels. Conclusions: Peak of IL-8 response on Day 2 of OT-101 treatment was correlated with OS in PAC patients. The correlation existed between OS whether patients received subsequent chemo or not suggesting that the IL-8 spike is a PD biomarker for OT-101. Clinical trial information: NCT00844064.
Comparison of guidelines, BRCAPRO, and genetic counsellors estimates for the identification of BRCA1 and BRCA2 mutations in pancreatic cancer.
Authors: Grant Robert C , Holter Spring , Borgida Ayelet , Pintile Melania , Akbari Mohammad R , Zogopoulos George , Gallinger Steven
Published: September 2018

e15784

Background: Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic adenocarcinoma (PDAC) are eligible for precision therapy trials and their relatives should undergo genetic testing and tailored cancer prevention. We assessed the performance of strategies to identify BRCA mutation carriers in PDAC. Methods: Incident cases of PDAC were prospectively recruited for BRCA sequencing in a multidisciplinary PDAC clinic. Probands were evaluated according to the National Comprehensive Cancer Network 2017 (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines for BRCA testing. The probability of each proband carrying a BRCA mutation was estimated using BRCAPRO and by surveying genetic counsellors. Guidelines were compared across sensitivity, specificity, and positive and negative predictive values (PPV and NPV). Estimates from BRCAPRO and the genetic counsellors were compared using the area-under-the-curve (AUC) for discrimination and the Hosmer-Lemeshow test for calibration. Results: 22/484 (4.5%) of probands carried a BRCA mutation. The mutation rate was higher in probands with Ashkenazi Jewish ancestry (7/57, p=0.009) or a first-degree relative with breast cancer (8/83, p=0.036). 119 genetic counsellors responded to the survey and each proband was assessed by a mean of 5.9 genetic counsellors. The Table displays the performance of the guidelines. Discrimination was similar for the estimates from genetic counsellors and BRCAPRO (AUC 0.755 and 0.775, respectively, p=0.701). Genetic counsellors generally overestimated (p=0.008), whereas BRCAPRO severely underestimated (p<0.001), the probability that each proband carried a mutation. Conclusions: The NCCN 2017 guidelines and estimates from genetic counsellors accurately identify BRCA mutations in PDAC. The MOHLTC guidelines and BRCAPRO should be updated to account for the association between PDAC and BRCA mutations. [Table: see text]
Phase II study of panitumumab in KRAS wild-type metastatic adenocarcinoma of the small bowel or ampulla of vater.
Authors: Gulhati Pat , Raghav Kanwal Pratap Singh , Shroff Rachna T. , Varadhachary Gauri R. , Javle Milind M. , Qiao Wei , Wang Huamin , Morris Jeffrey , Wolff Robert A. , Overman Michael J.
Published: September 2018

e15799

Background: Given the benefit noted with epidermal growth factor receptor (EGFR) antibodies in KRAS wild-type colorectal cancer, we conducted a phase II trial to evaluate the efficacy of panitumumab in metastatic small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC). Methods: This is a single-center open-label single arm two-stage phase II study. The primary objective was response rate (RR). Secondary objectives included overall progression-free survival (PFS), overall survival (OS) and toxicity. Eligibility included: KRAS exon 2 wild-type, ECOG PS 0-1, metastatic disease, adequate organ function and prior progression or intolerance to fluoropyrimidine with oxaliplatin. Panitumumab was administered at a dose of 6mg/kg IV every 14 days. Next generation sequencing panels were used for genomic analysis. Results: 9 patients [M/F 7/2, median age: 61 yrs (range: 40-74), ECOG PS 0/1: 2/7] were enrolled from September 2013 to October 2015. 1 pt had AAC (pancreaticobiliary subtype) and 8 pts had SBA (duodenal in 3, jejunal/ileal in 5). The most common toxicity was grade 1 acneiform rash in all patients. The most common grade 2/3 toxicities were anemia (33%), fatigue (22%), hypomagnesemia (22%) and skin infection (22%). None of the patients had a response, 2 patients had SD while the remaining 7 patients had PD. At a median follow-up time of 16.6 months, the median PFS and median OS were 2.4 months and 5.6 months, respectively. Extended RAS mutational testing identified 0/9 patients with mutations in extended KRAS or NRAS. Further genomic analysis of genes relevant to anti-EGFR activity (BRAF, PIK3CA and ERBB2) identified 2/9 patients with BRAF G469A mutation, 1/9 patients with PIK3CA H1047R mutation, and 0/9 patients with ERRB2 mutations. Conclusions: Although well tolerated, panitumumab had minimal clinical activity in patients with metastatic SBA and AAC. Given recent findings suggesting that right-sided colon cancers (hindgut derivation) benefit less from anti-EGFR therapy compared to left-sided colon cancers (midgut derivation), we propose that our findings may relate to the primarily foregut (proximal duodenum) and midgut (distal duodenum to ileum) derivation of the small bowel. Clinical trial information: NCT01202409.
Correlation of next generation sequencing (NGS) of urine with tumor and plasma in patients with non-muscle invasive bladder cancer (NMIBC).
Authors: Raymond Chris , Lahdya Alexandria , Hernandez Jenny , Garg Kavita , Henderson Samantha , Vakar-Lopez Funda , Li Mark , Montgomery Robert B. , Wright Jonathan Lawrence
Published: September 2018

e16002

Background: The current standard-of-care surveillance protocols for post-treatment NMIBC patients involve invasive procedures that result in poor patient compliance. Detection of recurrent NMIBC tumor DNA in plasma or urine would provide a less invasive alternative, and here we examine the feasibility of this approach by performing targeted NGS on tumor, plasma, and urine samples from NMIBC patients. Methods: 5 patients with untreated NMIBC (histology: Ta(n = 3), T1(n = 2)) have been analyzed to date. Urine and plasma samples were taken just prior to tumor resection. Samples were analyzed using a capture panel that includes common mutations found in > 80% of NMIBC patients. Coverage includes the promoter region of the TERT gene, the entire coding regions of KDM6A and FGFR3, and copy number variation in PD-L1 and JAK2. Results: Mutations were observed in all tumor samples, with the TERT -124C > T promoter mutation found in 4 patients (AF:16-84%) and the TERT -146C > T promoter mutation found in the other (AF:19%). Deleterious mutations were found in KDM6A for 4 patients, and FGFR3 activating mutations were found in 2 patients. Amplification of FGFR3 was seen in one sample. When the 4 matched pairs of urine and tumor samples were examined, all of the called mutations in tumor were also found in urine at similar allele frequencies. This includes the detection of gene copy alterations. No such mutations were observed in plasma samples despite extensive sequencing ( > 2000 unique read coverage). Conclusions: These data show that canonical NMIBC mutations are readily detectable in urine and correlate well with tumor, suggesting that NMIBC tumors shed prolifically into urine, and indicate that further investigation of NGS sequencing of urine as a means of detecting NMIBC recurrence is warranted.
Responses to chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline immunotherapy.
Authors: Szabados Bernadett , Van Der Heijden Michiel Simon , Gomez De Liano Lista Alfonso , Tang Yen Zhi , Powles Thomas
Published: September 2018

e16004

Background: The effect of prior immune checkpoint inhibition therapy (CI) on the efficacy of subsequent chemotherapy is largely unknown in MUC. The identification of the optimal sequence of chemotherapy and IO is yet to be determined, but may influence outcomes. Methods: A retrospective audit and comparison of patients who progressed after first and second line CI and received subsequent standard chemotherapy was performed. Date was collected across a broad spectrum of CI. We report on patient’s characteristics and response rates of 28 sequential patients collected from two institutions who received chemotherapy after CI. Patients were separated into 2 cohorts. Cohort A had not previously received chemotherapy (n = 14), cohort B had previously received at least 1 chemotherapy regimen (n = 14). Central radiology review was performed. We assessed objective response rate by RECIST v 1.1. Kaplan Meier method was used. Results: Median age for the whole cohort was 64 yrs (45-80). ECOG was 0/1 in 89,3% and 2 in 10,7% at the time of starting chemotherapy. The commonest chemotherapy regimen in cohort A and B were carboplatin-gemcitabine (71%) and carboplatin paclitaxel (50%) respectively. 75% of the patients were intermediate risk group. In Cohort A 63% responded to chemotherapy whereas in cohort B only 3 patients showed response. The median change in target lesions in the front line immunotherapy cohort was -60% (-81 to +1%). Both patients who responded to 2nd line chemotherapy after CI had a long interval between first and 2nd line chemotherapy (9-24 months). Conclusions: Chemotherapy maintains its efficacy after front line CI with deep responses. Although numbers are modest, results strongly suggest patients should be offered chemotherapy in this setting.
Title: A real-world study of chemotherapy treatment and costs in metastatic urothelial cancer (mUC) patients in the United States.
Authors: Malangone-Monaco Elisabetta , Wilson Kathleen , Varker Helen , Stetsovsky Diana , Shih-Wen Lin , Tayama Darren , Ogale Sarika
Published: September 2018

e16009

Background: Cisplatin (CIS)-based regimens are recommended for first-line (1L) treatment of mUC. Carboplatin (CAR) serves as an alternative for patients unfit to receive CIS. This study examined treatment patterns and costs for patients treated with CIS, CAR, and other treatment (OT). Methods: This was a retrospective cohort study of 9,436 patients from a U.S. insurance claims database between 1/1/2005-6/30/2015. Adult patients with ≥ 2 diagnosis codes for UC, ≥ 2 diagnosis codes for metastasis (first metastasis = index date), ≥ 6 months of continuous enrollment pre-index and no evidence of cystectomy were included. Results: The population was majority male (74%); with a mean age of 70. Sixty percent of the mUC patients did not receive 1L chemotherapy during the study period. Among the 3,750 who received treatment, 935 (25%) received 1L CIS, 1,505 (40%) received 1L CAR, and the remaining patients received OT. Patients treated with CIS were younger (62 vs. 69 and 68) and healthier (NCI comorbidity score 0.7 vs. 1.1, and 1.0) vs. patients treated with CAR and OT, respectively. Among CAR patients, 87% received it as combination therapy (CT), with GEM being the most common agent used with CAR. Only 16% of OT patients received CT. Per-patient-per-month (PPPM) 1L all-cause healthcare costs were similar across 1L regimens ($16,540 CIS, $15,739 CAR, and $16,443 OT) and 1L mUC-related healthcare costs were $9,043, $6,975 and $6,191 for CIS, CAR, and OT, respectively. Conclusions: In this real-world study, the majority of mUC patients did not receive 1L chemotherapy, and only a small fraction of those treated received CIS. The remaining patients were treated with CAR or OT, often as monotherapy, which tend to have poorer outcomes compared with CIS. Despite CAR and OT treated patients being younger and healthier, their total health care costs were similar to CIS patients. Newer therapies may provide safer and more efficacious treatment alternatives for patients who are not considered a good fit for CIS therapy.
Identification of a prognostic molecular signature composed of 3 genes involved in immunity in muscle-invasive bladder cancer.
Authors: LE Goux Constance , Damotte Diane , Vacher Sophie , Barry Delongchamps Nicolas , Sibony Mathilde , Terris Benoit , Zerbib Marc , Bieche Ivan , Pignot Geraldine
Published: September 2018

e16029

Background: Immunotherapy in bladder cancer appears to be promising. The aim of this study was to evaluate the involvement of 33 genes of anti-tumor immunity in a wide range of muscle-invasive bladder cancers (MIBC) and to identify new prognostic markers. Methods: The levels of expression of 33 genes involved in anti-tumor immunity were analyzed by real-time quantitative RT-PCR on a consecutive series of 83 TVIM and 15 normal bladder samples. Tissue samples were taken on a cystectomy patch in patients operated between 2002 and 2006. All patients have signed informed consent. The results of the transcriptomic analysis were confirmed by immunohistochemistry and coupled with survival analysis. Results: Of the 33 genes studied, 24 (72.7%) were significantly overexpressed compared to normal bladder tissue. In univariate analysis, overexpression of OX40L was significantly associated with a pejorative prognosis in terms of recurrence-free survival and overall survival (p = 0.0027 and p = 0.014 respectively) while overexpression of CD8 was associated with a better prognosis (p = 0.024 and p = 0.029 respectively). A clustering analysis allowed us to identify a molecular signature composed of 3 genes ( OX40L, CD8 and TIGIT) allowing to separate the tumors into 3 distinct prognostic subgroups. In a multivariate analysis including all clinico-pathological and molecular factors significant in univariate, molecular signature was an independent prognostic factor in terms of recurrence-free survival and overall survival (p = 0.0007 and p = 0.007 respectively). Conclusions: We identified several genes involved in the immune response during bladder urothelial carcinogenesis, as well as a molecular signature composed of 3 genes ( OX40L, CD8 and TIGIT) associated with MIBC prognosis, suggesting a potential interest in Individual step.
Growing teratoma syndrome: Is it a subtype of germ-cell tumors or another entity?
Authors: Dogan Mutlu , Bal Oznur , Olcucuoglu Erkan , Algin Efnan , Zengin Nurullah
Published: September 2018

e16040

Background: Growing teratoma syndrome(GTS ) is a process presenting with growing masses despite normal tumor marker levels(TML) after chemotherapy in non-seminomatous germ cell tumors (NSGCT). Methods: GTS patients between 2000-2016 were evaluated for clinicopathological features and survival outcomes retrospectively. Results: 17 (6,4%) of 266 NSGCT had GTS. Median follow-up was 57.7 ( 13.8-132.7) months. Median age 27 (17-51) years . Most (n = 14) of them had mixed germ-cell tumors & 12 had mature/immature teratoma in primary pathology at diagnosis. Most (n = 11) of them had stage 3 disease & 10 had high TML (S1-3). 11 GTS patients had good risk NSGCT. All (n = 17) had 4 BEP(bleomycin, etoposide, cisplatin) cycles. Recurrence occured in retroperitoneum (n = 13), lung (n = 3) & brain (n = 1). They were considered as GTS since they had normal TML despite growing masses. 5 patients were referred to surgery without salvage chemotherapy and they had teratoma on postoperative surgery. 13 had surgery after salvage chemotherapy (TIP: taxane, ifosfamide, platin) but 4 had unresectable disease and they had clinical benefit with interferone α2b. Two operated patients had diffuse necrosis on pathology whereas others had documented teratoma. Median DFS was 12.3 ( 5.7-18.8) months whereas median OS was 64.8 (15.5-158) months. 3 patients had no recurrence after surgery for GTS. 9 had salvage chemotherapy (gemcitabine/oxaliplatin, TIP) for NSGCT metastatic lesions with TML elevation and 2 of them had autolog stem cell transplantation. Conclusions: GTS is rare in NSGCT, but it should be considered in NSGCT patients with both growing masses & normal TML after primary treatment approach. GTS patients surgery with resectable masses should be referred to surgery since teratoma without viable tumor seems to have less benefit from chemotherapy and/or radiotherapy. Interferon α2b might be an option in unresectable GTS.
PSA-recurrence after radical prostatectomy for intermediate/high risk prostate cancer: A helpful parameter or just a patient stress amplifier.
Authors: Spahn Martin , Kruithof-de Julio Marianna , Boxler Silvan , Furrer Marc-Alain , Thalmann George N. , Studer Urs E.
Published: September 2018

e16535

Background: Development of biochemical recurrence with a rising PSA level after radical prostatectomy causes significant anxiety for patients and treating oncologist. Management of these patients is controversial. Here, we characterize the natural course and pattern of disease progression and survival in men with biochemical recurrence (BCR) after radical prostatectomy (RP) for intermediate and high-risk prostate cancer (PCa) untreated until clinical failure (CF). Methods: Retrospective analysis of consecutive men with BCR after RP for intermediate/high risk PCa. All patients underwent RP+extended pelvic lymph node dissection. A PSA level > 0.2 ng/ml on two consecutive measures was considered BCR. None received neoadjuvant or adjuvant therapy prior to documented clinical failure by body imaging, which was performed at the time point of BCR or symptoms and at least once per year. Results: Of the 622 men with BCR included into the analysis, 267 (43%) had high risk PCa. Median follow-up after RP was 9.4 yrs. (IQR 4.8-15.1) and median time from RP to BCR was 1.4 yrs. (IQR 0.4-3.6). Of the patients 324 (52%) never experienced CF (Æfollow-up from BCR 5.8yr, IQR2.1-11.9); 88 (14%) had local recurrence only; 59 (9%) had lymph node metastasis +/-local recurrence and 151(24%) distant metastasis. The median times from BCR to CF were: 9.5 yrs. (IQR 5.6-13.5) for local failure; 4.9 yrs. (IQR 3.1-8.8) for lymph node failure and 5.6 yrs. (IQR 3-10.5) for distant failure. The 10-yrs cancer specific (CSS) and overall survival (OS) of the entire group from time point of BCR was 78% and 66%, respectively. 5- and 7-yrs conditional CSS from time of CF was strongly depended on recurrence pattern and ranged from 90% and 79% (local only) to 70% and 47% (lymph node+/-local) and 47% and 36% (distant mets), respectively. PSA-doubling time < 12 months and > 2 positive nodes were independent predictors of outcome in multivariate analysis. Conclusions: These data may be useful in informing men with intermediate/high risk PCa regarding the natural course of PSA recurrence and counseling the timing of additional therapies.
Relative bioavailability (BA) and bioequivalence (BE) study of abiraterone acetate (AA) fine particle (AAFP) with methylprednisolone (MP) and a reference formulation with prednisone (PN) in healthy male subjects.
Authors: Hussaini Azra , Olszanski Anthony J. , Stein Cy Aaron , Bosch Bill , Nemeth Paul
Published: September 2018

e16538

Background: AA is approved for treatment of metastatic castration-resistant prostate cancer when taken in combination with PN. The originator AA (OAA) formulation is poorly absorbed and exhibits large pharmacokinetic (PK) variability. AAFP is a proprietary formulation (utilizing SoluMatrix Fine-Particle Technology™) that was designed to provide improved BA. In a prior study in healthy subjects, AAFP 500 mg was established as bioequivalent to OAA 1000 mg when given in the fasted state. In this study, AAFP was evaluated in subjects in a fasted state with steady state (SS) MP, an alternative steroid to PN. Methods: Subjects aged 18–50 years were randomized in a crossover design to receive MP (4 mg BID) or PN (5 mg BID) for 12 days in Period 1. On Day 11 of Period 1, subjects given MP received a single dose of AAFP 500 mg (test) and subjects given PN received a single dose of OAA 1000 mg (reference). After a 2-week steroid washout period, subjects received the alternate treatments in Period 2. Results: There were no statistical differences with regard to abiraterone AUC ( P≥0.38) and Cmax ( P= 0.22) between AAFP 500 mg and OAA 1000 mg (Table). Geometric mean ratio (GMR), a measure of BE, was 95.9% (90% CI: 86.0–106.9%) for AUC0-∞, 99.2% (90% CI: 88.7–110.9%) for AUC0-t, and 116.8% (90% CI: 102.2–133.4%) for Cmax. GMR of AUC0-∞ and AUC0-t, fell within the 80–125% range for BE, and Cmax 90% CI was just outside the upper limit. The coefficient of variance (CV) for both AUC and Cmaxwas smaller for AAFP compared with OAA. Both treatments were safe and well tolerated. Conclusions: AAFP 500 mg with MP gave comparable exposure to OAA 1000 mg with PN with respect to Cmaxand AUC. Less drug exposure variability was observed with AAFP compared with OAA. Reduced PK variability could improve clinical outcomes and warrants further study. [Table: see text]
SM88/SMK non-hormonal therapy in recurrent or untreated prostate cancer.
Authors: Hoffman Steve , Rothman John , Del Priore Giuseppe , Stega Jeanetta
Published: September 2018

e16540

Background: Prostate cancer (PC) has a poor prognosis. Androgen deprivation therapy is effective but has unacceptable short and long term side effects. SM88 (modulators of mTOR, mitochondrial stress, CYP3a4 and tyrosine isomers) is a novel combination of anti-cancer therapies with previously reported favorable results yet low toxicity in a heterogeneous group of 30 patients with cancer. We now report on a PC cohort treated with SM88. Methods: Retrospective chart review. Results: Between 2012 and 2014, 6 men with PC were treated with SM88, administered 5 days/week over a 6-week treatment cycle. SM88 consisted of daily oral and subcutaneous injection of the components. The average age was 54 years (range 32-66). Five (83.3%) were Caucasian, 1 (16.7%) was Hispanic. patients with prostate cancer were treated with SM88 daily, Monday-Friday, for between 6 to 31 wks (median 11). Four patients had castrate resistant disease, two declined ADT. One had failed prior chemotherapy (see Table). All subjects were not receiving other therapy. One subject died of disease complications approximately 3 months after starting treatment but only received approximately 20 days of therapy over a 6 week cycle. Three patients had PSA nadir responses of >90% reduction over pretreatment peak levels (see table). Two others had radiographic SD for between 10-14 wks. There were no significant toxicity except cutaneous hyperpigmentation. The duration of responses ranged from 10-114 weeks. Best overall responses included 2 patients with complete biochemical response. Four subjects improved their ECOG score during treatment and 2 had no change. Conclusions: SM-88 appears to be well tolerated and to have anti-tumor activity in prostate cancer without androgen deprivation toxicity. Additional confirmatory prospective studies in prostate are ongoing and planned in other cancers. [Table: see text]
Evaluation of immunological efficacy of Japanese herbal medicine, hochu-ekki-to and keishi-bukuryo-gan, in patients with castration-resistant prostate cancer under personalized peptide vaccination.
Authors: Koga Noriko , Moriya Fukuko , Waki Kayoko , Yamada Akira , Itoh Kyogo , Noguchi Masanori
Published: September 2018

e16584

Background: This randomized phase II study investigated the immunological efficacy of herbal medicines (HMs) using Hochu-ekki-to and Keishi-bukuryo-gan, in combination with personalized peptide vaccination (PPV) for castration-resistant prostate cancer (CRPC). Methods: Seventy patients with CRPC were randomly assigned (1:1) to receive PPV plus HMs, or PPV alone. PPV treatment used a maximum of four peptides chosen from 31 peptides derived from cancer antigens according to human leukocyte antigen types and antigen-specific humoral immune responses before PPV, for 8 subcutaneous weekly injections. Peptide-specific cytotoxic T lymphocyte (CTL), immunoglobulin G (IgG), regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (Mo-MDSC) and interleukin-6 (IL-6) responses were measured before and 8th vaccination. Clinical outcomes were also analyzed. Results: The combination therapy of PPV with HMs was well tolerated without severe adverse events but had no significant impact on antigen-specific IgG and CTL, Treg and clinical outcomes. The combination therapy of PPV with HMs stabilized the frequency of M0-MDSCs (1.91% to 1.92%, p = 0.96) and serum levels of IL-6 (19.2 pg/ml to 16.1 pg/ml, p = 0.63). On the other hand, the frequency of Mo-MDSC and levels of IL-6 in the PPV alone were significantly increased (0.91% to 1.49% for Mo-MDSC and 9.2 pg/ml to 19.4 pg/ml for IL-6, respectively). Conclusions: These results suggested that the combination usage of HMs reveals a potential to prevent the immunosuppression induced by Mo-MDSC or IL-6 during the immunotherapy. More research is needed to validate the findings of the present study. Clinical trial information: 000010290.
Vulvar cancer in Germany: Increase of incidence and change of tumor-biological characteristics in the period 1974-2013.
Authors: Barinoff Jana , Sehouli Jalid , Holleczek Bernd
Published: September 2018

e17031

Background: Incidence of vulvar cancer in Germany is increasing. Gynecological oncologists reported to observe increasing numbers of women presenting with small tumors. The aim of the presented study is to validate this observation on a population level and to extend available incidence data. Methods: Data from the population-based Saarland Cancer Registry (CR) were used and included 1,136 female patients diagnosed with invasive vulvar cancer (ICD-10 code: C51) between 1974 and 2013. Multiple imputation methodology was used to overcome loss of precision and potential bias. Incidence trends were investigated with regard to patient and tumor characteristics. Results: During the study period, the age standardized rate of incidence increased from 1.6 to 7.9 cases per 100,000 women per year (+390%). Since 1989, the incidence of squamous cell carcinoma increased from 1.7 to 7.1 (+320%), whereas no increase was observed in other morphologic types. Simultaneously, the incidence of small vulvar tumors <= 2 cm (T1) increased from 0.8 in 1989-93 to 6.6 in 2009-13 (the proportion of T1 tumors increased from 34% to 79%, respectively). Patients aged >= 75 years suffered from more advanced disease at the time of diagnosis. Conclusions: The detailed analyses revealed that the observed increase in vulvar cancer in the past 15 years mainly resulted from newly incident squamous cell carcinomas. Furthermore, the analyses showed an almost exclusive increase of T1 tumors. An increase in vulvar cancer incidence as shown for Germany could not be observed for any other European country.
When advanced ovarian cancer is not ovarian cancer.
Authors: Dood Robert , Fleming Nicole D. , Coleman Robert L. , Westin Shannon Neville , Sood Anil
Published: September 2018

e17066

Background:Tissue diagnosis of advanced ovarian cancer (OC) is not universally obtained prior to up-front surgery. This study sought to investigate non-OC cases discovered in the systemic laparoscopic (LSC) workup of presumed advanced OC. Methods: A prospective cohort of presumed advanced OC patients (based on elevated CA125 and/or imaging) presenting to our center without confirmed pathologic diagnosis. Patients with non-OC pathology confirmed in workup were characterized and compared to those with confirmed ovarian pathology using standard statistical tests. Results: 365 patients presented between 5/30/12 and 11/16/16. Non-OC was found in 27 cases (7.4%), including benign ovarian pathology (48%), and metastatic uterine (11%), breast (7%) and gastrointestinal (19%) cancers. A majority used diagnostic LSC or assessment at time of up-front surgery (see Table) for diagnosis. Non-OC cases were less likely to be confirmed by FNA or core biopsy, were more common in Asian patients, had better ECOG scores, and had a lower CA125. Only 1 non-OC patient (uterine sarcoma) received neo-adjuvant chemotherapy. Conclusions: A systematic LSC approach to advanced stage OC minimizes incorrect chemotherapy chemotherapy administration. Asian patients and those with low CA125 values are at highest risk of a false diagnosis of OC, but did not routinely have a diagnostic opportunity prior to systematic LSC. [Table: see text]
Characterization of differential genetic expression profiles in mesenchymal and epithelial components of uterine and ovarian carcinosarcomas.
Authors: Hernandez Blanquisett Abraham , Lopez-Reig Raquel , Romero Ignacio , Lopez-Guerrero Jose Antonio , Machado Isidro , Ballester Carmen Illueca , Ore Martin , Poveda Andres
Published: September 2018

e17104

Background: Gynecologic carcinosarcomas (GCS) are rare tumors with poor prognosis. Reasons include a high percentage of advanced stage at diagnosis and a low response to conventional treatments. GCS constitutes a model for research in both tumoral heterogeneity and the epithelial-mesenchymal transition (EMT) process. Our aim is to define molecular expression heterogeneity in GCS distinct morphologic components. Methods: A retrospective, single institution, IRB approved study of 13 patients diagnosed with GCS was undertaken. Total RNA was extracted from representative FFPE tissue blocks of both the epithelial and mesenchymal components. The expression profile for each component (n = 26) was determined using the GeneChip WT Pico Reagent Kit and the Clariom D Array (Affymetrix Inc., Santa Clara, CA, USA). Robust multi-array normalization (RMA) and t-statistics was used for detecting differentially expressed genes between the studied conditions. Genes with a p-value < 0.05 and with an absolute fold change (FC) value > 1.5 were selected as significant. Results: A total of 13 cases representing 26 distinct samples, 9 uterine (UCS) and 4 ovarian carcinosarcoma with a median age of 68 (range: 45-81), 38% presented FIGO IIIC-IV stage at diagnosis. Among UCS, 5 women had a previous personal history of breast cancer. A total of 101 genes appeared as differentially expressed between epithelial and mesenchymal components, highlighting 5 of them: HMGA2 (FC = 2.15, p = 0.04) and ERBB4 (FC = 2.14, p = 0.005) overexpressed in epithelial component and ANX2 (FC = 1.95, p = 0.0006), SPP1 (FC = 2.15, p = 0,005) and ERRFI1 (FC = 1.95, p = 0.001) overexpressed in mesenchymal component. Conclusions: This is the first expression profiling in GCS that helps identify candidate genes that show a distinct expression in mesenchymal and epithelial components that could have a potential prognostic and predictive role.
Inhibition of CK2 by CX4945 to induce autophagy-mediated cell death through dephosphorylating acetyl-CoA carboxylase in squamous cell carcinoma of head and neck cancer.
Authors: Su Ying-Wen , Cheng Jun-Jia , Huang Wen-Yu , Chang Yi-Fang
Published: September 2018

e17503

Background: Accumulating evidence has shown that overexpression of casein kinase 2 (CK2) in patients with squamous cell carcinoma of head and neck (SCCHN) correlates with worsened survival. Strong expression of phosphorylated acetyl CoA carboxylase (pACC) was found to be an independent prognostic marker for patients with node-positive SCCHN. Computational analysis showed that ACC was a potential substrate for CK2, and CK2 inhibition can suppress ACC phosphorylation in non-cancer cells. CX-4945, also known as silmitasertib, is an orally administered, highly specific, ATP-competitive inhibitor of CK2 and is under clinical investigation for treating malignancies. Methods: We investigated the anticancer activity of CX-4945 in 3 aggressive SCCHN cell lines. Autophagy induction and interference with cellular metabolism were characterized. Results: CX-4945 induced autophagic cell death in SCCHN cells. CX-4945 treatment caused time- and dose-dependent lipid droplet accumulation, inhibition of ACC phosphorylation, depressed cellular levels of acetyl Co-A, and severely suppressed mitochondrial respiration, without altering the expression of stress-related proteins in the endoplasmic reticulum. Conclusions: The findings demonstrated that inhibition of CK2 by CX-4945 contributed to deranged cellular energy metabolism in SCCHN cells, leading to autophagy-mediated programmed cell death. CX-4945 targeting to CK2 may be a promising therapeutic strategy against SCCHN cancer.
Patterns of HPV testing and treatment decision in patients with SCCHN.
Authors: Zanotti Giovanni , Martini Jean-Francois , Uehara Roberto , Hallworth Pamela , Byrne Katherine
Published: September 2018

e17526

Background: Human papillomavirus (HPV) is one of the main risk factors associated with squamous cell carcinoma of the head and neck (SCCHN). Although it is a prognostic factor, SCCHN patients are not routinely tested for HPV status because it may not be informative for therapy initiation. The objective of this study was to understand the real world testing patterns, and treatment decision of SCCHN patients. Methods: Real world data was gathered using Adelphi’s Disease-Specific Programme (DSP) - a real world, cross-sectional survey conducted in the USA, France, Germany and the UK (April - September 2016). The DSP incorporated 182 physician interviews (54 US, 128 EU) covering all stages of SCCHN caseloads and treatment patterns. Physicians also provided data for 8 consecutive consulting SCCHN patients regarding treatment patterns, progression, and symptoms. Results: A total of 2193 SCCHN patient cases were captured. HPV testing was carried out in 42% of patients within the DSP data set with no particular difference across the 4 countries. Of those tested, 35% of patients were HPV positive. Testing was mainly performed at the local level (51%, onsite or local hospital) apart from Germany where central testing was higher (73%). In over half of patients cases (54%) , physicians are unaware of the type of test performed for the HPV status determination; in fact, up to 10 different types of tests were used to determine the HPV status in this real world experience. Platinum based cetuximab and fluorouracil was used in 30% of the HPV positive patients while 20% received platinum monotherapy. In 2nd line, docetaxel/paclitaxel monotherapy was used in 22% of the patients. HPV negative patients also mainly received platinum based cetuximab and fluorouracil (27%) in 1st line, while in 2ndline, docetaxel/paclitaxel monotherapy was used in 20% of the patients. Conclusions: This analysis of real world treatment patterns and outcomes among SCCHN patients shows that HPV testing is not widely carried out for either patient characterization or to guide treatment decisions within this disease. Therapy choices were generally consistent standard clinical guidelines.
Landscape of genetic alterations in oropharyngeal squamous cell carcinoma (OPSCC) based on RNA-seq and WES analysis of FFPE samples and correlation with data from TCGA.
Authors: Seby Sandra , Rossi Michael R. , Magliocca Kelly R. , Patel Mihir , Griffith Christopher C , Steuer Conor Ernst , Wang Xu , El-Deiry Mark , Shin Dong Moon , Kowalski Jeanne , Chen Zhuo Georgia , Saba Nabil F.
Published: September 2018

e17527

Background: Whole human exome sequencing (WES) has identified well characterized somatic mutations (such as TP53, CDKN2A, PIK3CA and HRAS) in patients with squamous cell carcinoma of the head and neck (SCCHN). We sought to optimize a combined RNA-seq and WES approach for identifying actionable mutations and gene expression signatures in p16 + versus - OPSCC. Methods: Relying on formalin fixed and paraffin embedded (FFPE) samples we applied a minimal mutation and copy number content (151 genes) on DNA and an extensive RNA panel on a total of 27 OPSCC (22 p16 +, and 5 p16 -). SAMSeq was used to identify the differentially expressed genes. Unsupervised hierarchical clustering of the TCGA OPSCC samples with available p16 status (n = 31) was performed for external validation of the results. Statistical significance was further tested by Fisher’s exact test. Results: We identified a gene signature differentially expressed in p16+ and p16- OPSCC. External validation showed a significant association between gene expression and p16 status (P = 0.00033). We did not however find an association with mutation burden and smoking history. A number of pathways associated with this gene signature such as NCAM1 may have relevant biologic implications in OPSCC. Conclusions: Our results underscore the reliability of integrating data from FFPE samples in distinguishing gene signatures characteristic of p16 + versus p16- OPSCC; these signatures need to be further explored for their biologic relevance in OPSCC (This research was supported by a grant NCI R21 CA182661-01A1to NFS and GZC).
Treatment response and prognosis according to pre and post treatment Ebstein-Barr virus DNA level in nasopharyngeal carcinoma patients.
Authors: Ahmedova Aysel , Ozkaya Kubra , Tambas Makbule , Gezer Ugur , Ozgur Emre , Sahin Dilek , Sanli Yasemin , Altun Musa
Published: September 2018

e17544

Background: To evaluate pre and post-treatment Epstein-Barr virus (EBV) DNA copy numbers, to investigate changes with treatment and the possibility of using it as a follow-up marker in nasopharyngeal carcinoma (NPC) patients. Methods: Blood samples were obtained before (0-3 weeks) and after treatment (mean 6 weeks) and number of EBV DNA copies were determined by PCR . Treatment was administered as concomittant chemoradiotherapy ± induction chemotherapy. MRI and PET-CT were performed prior (0-4 weeks) and after (6-16 weeks) treatment. Mann Whitney test was used for 2 group comparisons of parameters with no normal distribution and comparison of quantitative data. Fisher-Freeman-Halton and Wilcoxon Signed Ranks tests were used for comparison of qualitative data and intra-group comparison of parameters with non-normal distribution. Kaplan Meier Survival analysis was used to assess survival. Results: The study included 50 NPC patients treated between 2011 and 2015. Median follow-up is 25.3 (27.5 ± 14) months. 12 patients had residual-recurrent or metastatic (3 patients initially had distant metastasis) disease. Mean survival is 49.77 ± 2.4 months. Median posttreatment EBV DNA level is lower than pretreatment EBV DNA level (p = 0.001). Pretreatment EBV DNA copy numbers are higher in patients with residual-recurrent or metastatic disease (RRM) than those without RRM (p=0.05). Mortal patients had higher pre (p = 0.015) and post (p = 0.043) treatment EBV DNA levels than those who survived. Overall survival (OS) is higher in patients with undetectable (n:41) than those with detectable (n:9) EBV DNA levels after treatment (p = 0.02). Conclusions: The OS is lower in patients with higher pretreatment and detectable posttreatment EBV DNA levels. This study implies that pre and post treatment serum EBV DNA levels can be used as prognostic indicators and also be beneficial as a follow up marker in NPC patients. [Table: see text]
Acute kidney injury in head and neck cancer patients treated with chemoradiation with cisplatin: A single-center cohort study.
Authors: Meerten Esther Van , Owusuaa Catherine , Hoorn Ewout , De Hoop Esther Oomen
Published: September 2018

e17559

Background: Patients with advanced head and neck cancer (HNC) are commonly treated with chemoradiation with concomitant cisplatin. Acute kidney injury (AKI) is considered a dose-limiting toxicity of cisplatin. We aim to describe the incidence and risk factors of AKI. Methods: In our tertiary center, we retrospectively identified 261 patients with advanced HNC and adequate renal function who were treated curatively from 2008 to 2015 using radiotherapy and concurrent three-weekly cisplatin. Outcome was the first AKI episode, defined according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines as a ≥50% rise in serum creatinine compared to baseline. Several potential predictors were investigated by means of logistic regression analyses. Results: In our cohort (mean age 58 ± 8 years, 74.3% male), a total of 102 (39.1%) patients developed AKI. Factors significantly associated with AKI in the univariate analysis were: age, alcohol consumption, excessive smoking, diabetes, hypertension, diuretic use, renin-angiotensin-aldosterone-system blockers, and administration of furosemide when indicated during first cisplatin cycle. In the multivariable model smoking 6-25 and > 25 cigarettes per day (OR 1.85; 95% CI 1.01-3.39 and OR 3.22; 95% CI 1.34-7.70, respectively), diabetes (OR 2.58; 95% CI, 1.01-6.61), furosemide (OR 2.39; 95% CI, 1.36-4.18) , and hypertension (OR 2.79; 95% CI, 1.52-5.12) remained independent risk factors for AKI. Conclusions: The identified risk factors smoking, diabetes, and hypertension may have caused pre-existing kidney damage and therefore have predisposed to AKI. Co-administration of furosemide with cisplatin is a potentially reversible risk factor for AKI.
Change of surgical procedure for thyroid tumor after collaboration with Nagasaki (Japan) and Semipalatinsk (Kazakhstan).
Authors: Maeda Shigeto , Adylkhanov Tasbolat
Published: September 2018

e17590

Background: From 1949 to 1989, 456 nuclear tests were conducted by the former Soviet Union at the Semipalatinsk Nuclear Test Site (SNTS) in Kazakhstan. It is very important to assess the clinical behavior of thyroid cancer which may be affected by SNTS in the control of an accurate diagnosis and standardized surgery. We have collaborated with the Semipalatinsk Oncology Center since 1999, in order to establish an optimal method to diagnose and perform a thyroidectomy and a lymph node dissection for the patients with papillary thyroid cancer that is better suited for the Semipalatinsk environmental effects. Methods: To assess the change of diagnostic accuracy and thyroid surgery from 1999 to 2010 in Semipalatinsk Oncology Center in collaboration with Nagasaki University and Nagasaki Medical Center. Material: A total of 200 patients with thyroid cancer who underwent thyroid surgery at the Semipalatinsk Oncology Center were evaluated. From the 200 patients, 145 patients with papillary thyroid cancer were assessed for surgical procedure. This was a cross-sectional observational study. Results: 1) Before 2001, there were few preoperatively diagnosed thyroid cancers and from 2002, preoperatively diagnosed papillary cancers increased. 2) The partial lobectomies were mainly performed until 2001. From 2002 to 2010, total lobectomies were chosen for the majority of the patients, but total thyroidectomies were rarely performed. 3) Up to 2014, there are no local and distant metastasis were seen in those patients with papillaty cancer. Conclusions: An accurate diagnosis and standardized surgery for thyroid cancer helped to evaluate the biological characteristics of thyroid cancer which may be affected by SNTS in next decade.