bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of DNA repair factors with overall survival in advanced urothelial carcinoma treated with platinum-based chemotherapy.
Authors: Guancial Elizabeth Ann , Werner Lillian , Stack Edward , Lis Rosina , Signoretti Sabina , Loda Massimo , Gallardo Enrique , Rojo Federico , Lloreta Jose , Regan Meredith M. , Park Rachel , O'Brien Robert , Berman David M. , Bellmunt Joaquim , Rosenberg Jonathan E.
Published: February 2017

291

Background: DNA repair factors are hypothesized to mediate chemosensitivity to cytotoxic agents that produce DNA damage and may be predictive for response to platinum-based chemotherapeutic regimens. Primary urothelial carcinoma (UC) tumors of patients who developed metastatic disease were evaluated for expression of a panel of DNA repair factors by immunohistochemistry (IHC).

Methods: A cohort of 132 clinically annotated, uniformly-treated (platinum-based combination chemotherapy) UC patients who subsequently developed distant metastases with FFPE primary tumor tissue available was identified. Tumor bearing areas were evaluated by a single urologic pathologist. Tissue arrays were constructed for IHC analysis of the following DNA repair factors: ERCC1, Rad 51, BRCA1/2, PAR and PARP1. Tumor was deparaffinized and specific antigen retrieval determined for individual antibodies. Pathologist supervised IHC analysis of nuclear versus cytoplasmic expression was performed using spectral imaging analysis. Overall survival (OS) was defined from start of chemotherapy for metastatic disease to death (N=67) or censored on the last known alive date. Percent of positive nuclear staining was categorized as quartiles or previously identified cut-points. Cox regression evaluated the associations of percent positive nuclear staining levels and OS in multivariable analysis (HRs and 95% CIs included) that controlled for known prognostic variables (performance status and visceral metastases).

Results: Higher percentage of nuclear staining of ERCC1 [HR=2.7 (1.5, 4.9), p=0.0007]; Rad51 [HR=5.6 (1.7, 18.3), p=0.005]; and PAR [HR=2.2 (1.1, 4.4), p=0.026] in tumor tissue were associated with poor outcome; each was independent of the other two repair factors and known prognostic variables. Neither nuclear nor cytoplasmic staining for BRCA1/2 or PARP1 reached statistical significance for an association with OS.

Conclusions: DNA damage repair factor levels measured by IHC impact outcomes in advanced UC. External validation is ongoing and will be presented. Further studies are required to determine whether these biomarkers are prognostic or predictive in this setting.
Phase II study of docetaxel (D) and oxaliplatin (O) in recurrent metastatic transitional cell cancer (mTCC) of the urothelial tract.
Authors: Chatta Gurkamal S. , Appleman Leonard Joseph , Friedland David , Tribble Gail , Davar Diwakar
Published: February 2017

296

Background: First-line regimens for mTCC of the bladder are either MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or the cisplatinum-gemcitabine doublet. There is no approved second-line option for mTCC. Both single agent D and O have response rates of 10 to 20%, and O in cisplatin-resistant patients (pts). Hence the combination of D and O may be useful in recurrent mTCC.

Methods: The combination of D and O was primarily tested for efficacy in recurrent mTCC. All pts had histologically proven TCC with measurable disease, and had prior treatment with at least 1 platinum-containing regimen. D 60 mg/m2 followed by O 110 mg/m2 were administered every 3 weeks. Pts were evaluated for response every 2 cycles and were treated either till progression or for a maximum of 6 cycles.

Results: 22 pts were enrolled of whom 19 were evaluable for response. Median age was 72 years (range 44 – 87). All pts had prior treatment with at least 1 cytotoxic regimen, with 8 pts having received 2 or more prior regimens. The mean number of cycles administered was 3. Of the 19 pts evaluable for efficacy, objective response was documented in two pts (both partial responses), three had stable disease, and the remaining fourteen progressed on therapy for an overall disease stabilization rate of 26%. Median time to progression (TTP) was 3.0 months (95% CI 0.2 to 5.8) and median overall survival (OS) was 7.0 months (95% CI 4.6 to 9.4). Toxicity, evaluated in all 22 patients, was relatively mild: grade 3-4 diarrhea in 6 patients, grade 3-4 hematological toxicity in 4 pts and grade 3-4 fatigue in 1 pt. No grade 3-4 neuropathy was observed and no toxic deaths were noted. The median follow-up period was 7.0 months (95% CI 4.5 to 9.5).

Conclusions: The combination of D and O is active in previously treated pts with mTCC. This regimen appears to be well tolerated with overall mild toxicity. Whilst this study was not powered for assessing survival, the presence of stable disease in 26% of pts suggests that further investigation of the combination in carefully selected pts maybe warranted.
Examining the management of muscle-invasive bladder cancer (MIBC) by medical oncologists (MO).
Authors: Apolo Andrea Borghese , Bochner Bernard , Steinberg Seth M. , Bajorin Dean F. , Kelly William Kevin , Quinn David I. , Vogelzang Nicholas J. , Sridhar Srikala S.
Published: February 2017

298

Background: Neoadjuvant chemotherapy (NC) for the treatment of MIBC remains underutilized in the United States despite evidence supporting its use. The aim of this project is to examine the current management of MIBC by MO to move towards standardization of practice.

Methods: An electronic 26 question survey was emailed to 92 MO belonging to the Bladder Cancer Advocacy Network or the American Society of Clinical Oncology, and posted on the US Oncology portal for 8 wks. The study was approved by the Office of Management and Budget (0925-0046). Percentages are based on the fraction that responded to a given question.

Results: Of the 83 respondents: 48% were non-academic. 51% were general oncologists and 45% focused on GU malignancies. The majority of MIBC referrals came from urologists (79%). Initial CT staging with abd/pelvis was required by 88%, CT chest by only 72% and PET by 21%. NC is offered by 79% of MO to all MIBC pts and by 45% to all pts with high grade upper tract urothelial carcinoma. Adjuvant chemotherapy (AC) was offered by 46% to all MIBC pts and by 41% to pts with upper tract disease. NC was not offered if ECOG performance status (PS) was >3 (49%), in T2 disease without lymphovascular invasion (29%), or with GFR of <50 ml/min (35%). Chemotherapy regimens used for NC included gemcitabine/cisplatin (90%); methotrexate/vinblastine/adriamycin/cisplatin (MVAC) (30%), dose dense MVAC (20%); gemcitabine/carboplatin (36%); single-agent gemcitabine (10%), other regimens described include carboplatin/paclitaxel and ifosfamide/doxorubicin/gemcitabine. Response to NC was assessed by CT abd/pelvis (82%), CT chest (39%), cystoscopy (30%) and PET (12%). Pts with pathologic residual disease (>pT2 or positive LN) after NC were generally observed (74%).

Conclusions: The majority of MO do offer perioperative chemotherapy for MIBC pts with a trend towards increased use of NC over AC, which follows best evidence. The main reason for not offering perioperative chemotherapy was poor PS. The majority offer cisplatin-based combination therapy by preference. Increasing the rate of referrals of MIBC pts to MO, will result in more pts receiving perioperative cisplatin-based chemotherapy and may lead to better outcomes in this disease.
Impact of multiparametric endorectal coil prostate MRI on disease reclassification among active surveillance candidates: A prospective cohort study.
Authors: Margel David , Yap Stanley , Lawrentschuk Nathan , Klotz Laurence , Haider Masoom A. , Finelli Antonio , Zlotta Alexandre , Trachtenberg John , Fleshner Neil Eric
Published: February 2017

30

Background: One troubling aspect of active surveillance (AS) is that a subset of patients diagnosed as very-low risk prostate cancer (PCa) appear to be under sampled and, in fact, harbour larger often higher grade cancers.The aim of this study is to report MRI findings among unselected men with low-risk PCa prior to AS.

Methods: We prospectively enrolled men with low-grade, low-risk, localized PCa. All patients underwent multiparametric endorectal coil MRI scanning and offered a confirmatory biopsy within one year of MRI. The primary outcome was the impact of MRI in identifying patients reclassified as no longer fulfilling AS criteria by a confirmatory biopsy. We further aimed to identify clinical parameters associated with reclassification. Cohort was stratified as follows: normal MRI; cancer on MRI concordant with initial biopsy (less than 1 cm); cancer on MRI larger than 1cm. We performed a univariate analysis to assess differences in clinical parameters between groups.

Results: MRI did not detect cancer in 23 (38%) while MRI and initial biopsy were concordant in 24 patients (40%). MRI detected a 1cm or larger lesion in 13 patients (22%). Eighteen patients (32.14%) reclassified. When no cancerous lesion was identified on MRI only 2 patients (3.5%) reclassified. The positive and negative predictive values for MRI predicating reclassification were 83% (95% CI, 73%-93%) and 81% (95% CI, 71%-91%), respectively. PSA density was elevated among patients with larger than 1 cm MRI lesions compared to those with no cancer on MRI (medians of 0.15 vs 0.07 ng/ml/cc, respectively p=0.016).

Conclusions: MRI appears to have a high yield in predicting reclassification among men choosing AS. Upon confirmation of our results MRI may be used to better select and guide patients before AS.
The neoadjuvant management of muscle-invasive bladder cancer (MIBC) in Canada: A national survey of urologists.
Authors: Sridhar Srikala S. , Chi Kim N. , North Scott A. , Black Peter C. , Wood Lori , Hsu Tina
Published: February 2017

303

Background: There is level 1 evidence and a 5% absolute survival benefit supporting the use of cisplatin-based neoadjuvant chemotherapy (NC) for the management of MIBC. Despite this, it is well known that the majority of eligible patients undergoing cystectomy do not receive NC. We previously surveyed medical oncologists and found that the majority will offer NC to MIBC patients depending on stage, renal function, performance status (PS), and comorbidities. However, the number of MIBC patients being referred for consideration of NC by urologists remains low. The aim of this followup survey to urologists was to better understand their approach to MIBC, and referral patterns for NC.

Methods: A survey consisting of 24 questions was administered to Canadian urologists belonging to the Canadian Urologic Oncology Group. Respondents completed the survey and mailed/faxed back their responses. The survey was similar to, but not identical to the previous medical oncology survey.

Results: Of the 25 respondents, 21/25 (84%) were academic, >90% were in full-time practice, and 72% were practising for >10 yrs. Most (84%) treated over 20 bladder cancer cases annually. Overall, 22/25 (80%) will offer a NC approach if appropriate. In 2009, 9/24 (38%) sent >6 referrals for NC; 2/24 (25%) sent 5-6 referrals, 6/24 (20%) sent 3-4 referrals, and 5/24 (8%) sent 1-2 referrals. NC was offered as standard of care or to downsize tumors. Initial staging included cystoscopy, CT chest/abdo/pelvis and bone scan. Key factors cited for not offering NC were: T2a disease, GFR <40ml/min, age >85 or PS 3 or 4. Average time from NC to cystectomy was 4-6 wks.

Conclusions: The majority of academic urologists in Canada will refer MIBC patients for NC except those with T2a disease, poor renal function, age >85 or poor PS. Non-academic urologists are underrepresented in this survey, and may represent the group facing the greatest challenges in offering NC, due to issues such as access to medical oncology, or lack of local expertise in managing MIBC. Targeting non-academic urologists, and encouraging consultation with a medical oncologist for all patients with MIBC, may lead to increased utilization of NC, and better outcomes in this disease.
Adaptive planning study of “plan of the day” versus “composite planning” for muscle-invasive bladder cancer (MIBC).
Authors: McIntosh David E , Webster Gareth , Stratford Julia , Jegannathen Apurna , Cowan Richard , Logue John P. , Wylie James , Livsey Jacqueline E. , Elliott P. Anthony , Choudhury Ananya
Published: February 2017

309

Background: Bladder motion during treatment can be considerable resulting in either inadequate coverage of planning target volume (PTV) or significant overdose to organs at risk (OAR). Adaptive radiotherapy planning using either “plan of the day” or “composite planning” may offer a method to reduce PTV, while optimizing the clinical target volume (CTV) coverage and reducing the dose to OAR.

Methods: Patients were planned using a radiotherapy CT planning scan (RTP). CTV was defined as whole bladder and this was expanded by 1.5 cm to form the PTV. PTV was treated to 52.5 Gy in 20 fractions over 4 weeks. Off line correction was performed using cone beam imaging (XVI) taken on days 1-3 and weekly thereafter, as a minimum. We performed a retrospective planning study on 8 patients treated for MIBC. For “plan of the day,” 4 separate plans were created by expanding the superior CTV margin by 0.5 cm, 1 cm, 1.5 cm, or 2 cm. All other margins were 1.5 cm in all directions. Composite plans were created from the CTV drawn on the first 3 XVIs. This composite CTV was grown by 5mm to create PTV1 and by 10mm to create PTV2. Subsequent XVIs were assessed to determine if the CTV was encompassed by the 95% isodose for each plan. We compared the PTV for each plan with the standard RTP volume.

Results: Preliminary data reveal that the composite plan using a 10mm margin resulted in adequate coverage for all remaining treatments as assessed by XVI. The composite plan with a 5mm margin failed to adequately cover the CTV. Using the composite plan with a 10mm margin the PTV is decreased by a mean of 27.5% compared with conventional planning. Plan of the day resulted in a mean decrease in PTV of 17.0%.

Conclusions: This data suggests a potential advantage of adaptive planning with both techniques showing a reduction in PTV compared with conventional planning. This could lead to an associated reduction in dose and toxicity to OAR. Composite planning with a 10mm margin showed the greatest benefit in terms of reduced irradiated volume while adequately covering the CTV. Further studies are needed to investigate any effect on toxicity due to reduced dose to OAR.
Low-dose gemcitabine and paclitaxel combination therapy as second- or third-line treatment in patients with advanced urothelial cancer: Pain relief and tolerability.
Authors: Miyata Yasuyoshi , Ohba Kojiro , Matsuo Tomohiro , Sakai Hideki
Published: February 2017

310

Background: Pain is the most devastating symptom of advanced urothelial cancer (UC). In addition, analgesics often decrease quality of life. So, pain relief and reduction of dosage are important goals for patients with such advanced UC. Cisplatin (CDDP)-containing chemotherapy is most effective regimen in patients with metastatic or recurrent UC. On the other hand, there is no established regimen for advanced UC after CDDP-containing chemotherapy. We performed low-dose combined therapy of gemcitabine (GEM) and paclitaxel (PTX), named GP therapy, as second- or third-line treatment for these patients.

Methods: Thirty-three patients with metastatic and/or recurrent urothelial cancer (upper urinary tract = 13 and bladder =20 patients) previously treated with CDDP-containing chemotherapy were treated with GP therapy (GEM = 70 mg/m2 and PTX = 700 mg/m2 on day 1 and 8, repeated every 28 days). Survival was calculated from judgment of tumor progression. Pain was measured on a visual analog scale of 0–10. Positive effects for pain relief were defined as a decrease in analgesic consumption or a decrease in pain grade according to the visual analog scale, without increasing the dose of analgesics. Regulation of analgesics was performed by independent team that did not know this study. Pain relief and survival were compared with other chemotherapy (control; GEM alone = 9 and PTX-based chemotherapy except for GP therapy = 14).

Results: At the start of this treatment, 31 patients had abdominal or back pain due to UC. In addition, 3 patients also had bone pain of metastatic tumors. In GP therapy, 28 patients (84.8%) were judged as positive in pain and only 1 patient needed to increase analgesics. On the other hand, control group showed 13 of 23 patients (56.5%) were stable and 7 (30.4%) were judged as positive in pain. Kaplan-Meier survival curves showed overall survival periods in patients with GP therapy were better compared to control group (p=0.023). All patients were received in the outpatient setting because severe side effect was not occurred.

Conclusions: Low-dose GP therapy is feasible and well-tolerated as second/third-line chemotherapy in patients with advanced UC.
Methylation-specific high-resolution melting analysis (MS-HRM)-based DNA promoter profiling in paired FFPE bladder cancer samples.
Authors: Meng Wei , Chakravarti Arnab , Lautenschlaeger Tim
Published: February 2017

315

Background: DNA methylation and histone modification are widely studied epigenetic events that can decrease gene expression levels. Promoter hypermethylation has been proposed as a potential diagnostic or prognostic biomarker in various cancers. We studied DNA promoter methylation of 5 cancer-associated genes (MRE11, APX1, ERCC1, RASSF1A and RASSF2A ) in paired FFPE bladder cancer tissues and normal adjacent tissue. The MRE11/Rad50/NBS1 complex serves as a single-strand DNA nuclease which participates in the repair of DNA double-strand breaks and replication errors. APX1 plays a key role in regulating H2O2 levels and H2O2 signaling. DNA repair machinery, ERCC1 protein levels in tumor tissue have been shown to predict response to platinum-based chemotherapy. RASSF1 is thought to be a tumor suppressor gene, while the function of RASSF2 is less well understood.

Methods: 16 bladder cancer cases with available paraffin-embedded tumor and matched normal adjacent tissue specimens (32 tissue samples) were analyzed. DNA was extracted by Ambion RecoverAll Total Nucleic Acid Isolation kit. FFPE DNA bisulfite modification was performed using Zymo EZ DNA Methylation Kit. Methylation Specific-High Resolution Melting (MS-HRM) analysis was used to assess methylation status. MS-HRM monitors the melting behavior of PCR amplicons by using a DNA intercalating fluorescent dye.

Results: MRE11 and APX1 promoters were not methylated in either cancer or normal adjacent samples. The ERCC1 gene was heavily methylated in 94% (30/32) of all cancer and wild type samples. RASSF1A and RASSF2A promoter methylation was significantly different between cancer and normal adjacent tissue. 50% (8/16) RASSF1A and 25% (4/16) RASSF2A had promoter methylation in cancer tissues, while only 6% (1/16) RASSF1A and 0% (0/16) RASSF2A had promoter methylation in normal adjacent tissues. 69% (11/16) of bladder cancer tissues were positive for RASSF1A or RASSF2A promotor methylation while only 1/16 normal adjacent tissue samples was positive for either promotor methylation.

Conclusions: The results show that cancer and non-cancer tissue have different RASSF1A and RASSF2A promoter methylation patterns.
Urothelial cancer: Impact of gender on stage at diagnosis and survival.
Authors: du Manoir Jeanne Michelle , Richter Suzanne , Sridhar Srikala S.
Published: February 2017

316

Background: Gender differences for disease course and survival in various cancers exist. Gender disparity for both stage at diagnosis and overall survival (OS) has been observed in urothelial cancer (UC). We report a single institution analysis of UC patients treated with chemotherapy to further investigate gender differences in outcomes.

Methods: We identified 198 bladder cancer pts treated with chemotherapy since 2002. Chemotherapy was either given as adjuvant or palliative and the most common regimens used were gemcitabine and cisplatin, gemcitabine and carboplatin or gemcitabine alone. Age and stage at diagnosis, sex, smoking status, radiation exposures, bloodwork as a measure of organ dysfunction and overall survival info was collected. Outcomes were compared using Chi Square Statistic.

Results: Age at diagnosis, smoking status and prior pelvic radiation were not significantly different (females 66.1 yrs vs males 63.6 yrs; 54% smokers in both groups; 8.3% females vs 7.6% males exposed to radiation). Significantly more females were diagnosed with advanced disease than men (70.8% vs 58.7%, p=0.049) vs earlier stages (stage 0-I) (12.2% vs 35.9%, p=0.03). For patients deceased, OS was not significantly different between genders when analysed for all stages combined (deceased 41.5 vs 39.9 mos), or for those diagnosed only at Stage IV (deceased 12.4 vs 8.6 mos). Of patients still alive at time of review, a survival advantage was apparent for men at all stages (54.8 vs 38.7 months), as well as with stage IV disease (35.9 vs 19.7 months). Gemcitabine-cisplatin was given more often to men with stage IV disease than females (93% vs 63%, p<0.02) despite no difference in organ dysfunction, or ECOG performance status in females.

Conclusions: We observed that while both genders are similar with respect to age at UC diagnosis, risk factors exposures (smoking, radiation) and pathological variants, females were diagnosed at later stages, and receive standard first line therapy less often. Our data suggest that this impacts negatively on OS in females diagnosed in earlier disease stages. Further research is needed to identify if we can improve outcome by promoting earlier diagnosis and more aggressive management in earlier disease in females.
A single-center experience of chemotherapy for muscle-invasive bladder cancer after radical cystectomy.
Authors: Kotowski Adam S. , Stegemann Andrew , Rehman Shabnam , Attwood Kristopher , Levine Ellis Glenn , Guru Khurshid , Trump Donald L. , Pili Roberto
Published: February 2017

318

Background: Muscle invasive bladder cancer (MIBC) is a chemo-sensitive disease that responds to therapy before or after curative-intent radical cystectomy (RC). Neoadjuvant chemotherapy (NAC) improves overall survival by 5-8% in current meta-analyses. Adjuvant chemotherapy (AC) has shown benefit but is less rigorously tested.

Methods: We retrospectively reviewed the cystectomy database at our institute from 2005-2011 and analyzed patients who have received NAC or AC for MIBC. The Log rank test was used to compare survival between groups and Cox regression models were used for adjusted comparisons of survival.

Results: 45 patients (p) (13 NAC and 32 AC) were evaluated with a mean age of 65.5 years (50-82), including 77% males and 23% females. Patients were most commonly offered chemotherapy because of co-morbidities and performance status. NAC was most commonly gemcitabine (G)/cisplatin (n=9) and AC was usually G/platinum (n=27). Sixty-nine percent of patients were downstaged and 23% had a complete pathologic response following NAC. Three p in AC group had positive margins; all of these cases were T4 cancers. Pathologic staging showed 84% ≥T3 and 53% node positive disease. Patients receiving AC had a mean interval of 64.8 days (42-129) to the start of treatment. NAC and AC patients received median 4.1 (3-7) and 4.5 cycles (1-12), respectively, throughout entire course of treatment. The median overall survival (OS) was 24.5 months (m) (17.1 m-not reached) and 24-month survival rate was 47%. Progression free survival (PFS) was 12.3 m (8.5-23.5 m) for all patients. There was no difference for OS or PFS based on age, gender, time after surgery to first dose of therapy, or mode of therapy (NAC or AC). When adjusted for number of cycles completed, a trend toward improved median OS (not reached vs. 22 m p= 0.092 ) and a significant PFS improvement (28.5 vs 11.5 m p=0.026) with NAC vs. AC was observed. Grade 3-4 urologic toxicity was negligible in both groups, however the AC group had a higher percentage of grade 3-4 hematologic toxicity.

Conclusions: Despite a small sample size, results from our series favor NAC based upon efficacy and tolerability for patients with locally invasive bladder cancer.
Postchemotherapy AKR1B10 expression correlates with disease-free survival in muscle-invasive bladder cancer.
Authors: Hashimoto Yasuhiro , Koie Takuya , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Kamimura Noritaka , Ohyama Chikara
Published: February 2017

319

Background: AKR1B10 is a member of the aldo-keto reductase superfamily of NAD(P)H-dependent oxidoreductases.AKR1B10 is considered to contribute to cell proliferation and chemo-resistance. In the present study, we examined whether AKR1B10 expression correlates with disease free survival in bladder cancer specimens.

Methods: The cohort includes consecutive 57 patients with muscle-invasive bladder cancer who received neoadjuvant chemotherapy followed by radical cystectomy. All patients received two cycles of neoadjuvant chemotherapy with gemcitabine plus carboplatin. Bladder cancer specimens were obtained at pre- and post-neoadjuvant chemotherapy, which were subjected to quantitative real-time PCR and immunohistochemistry to evaluate AKR1B10 expression. Intensity scoring for immunohistochemistry was categorized using a 4-graded scoring system according to a previously published method, with positive cells for each specific marker expressed as a percentage of the total number of cells as follows: 0%–10% = 0; 11%–30% = 1; 31%–70% = 2; 71%–100% = 3.

Results: AKR1B10 mRNA expression was significantly higher in the post-chemotherapy groups than in the pre-chemotherapy groups (p < 0.001). The average immunohistochemical intensity score in the pre-chemotherapy group was 0.83 ± 1.08, compared to a significantly higher average intensity score of 2.03 ± 1.03 in the post-chemotherapy group (p < 0.001) Disease free survival of the post-chemotherapy AKR1B10(+) patients (61.2%) was significantly lower than that of AKR1B10(−) patients (100%) (log-rank test: p = 0.039).

Conclusions: Although the present study is small and preliminary, post-chemotherapy AKR1B10 expression may have a predictive potential for response of chemotherapy and disease recurrence after definitive therapy for muscle-invasive bladder cancer. Further study is warranted to elucidate its clinical significance.
Radiotherapy planning study comparing volumetric modulated arc therapy (VMAT) with intensity modulated radiotherapy (IMRT) in the treatment of bladder and pelvic lymph nodes.
Authors: Harris Victoria , Warren-Oseni Karole , Huddart Robert Anthony
Published: February 2017

320

Background: VMAT is increasingly used as an alternative to IMRT and has been shown to reduce treatment time and monitor units delivered. We report a radiotherapy (RT) planning study of bladder and pelvic lymph node (LN) RT comparing dosimetric outcomes of VMAT and IMRT techniques.

Methods: 8 patients with/at high risk of LN+ bladder cancer were treated with bladder/pelvic LN IMRT. 4 clinical target volumes (CTVs) were defined: Whole bladder (CTV1), Pelvic LN (CTV2), Involved Bladder (CTV3) and Involved LNs (CTV4). Margins were applied to create 4 corresponding PTVs. IMRT plans were compared with VMAT plans in order to assess planning target volume (PTV) and organ at risk (OAR) coverage. The same PTV/OAR volumes and doses were used for each technique.

Results: The mean dose statistics were compared for each dosimetric parameter for both techniques. The Wilcoxon signed-rank test was used to compare techniques with statistical significance assumed as p<0.05. Both techniques met prescription goals for PTV coverage. Comparison of conformity indices revealed no significant difference between techniques. VMAT achieved significantly better homogeneity in coverage of PTV2, although this finding was not replicated in the other PTVs (Table). Homogeneity index (HI) was defined as HI = 100x(D2-D98)/ Dp, where Dp = prescribed dose. VMAT resulted in significantly larger volumes of bowel (4.7%) and rectum (4.8%) receiving low dose radiation (15 Gy) than IMRT, although there was no significant difference seen at higher dose levels. Comparison with 3D conformal radiotherapy (3D-CRT) showed that both techniques resulted in a large reduction in bowel irradiation to 45Gy (IMRT = 123cc, VMAT = 145cc and 3D-CRT = 218cc).

Conclusions: VMAT offers an attractive alternative to IMRT with similar conformality. Whilst increased low dose RT to OARs was seen with VMAT, it is of doubtful significance relative to the higher doses received by these structures.

[Table: see text]
Prevalence of testicular microlithiasis association with testicular and extragonadal germ cell tumors in a Latin American population.
Authors: Neciosup Silvia P. , Quesada Jose , Callacondo David , Aguilar Ivan
Published: February 2017

331

Background: Testicular microlithiasis (TM) is a entity characterized by multiple areas of increased echogenicity on scrotal ultrasonography (U.S.). Studies have reported association between TM and testicular germ cell tumors (TGCT). However, a study assessing the association of TM and extragonadal germ cell tumors (EGCT) has not been performed.

Methods: Scrotal U.S. were reviewed in 441 men randomly selected from our computerized database during the period 1998 and 2010 at our tertiary-care cancer hospital. The association of U.S. findings with medical records and a history of germ cell tumors (GCT) were evaluated. The type of tumor was confirmed at histology after surgery or biopsy. Exclusion criteria included age <15 years and history of orchidectomy.

Results: The median age was 32 years (range 15 – 88). TM was present in 95 patients (22%) and GCT were found in 130 patients (29%). 105 of these had TGCT (seminoma, n=56 and no seminoma, n=49) and 25 had EGCT (mediastinal, n=16, retroperitoneal, n=6 and CNS, n=3). Concurrent diagnosis of a TGCT was more prevalent in TM patients than in patients without TM (36/95 [38%] versus 69/346[20%] OR 2.45 95% CI 1.49–4.0; p<0.0001) while a diagnosis of an EGCT was present in 13 patients with TM and 12 patient without TM (13/95 [14%] versus 12/346 [3%] OR 4.41 95% CI 1.94–10.03; p<0.0001). No statistical differences were found for histology type.

Conclusions: The prevalence in Latin American of TM is higher than previous reports and strongly associated with TCGT and EGCT. The clinical impact of the relationship between EGCT and TM is yet unknown and further studies are needed to clarify its role in the management. We suggest that young high-risk referral patients with TM should undergo scrotal U.S. annually; when a testicular tumor is not evident by U.S., investigations to rule out an EGCT, as thoracic or abdominal CT scans, should be considered individually in each case.
Normal tissue exposure during retroperitoneal radiotherapy for pure seminoma of the testis.
Authors: Katz Leah Minnie , Efstathiou Jason Alexander , Opraseuth Jonathan , Killoran Joseph , Paly Jonathan J. , Weathers Rita , Stovall Marilyn , Beard Clair
Published: February 2017

334

Background: Emerging data suggest risk of cardiovascular disease following radiotherapy to the retroperitoneal nodes in stage I/II seminoma patients. This study quantifies radiation dose to organs contributing to cardiovascular disease.

Methods: Organs at risk (OAR) were contoured using Eclipse. OARs consisted of the cardiac ventricles, kidneys, abdominal aorta, renal arteries, common iliac arteries, and external iliac arteries. Four dose-volume histograms corresponding to 4 treatment plans were generated for each patient. Each patient was planned as if being treated for a left primary seminoma. Plans 1/2 consisted of a standard PA strip field, while plans 3/4 consisted of a standard extended-field configuration. Field width for plans 1/3 spanned the transverse processes, while plans 2/4 included treatment of the left renal hilum. OAR doses were cumulatively reported for all 22.

Results: Median doses to the left kidney for plans 1, 2, 3 and 4 were 1.2, 2.2, 1.3 and 2.7 Gy, respectively. The median dose in treatment plan 2 was 1.0 Gy higher than plan 1, and in plan 4 it was 1.4 Gy higher than plan 3; suggesting increased left kidney dose when the renal hilum was included. The maximum distance between the top of the treatment field and the inferior ventricle was 7.1 cm, while the maximum ventricular-field overlap measured 1.81 cm. There were 4 of 22 patients (18%) who had overlap with 16.7 to 46.44 cm3 of contoured ventricle within the field. The dose received by the cardiac ventricles ranged from 0–26.5 Gy, with the maximum dose of 26.5 Gy received by the patient with the greatest amount of overlap (1.81 cm).

Conclusions: Adjusting treatment fields to include the renal hilum results in a higher dose to the kidneys and a mild increase in dose to the heart. While most patients have good separation of the heart and treatment field with extremely low cardiac doses, those whose ventricles are in field experience potentially significant cardiac doses. Our data suggests that for those patients with less than 2 cm between the superior portion of the treatment field and the inferior ventricle, the dose to the ventricles is at or approaches prescription dose. Clinicians treating seminoma patients may wish to consider this when determining candidacy for RT.
Multimodality treatment of locally advanced penile cancer: A contemporary dosimetric comparison and case presentation.
Authors: Cox John A. , Suri Jaipreet S. , Jana Bagi RP , Orihuela Eduardo , Sturgeon Jared D. , Endres Eugene C. , Colman Martin , Swanson Todd A.
Published: February 2017

346

Background: There is a paucity of data on the optimal therapy for locally advanced penile cancer (PC). However, advances in other HPV associated neoplasms utilizing combined modality therapy (CMT) have been encouraging. We describe the management of advanced PC with such an approach.

Methods: The patient presented following partial penectomy and inguinal dissection with T2N3 disease and extra-capsular extension (ECE). In a multi-disciplinary setting, it was decided to treat him post-operatively with concurrent chemoradiation. CT data sets were used for dosimetric comparison of critical structures (small bowel, rectum, bladder, scrotum, testes, bone marrow, skin, bowel, and femoral heads) and plans were generated using conventional penile fields (3D), Intensity Modulated Radiation Therapy (IMRT), and Volumetric Modulated Arc Therapy (VMAT), minimizing dose to organs at risk while optimizing treatment dose.

Results: The patient was treated with IMRT (45 Gy to penile stump, pelvic and inguinal nodes (INs) with a 9 Gy boost to left INs and 15 Gy boost to right INs, due to ECE) and weekly Cisplatin (20 mg/m2). IMRT gave similar coverage and avoidance of normal structures compared to VMAT but with lower mean scrotal dose ( IMRT 27.0 Gy , VMAT 29.9 Gy, 3D 45.6 Gy). There was no >grade II toxicities, with grade II scrotal edema and moist desquamation of bilateral inguinal folds, not requiring treatment breaks. Acute RT toxicities had near resolution at 1 month. The IMRT and VMAT plans vs. the 3D plan had lower mean doses to the normal structures. 3D planning had unacceptable max doses to femoral head (62 Gy) and scrotum (55 Gy). Small bowel, V15Gy ≤ 150 cc was achieved by all plans. Dose homogeneity was improved for IMRT/VMAT vs. 3D planning (max dose 119%).

Conclusions: This is one of the first comparisons of contemporary radiation techniques in the multimodality setting of PC. We demonstrate that utilizing IMRT concurrently with Cisplatin is feasible and well tolerated suggesting it a reasonable strategy to obtain durable local control, without which the prognosis is uniformly dismal. Larger studies are warranted to explore this contemporary CMT approach to locally advanced PC.
Mesenteric lymphadenopathy in patients with germ cell tumor.
Authors: Djaladat Hooman , Nichols Craig R. , Daneshmand Siamak
Published: February 2017

347

Background: Mesenteric lymphadenopathy may be secondary to inflammatory, infectious or tumoral pathologies. The most common malignancies causing mesenteric adenopathy are gastrointestinal and lymphoma. To the best of our knowledge, there are no reports of germ cell tumor (GCT) presenting with mesenteric adenopathy.

Methods: Four patients with GCTs presenting with mesenteric adenopathies were treated in two academic centers (OHSU and USC) by a single surgeon since 2004. All pathologies were non-seminomatous GCT. Their presentation, clinico-pathologic findings and outcome are reviewed.

Results: Two cases (19 and 51 yo) were IGCCC poor risk, stage II, testicular GCTs presenting with bulky retroperitoneal, periportal and mesenteric adenopathy. They both underwent post-chemo RPLND with mesenteric lymph node biopsy/resection. The intraoperative mesenteric lymph node frozen section study in one case revealed embryonal cell carcinoma and teratoma; he had early postoperative recurrence and is awaiting high dose chemotherapy and autologous stem cell transplant (HDC/ASCT). The other was teratoma and underwent resection, however he developed lung metastases with elevated AFP 6 months later and was treated with HDC/ASCT, being disease free for 2.5 years. The third case was a 29 yo IGCCC good risk testicular GCT who presented with retroperitoneal (II B) and mesenteric lymphadenopathy. He underwent post-chemo exploration and intraoperative frozen section of the mesenteric lymph nodes showed fibrosis and histiocytic infiltration; therefore classic RPLND was completed. The fourth case was a 24 yo HIV (-) patient with extragonadal GCT originating from the rectosigmoid. At presentation, he had a widespread mesenteric adenopathy, partially responded to primary (BEP) and salvage chemotherapy (VIP); he underwent recto/sigmoid resection, RPLND and PLND and had 52/104 lymph nodes positive for yolk sac tumor. He was referred for HDC/ASCT. Three cases were done recently with limited follow-up.

Conclusions: The most common etiologies for mesenteric adenopathy are inflammatory, infection and neoplastic diseases. In the presence of germ cell tumor however, mesenteric adenopathy is most likely secondary to metastasis rather than secondary pathology.
Meta-analysis of randomized control trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors.
Authors: Richards Christopher J. , Je Youjin , Schutz Fabio A. B. , Choueiri Toni K.
Published: February 2017

349

Background: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have become the cornerstone in the treatment of several malignancies. These drugs have also been associated with an increase in the risk of potentially life-threatening adverse events, such as arterial thrombotic events, bleeding, congestive heart failure, and others. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in patients with cancer treated with VEGFR TKIs.

Methods: MEDLINE and PubMed databases were searched for articles published from January 1966 to February 2011. Eligible studies were limited to trials of US Food and Drug Administration– approved VEGFR TKIs (pazopanib, sunitinib, and sorafenib) that reported on patients with cancer with any primary tumor type, randomized design, and adequate safety profile. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% CIs by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies.

Results: In all, 4,679 patients from 10 randomized controlled trials (RCTs) were included, with 2,856 from sorafenib, 1,388 from sunitinib, and 435 from pazopanib trials. The incidence of FAEs related to VEGFR TKIs was 1.5% (95% CI, 0.8% to 2.4%) with an RR of 2.23 (95% CI, 1.12 to 4.44; P .023) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between different VEGFR TKIs or tumor types. No evidence of publication bias was observed.

Conclusions: In a meta-analysis of RCTs, the use of VEGFR TKIs was associated with an increased risk of FAEs compared with control patients.
Conditional survival (CS) for patients with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy (TT): Results from the International mRCC Database Consortium.
Authors: Choueiri Toni K. , Xie Wanling , Harshman Lauren Christine , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Wood Lori , Vaishampayan Ulka N. , Tan Min-Han , Rha Sun Young , Donskov Frede , Agarwal Neeraj , Kollmannsberger Christian K. , North Scott A. , Rini Brian I. , Heng Daniel Yick Chin
Published: February 2017

358

Background: Survival estimates for patients with mRCC are traditionally reported from the time of TT initiation. These survival projections, however, may not be applicable to patients who have already survived a period of time after initiating therapy. CS accounts for elapsed time since starting therapy, providing more relevant prognostic information.

Methods: Data on 1673 patients treated with first-line VEGF TT between 4/7/2003 and 10/12/2010 was analyzed. Median follow up for patients still alive is 20.1 months. Conditioned survival was calculated on the set of patients alive or on TT at 3 months and using 3 months increments for up to 18 months.

Results: The 2-year CS probability tends to slightly improve from 44 to 51% when conditioned on having already survived 0 to18 months since initiation of TT, respectively. The Heng et al (JCO 2009) risk criteria (defined at therapy initiation) retains prognostic ability over time independent of previous survival time or previous time on TT up to 18 months (p<0.0001 for all comparisons). In the subgroup analysis stratified by Heng risk groups, 2-year CS minimally changes over time in the favorable (FAV) and in the intermediate (INT) groups, but in the poor risk group, the 2-year CS improves from 11% initially to 33% after 18 months. When conditioned on time on TT, 2-year CS improves from 44% to 68% overall, from 74% to 90% in the FAV risk group, 49% to 57% in the INT risk group and 11% to 73% in the poor-risk group.

Conclusions: Conditional survival may be a more relevant measure of prognosis for those who have already survived or have been on TT for a period of time. The largest improvement was seen in patients in the poor risk group.

[Table: see text]
Cytoreductive nephrectomy in the United States: Patterns of care and patient characteristics.
Authors: Tsao Che-Kai , Moshier Erin , Small Alexander C. , Sonpavde Guru , Godbold James , Oh William K. , Galsky Matt D.
Published: February 2017

366

Background: Two randomized trials published in 2001 established cytoreductive nephrectomy (CyNx) for patients (pts) with metastatic renal carcinoma (mRCC) as a treatment standard in the cytokine era (Flanigan, J Urol, 2004). However, first-line systemic therapy for mRCC changed in 2005 with FDA approval of VEGFR tyrosine kinase inhibitor (TKIs). We evaluated the patterns of use of CyNx in the pre- and post-TKI era and characteristics of pts undergoing CyNx.

Methods: The National Cancer Database was queried for pts diagnosed with mRCC between 2000 and 2008. Pts who underwent CyNx were identified and were further categorized by pre- versus post-TKI era (2000–2006 vs. 2006–2008), race, insurance status, and hospital. For these subcategories, prevalence ratios (PR) were generated using the proportion of pts with mRCC undergoing CyNx versus those not undergoing CyNx.

Results: Of the 47,417 patients (pts) with mRCC diagnosed between 2000 and 2008, 25,616 pts (54%) did not undergo CyNx. The prevalence of cytoreductive nephrectomy increased 3% each year from 2000 to 2006 (p<0.0001), then decreased 3% each year from 2006 to 2008 (p=0.0048), with a significant difference between the pre- and post-2006 PR (0.97 versus 1.025; p<0.0001). Blacks (PR 1.17) and Hispanics (PR 1.05) were significantly more likely than Caucasian to not undergo CyNx (p<0.008). Pts with Medicaid (PR 1.25), Medicare (PR 1.40), and no insurance (PR 1.42) were significantly more likely than pts with private insurance to not undergo CyNx (p<0.0001). Pts diagnosed at community hospitals (PR 1.29) were significantly more likely than pts at teaching hospitals to not undergo CyNx (p <0.0001).

Conclusions: The use of CyNx has declined in the post-TKI era. In addition, racial and socioeconomic disparities exist in the use of CyNx. The results of pending randomized trials evaluating the role of CyNx in the post-TKI era are awaited to optimize use of this modality.
Results of a high-throughput screen to identify compounds that modulate VHL proteostasis.
Authors: Ding Zhiyong , German Peter , Bai Shanshan , Gao Meng , Sobieski Mary M. , Stephan Clifford C. , Mills Gordon B. , Jonasch Eric
Published: February 2017

369

Background: Mutated von Hippel Lindau (VHL) protein causes disease in sporadic renal cell carcinoma (RCC), and in the eponymous hereditary VHL disease. We developed and tested a cell-based screening tool to identify compounds that stabilize or upregulate full-length, point mutated VHL, and potentially reverse the disease phenotype.

Methods: The 786-0 cell line was infected with full-length W117A mutated VHL linked to a C-terminal Venus fluorescent protein. This VHL-W117A-Venus line was used to screen the Prestwick drug library and was tested against the known proteasome inhibitors MG132 and bortezomib. Western blot validation and evaluation of downstream functional readouts, including HIF and GLUT1 levels, were performed.

Results: The proteasome inhibitors bortezomib and MG132, and the Prestwick compounds 8-azaguanine, thiostrepton and thioguanosine were found to reliably upregulate VHL-W117A-Venus in 786-0 cells. Thiostrepton has also been recognized as having proteasome inhibitory effects. 8-azaguanine was found to downregulate HIF2α levels, and was augmented by the presence of VHL W117A. VHL p30 band intensities varied as a function of compound used, suggesting alternate post-translational processing. In addition, nuclear-cytoplasmic localization of pVHL varied amongst the different compounds, additionally suggesting unique effects of each of the agents on VHL homeostasis.

Conclusions: We have successfully identified compounds that stabilize mutated VHL, including several proteasome inhibitors. It is possible that proteasome inhibition will have a specific clinical effect on patients with point-mutated pVHL. Further work is currently underway to further test this hypothesis in animal xenograft studies using cell lines containing various mutated VHL isoforms, and clinical trials using next-generation proteasome inhibitors are being explored.