bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative efficacy of adjuvant chemoradiation versus chemotherapy in surgically resected adenocarcinoma of stomach
Authors: Aziz S. A. , Banday M. A. , Mir M. H.
Published: August 2020

e15639

Background: Outcome of carcinoma of stomach has not changed over the past decades and surgery remains the time tested primary modality of treatment. Attempts to improve survival have been strengthened by recent studies of adjuvant chemoradiation in these patients. The present study focuses to compare the efficacy of adjuvant chemoradiation Vs Chemotherapy alone in surgically resected adenocarcinoma of stomach. Methods: Over a two years period (Nov. 2006 to Oct 2008) 60 patients were enrolled and randomized to two arms with 30 patients in each arm. ArmA received adjuvant chemoradiation and arm B received chemotherapy only. Chemoradiation protocol included Inj. 5 - FU 425mg/m2 and Inj. CLV 20mg/m2 I/V d1 - d5 followed by EBRT (45 GY) over 20 #s starting on d29. During first 4 days and last 3 days of radiation patients also received inj. 5 - FU 400mg/m2 I/V and CLV 20mg/m2 I/V bolus. Arm B received chemotherapy alone with Inj Cisplatin 100mg/m2 divided over 3 days, Inj 5- FU 500 mg/m2 I/V bolus d1 - d3 and Inj. CLV 20 mg/m2 /IV d1 - d3 q 21 days × 6 cycles. Results: All patients were followed post treatment for EFS and PFS for a maximum period of 24 months with a median followup of 19 months. EFS and PFS for two arms were; Arm A - 17.7 months and 19.0 months and Arm B - 16.0 months and 17.4 months respectively. Treatment related morbidity was significant in arm B. General well being and surrogate laboratory markers including hemogram were compared as well, favouring arm A. Conclusions: Although interim survival trends favour adjuvant chemoradiation, yet results are not statistically significant necessitating a longer followup of these patients to arrive at a definite conclusion as for as decision regarding efficacy of chemoradiation is established. Also these findings need to be reproduced by further studies.

No significant financial relationships to disclose.
Prognostic value of response assessed by RECIST and WHO criteria to neoadjuvant chemotherapy in locally advanced gastric cancer patients
Authors: Park S. R. , Lee J. S. , Kim Y. W. , Choi I. J. , Ryu K. W. , Lee J. H. , Lee J. Y. , Park Y. L. , Park S. Y. , Park Y. I. , Kim N. K.
Published: August 2020

e15647

Background: In metastatic gastric cancer, the response to chemotherapy is assessed by RECIST or WHO criteria according to the change of tumor size. There are no data, however, on the usefulness of those criteria in evaluating tumor response in the setting of neoadjuvant chemotherapy. The aim of this study was to evaluate the relationship between tumor response to neoadjuvant chemotherapy-as assessed by RECIST and WHO criteria-and clinical outcome in locally advanced gastric cancer (LAGC) patients. Methods: This study recruited LAGC patients who, from January 2003 through November 2005, entered the neoadjuvant arm of prospective randomized phase II trials comparing neoadjuvant chemotherapy to adjuvant chemotherapy. LAGC was defined as stage III or IV (M0) disease based on computed tomography (CT) according to the Japanese Classification of Gastric Carcinoma. Patients with measurable lesions received 3 cycles of neoadjuvant chemotherapy consisting of docetaxel (36 mg/m2) and cisplatin (40 mg/m2) on days 1 and 8 every 3 weeks, followed by surgery. Results: After chemotherapy, 40 (95%) patients underwent surgery and the remaining 2 patients showed new distant metastasis on CT scan. Thirty-five (83%) patients had curative R0 resection. Twenty-eight (67%) patients had a clinical response to neoadjuvant chemotherapy according to RECIST/WHO criteria. Although R0 resection rate (93% vs 64%, P = 0.03), median relapse-free survival (RFS) (43.2 vs 7.5 months, P = 0.14), and overall survival (OS) (not reached vs 27.0 months, P = 0.10) were better in responders than non-responders, they did not differ significantly in the subgroup that subsequently underwent surgery. When we redefined the decrease in tumor size judged as a response by RECIST (≥60% rather than ≥30%) and WHO (≥75% rather than ≥50%) criteria, response correlated significantly with both RFS (P = 0.03) and OS (P = 0.02). Conclusions: In the neoadjuvant setting, which frequently involves smaller measurable lesions than the metastatic setting, larger changes in tumor size than those specified by RECIST and WHO criteria are needed to predict postoperative outcome.

No significant financial relationships to disclose.
Incidence of therapy-related leukemia following chemoradiotherapy for esophageal cancer
Authors: Tsujimura H. , Mimura N. , Ise M. , Sakai C. , Shimada H. , Nagata M. , Kumagai K.
Published: August 2020

e15663

Background: The combination of chemotherapy and concurrent radiotherapy (CRT) has recognized as a curative alternative for several stage of esophageal cancer. On the other hands, a sufficiently long survival time has increased treatment-related late toxicities. However, the frequency and the pathogenesis of secondary malignancies that is the most serious late-onset complication are still unclear. Methods: From July 2000 to March 2008, 348 patients with esophageal squamous cell carcinoma underwent CRT. All patients received chemotherapy consisting with nedaplatin (80 mg/m2, div day1) and fluorouracil (700 mg/m2, ci day 1–5) and concurrent long T field irradiation (2 Gy daily, up to 30 Gy). A hundred patients received a single course as the neoadjuvant setting. Two cycles of CRT as the definitive or palliative setting were administered in 248 patients. Median and average follow-up durations are 8 and 21 months (1 to 92), respectively. Results: Four patients, who achieved CR after CRT, developed leukemia. Case1, 60-yo-male, developed overt acute myeloid leukemia (AML) from myelodysplastic syndrome 48 months after CRT. Cytogenetic analysis showed complicated abnormalities including deletion 5q. Case2, 64-yo-male, developed AML M0 with t(9;22)(q34;q11) 44 months after CRT. Case3, 72-yo-male, developed Burkitt leukemia with t(8;14)(q24;q32) 19 months after CRT. Case4, 65-yo-male, developed myeloid crisis of chronic myelogenous leukemia with complicated abnormalities including t(9;22)(q34;q11) 48 months after CRT. Case 1 and 3 had localized disease and received single course of neoadjuvant CRT. Case 2 and 4 had advance disease and received 2 courses of CRT. All patients eventually died of leukemia. Conclusions: Since platinum and fluorouracil have shown relatively low chance of secondary neoplasm, our data demonstrates that the concurrent radiotherapy which involves massive bone marrow tissue may increase the risk of leukomogenesis. To this end, atypical cytogenetic abnormalities seen in the present cases give a new insight into the biology of therapy-related leukemia. Notably, this is the first report presenting the incidence of secondary leukemia by nedaplatin.

No significant financial relationships to disclose.
S-1 monotherapy for the treatment of elderly patients with advanced gastric cancer
Authors: Lim J. , Kim J. , Yi H. , Kim H. , Lee M. , Kim C.
Published: August 2020

e15671

Background: Elderly patients have often been excluded from clinical trials and only limited data are available regarding treatment of these patients. The efficacy of S-1 chemotherapy for elderly patients with advanced gastric cancer (AGC) is not well investigated. The aim of this study is to evaluate the efficacy and safety of S-1 monotherapy in elderly patients with AGC to whom conventional chemotherapy is difficult to deliver. Methods: From January 1, 2007 to August 31, 2008, a total of seventeen patients older than 70 were given S1 monotherapy. They received S-1 at a dose of 40mg/m2 BID either every 3 weeks (2 weeks on, 1 week off) or every 6 weeks (4 weeks on, 2 weeks off). Response was assessed according to RECIST criteria. Results: The patients consisted of 11 men and 6 women whose median age was 77 years (range: 71–83) with their performance status in 1 to 2. Five patients had recurrent AGC and the other 12 patients metastatic AGC at the time of diagnosis. Total 89 cycles of S-1 chemotherapy were given (median 4 cycles, range 2–12). Fifteen patients were evaluable for response because of early death in 2 patients. Response rate was 17.6% (95% Condifence Interval, 0 to 35.7); Complete remission in 0, partial remission in 3 (17.6%) and stable disease in 5 patients (29.4%). At a median follow up of 9.7 months (range: 8–11.4), median progression free survival was 5.1 months (range: 3.5–6.7) and overall survival was 9.5 months (range: 5.6–15.5). Most of the adverse effects of S1 monotherapy did not extend beyond grade 3. Grade 3 or 4 non- hematologic toxicities were not frequent and were easily manageable except in two, one of whom died of neutropenic sepsis and the other who died of subdural hemorrhage in grade 4 thrombocytopenia. Conclusions: S1 chemotherapy showed modest efficacy in elderly patients with AGC. The hematologic toxicity should be cautiously monitored in these elderly patients to avoid fatal events. Further studies are warranted for optimal management of elderly patients with metastatic or recurrent AGC.

No significant financial relationships to disclose.
Prevalence of depression, sleep-related disturbances, and anxiety and their effect on quality of life in patients with adenocarcinoma of the pancreas
Authors: Brown D. , Boyd A. , Henrickson C. , Hampton J. , Almani F. , Ben-Josef E. , Zalupski M. , Simeone D. , Taylor J. , Armitage R. , Riba M.
Published: August 2020

e15678

Purpose: To evaluate the prevalence of depression, sleep related disturbances and anxiety and their effect on quality of life in patients with recently diagnosed adenocarcinoma of the pancreas who present to a multidisciplinary pancreatic cancer clinic. Methods: Cross-sectional and longitudinal psychosocial distress was assessed utilizing Personal Health Questionnaire 9 (PHQ9) to screen for depression and monitor symptoms during the course of care, the Penn State Worry Questionnaire (PSWQ) for generalized anxiety, and the Sleep Problems Questionnaire 4 (SPQ4)/ University of Michigan Sleep Questionnaire to monitor sleep symptoms. Patients were evaluated at their intake consultation and at subsequent follow up visits. Results: 24 patients (pts; mean age 66 years, 48% females) consented to participate during the 6 month pilot study with longitudinal follow up for 13. The PHQ9 scores on presentation revealed mild to moderate depressive symptoms in 54% (13 pts) of pts and moderately severe depressive symptoms in only 8% (2 pts). A minority (2 pts, 8%) had PSWQ scores characteristic of an anxiety disorder, while 33% (8 pts) had moderate anxiety scores. Only 3 pts (12.5%) scores revealed a clear sleep problem; 10 pts, (41.67%) had no sleep problem and 10 pts had a potential sleep problem. Due to the limited follow up, a statistical difference in scores over time was not observed. Conclusions: Our results indicate that mild to moderate depressive symptoms, anxiety and potential sleep problems are common in patients referred to a multidisciplinary pancreatic cancer clinic. Moderately severe depressive symptoms, severe anxiety and clear sleep problems are not as prevalent as is generally believed. To better characterize the relationship of depression (and potential causes) with pancreatic cancer, additional prospective longitudinal studies are needed.

No significant financial relationships to disclose.
HER-2/Neu overepression in gastric cancer
Authors: Vergara R. , Torrazza I. , Castillo Fernandez O.
Published: August 2020

e15679

Background: Gastric cancer is one of the most frequent causes of cancer-related deaths in the world.Overexpression of human epidermal growth factor receptor 2 (HER-2) has been shown to be a significant negative prognostic variable, with estimates ranging from 6- 35%. This is the first study done in our country regarding HER-2 overexpresion in gastric cancer. Methods: 90 cases with histologic diagnosis of gastric cancer were reviewed, in the period between October 2007 and July 2008. Formalin-fixed paraffin- embedded gastric cancer specimens were tested for HER-2 status using Herceptest (Dako). They were analyzed with HER-2 scores for gastric cancer. Other parameters evaluated were: demographic, clinical, histological characteristics, and treatment administrared. Results: The average age of our patients was 60.3 ± 15.8 years, with similar gender distribution. The more frequent symptoms of presentation were loss of weight (68.9%) and dyspepsia (58.9%). The most frequent anatomical location was the antrum (32%). HER-2 overexpression was 5.6% (four cases of intestinal type and one case of diffuse type). 63.3% of the patients presented with clinical stage IV, which is associated with worse survival (p< 0.001). 40% of the patients underwent complete surgical excision of the neoplasia, from which 44% received adjuvant chemotherapy and radiotherapy. 52.2% of the patients had already died when developing this study. Conclusions: The majority of our patients presented with advange stage at the time of diagnosis, HER-2 overexpression was 5.6%. There was no statistical significance when comparing it with the histological type, nor survival (p= 0.086).

No significant financial relationships to disclose.
Treatment outcome and survival for patients (pts) with sarcomatoid-variant metastatic renal cell carcinoma (RCC): Memorial Sloan-Kettering Cancer Center (MSKCC) experience
Authors: Molina A. M. , Tickoo S. K. , Ishill N. , Trinos M. J. , Schwartz L. H. , Russo P. , Feldman D. R. , Patil S. , Motzer R. J.
Published: August 2020

e16017

Background: Sarcomatoid-variant represents a spindle cell phenotype of RCC that can be present in any subtype, usually showing aggressive biological behavior. MSKCC experience was studied to provide data on outcome and survival to systemic therapy for metastatic, sarcomatoid-variant RCC. Methods: Clinical features, treatment outcome and survival were reviewed in 63 pts with sarcomatoid-variant metastatic RCC from a database of 650 pts treated at MSKCC with systemic therapy (cytokines, anti-angiogenesis targeted therapy and chemotherapy). Response to therapy, progression-free survival (PFS), and overall survival (OS) was determined for pts based on their first treatment at MSKCC. The percentage of sarcomatoid component in the tumors was assessed. Results: Histology subtypes with sarcomatoid-variant among the 63 pts included 46 clear cell, 5 papillary, 5 chromophobe, 1 collecting duct, and 6 unclassified. 60 pts had prior nephrectomy. MSKCC risk group distribution was 37% good risk, 59% intermediate risk, and 5% poor risk. 34 pts received targeted therapy (29 sunitinib, 3 sorafenib, 2 temsirolimus), 20 pts received cytokine therapy (19 interferon, 1 interleukin) and 9 received other therapies. 5/63 pts achieved an objective response: 1/19 to interferon and 4/29 to sunitinib. In 63 pts, median PFS was 3 months (95% CI 2–4) and median OS was 10 months (95% CI 8–14). Differences in PFS were observed based on therapy (sunitinib vs. all other) and histology (clear cell vs. non-clear cell). The median PFS for sunitinib therapy was 4.4 months (95% CI 2.2–6.7) versus 2 months (95% CI 1.7–2.7) for all other therapies (p = 0.02); and 3 months (95% CI 2.3–4.5) for clear cell versus 1.6 months (95% CI 1.0–2.1) for non-clear cell histology (p = 0.007). In a subset (n = 31) with available specimen, the median % sarcomatoid content was 20% (range 2%-100%). No difference in PFS or OS was observed according to % sarcomatoid content. Conclusions: Metastatic sarcomatoid-variant RCC is associated with a poor prognosis. Sunitinib resulted in a modest response rate and longer PFS versus other therapies. Studies to assess outcome, characterize tumor biology, and develop novel treatment strategies are warranted.

[Table: see text]
Outcome of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with systemic therapy without cytoreductive nephrectomy (CN)
Authors: Richey S. L. , Culp S. H. , Wood C. G. , Corn P. G. , Jonasch E. , Tannir N. M.
Published: August 2020

e16035

Background: Targeted therapies (TT) have replaced cytokines in the management of pts with mRCC. CN has been incorporated in the management of pts with mRCC but many pts are not suitable candidates for CN. The median overall survival (OS) time of pts treated with interferon alfa (IFN-α) without CN was 7.8 months (mos) [Flanigan et al. Journal of Urology 2004]. The median OS time for pts with mRCC treated with TT sequentially without CN is unknown. Methods: We retrospectively reviewed the medical records of pts with mRCC who did not undergo CN and who received one or more TT (bevacizumab, sorafenib, sunitinib, or temsirolimus) sequentially for at least one month with or without chemotherapy (gemcitabine + capecitabine or 5-FU). We calculated OS time from date of diagnosis until date of death or last follow up. We excluded pts who had embolization, radiofrequency ablation or cryotherapy of the primary tumor. Results: We identified 88 pts between Jan 2002 and Dec 2007. Median follow-up time is 9.7 mos (range: 1.2–49.2). Median OS time for all pts is 10.7 mos (95% CI: 7.6–15.4). 55 pts (62.5%) had clear-cell and 33 (37.5%) had non-clear cell histology, with median OS times of 15.1 mos (95% CI: 9.6–17.7) and 7.4 mos (95% CI: 4.4–13.0), respectively. ECOG performance status (PS) at time of diagnosis was correlated with OS (HR 1.54; 95% CI: 1.16–2.05; p<0.01). Pts with PS 0, 1, 2, and 3 had median OS times of 22.8 mos (95% CI: 5.7,*), 16.5 mos (95% CI: 8.1–24.7), 7.6 mos (95% CI: 5.7–11.9), and 7.1 mos (95% CI: 3.3–9.6), respectively. Pts with clinical evidence of lymph node (LN) involvement had worse outcome,with median OS time of 7.6 mos (95% CI: 5.6–9.8) versus 17.2 mos (95% CI: 9.8–35.5) for pts without clinical evidence of LN involvement. Conclusions: In this analysis, median OS time for pts with mRCC treated in the modern era with TT without CN is superior to historical experience with IFN- α.Compromised PS, LN involvement, and non-clear cell histology were associated with worse outcome. This data is useful in the design of randomized trials investigating the role of CN in mRCC.

[Table: see text]
Cardiovascular events (CVEs) associated with tyrosine kinase inhibitor (TKI) therapy in patients with metastatic renal cell carcinoma (mRCC) at a regional cancer center
Authors: McGhie J. , Mackenzie M. J. , Winquist E. , Ernst S. , Sax L. , O'Brien P.
Published: August 2020

e16040

Background: Recent studies suggest the incidence of CVEs associated with TKIs has been underestimated. Phase III trials have reported low incidences of heart failure, cardiac ischemia and hypertension. A recent observational study reported that one third of patients taking sunitinib or sorafenib experienced a cardiovascular event often without symptoms. We assessed the incidence of CVEs in mRCC patients who received TKIs at our centre. Methods: Eligible mRCC patients were identified from a mRCC database between January 2006 and November 2008. Data was retrospectively extracted including age, sex, diagnosis, histology, past cardiac history, cardiac risk factors, number and type of TKI regimens, and CVEs. A CVE was defined as unexplained death, acute coronary syndrome (ACS), heart failure, or arrhythmia requiring intervention. We also identified any new or exacerbated cases of hypertension after the start of TKI therapy, as a CVE. Results: Eighty-five eligible patients were identified. Average age was 61 years (range, 23–78), 72% were male and 80% were clear cell in origin. A total of 31 CVEs occurred in 28 patients (33%). These events occurred at a median of 5 weeks of TKI therapy (range, 1 - 64 weeks). There were 8 cases of ACS, 2 of heart failure, 2 of arrhythmia, and 3 unknown causes of death. Only 2 of these particular CVEs were associated with new or increased hypertension. There were 16 cases of hypertension alone. Those who had CVEs had a higher mean number of cardiac risk factors. They were also more likely to have an echocardiogram during treatment, and less likely to receive sorafenib following sunitinib. Conclusions: Our study suggests a lower rate of CVEs than recent studies, but the true rate may be underestimated, as routine cardiac studies were not performed in all patients. Rational surveillance strategies for patients receiving TKI therapies should be developed. Prospective trials should address predictive and prognostic factors for CVEs. [Table: see text]

[Table: see text]
Vaccination with survivin and PSMA-derived peptides for controlling biochemical recurrence in prostate cancer: A pilot study
Authors: Valdagni R. , Marrari A. , Squarcina P. , Villa S. , Filipazzi P. , Salvioni R. , Rancati T. , Asioli M. , Parmiani G. , Rivoltini L.
Published: August 2020

e16042

Background: A significant percentage of patients (pts) progress after first line treatment of prostate cancer (PCa). We present preliminary results of pilot study using a multiple peptide-based anti-tumor vaccine. Methods: A phase I-II trial of vaccination (vax) with HLA-A*0201-restricted peptides from PSMA and Survivin was carried out in 20 pts with b-failure after surgery or radiotherapy (mean pre-vax PSA: 1.83 ng/ml). Vax consisted of two peptides from PSMA (PSMA4–12 and PSMA711–719) and one from Survivin (SVV96–104/97M) given by 4 fortnightly (priming) and 4 monthly administrations (boosting). To selectively eliminate regulatory T cells (Treg) and possibly enhance immunization, peptides were preceded by low dose cyclophosphamide (CTX, 300 mg/mq, i.v.). Antigen (Ag) and tumor-specific T cell responses were extensively monitored in peripheral blood together with CD4+CD25+Foxp3+ Treg frequency. PSA trend was also registered. Results: Vax was well tolerated. Most pts (19/20) showed a significant increase of SVV96–104/97M-specific T cells (mean 14 in pre-vax vs 170 in post-vax PBMC), while response to PSMA was achieved in about half of the pts and only to PSMA711–719 peptide (mean 12 in pre-vax vs 86 in post-vax PBMC). Increments of HLA-A*0201/SVV96–104/97M or PSMA711–719 multimer+ CD8+ T cells were induced in 50 and 35% pts, respectively. Vax-induced Ag-specific T cells displayed however limited cross-reactivity with HLA-A*0201+ PCa cells. No effect of CTX on Treg frequency was observed. 6 pts had no biochemical response to vax and switched to hormonal therapy, while 14/20 exhibited a significant although transient PSA decrease during vax (11 in the priming phase and 3 in boosting). Conclusions: Peptide vax could rapidly enhance Ag-specific immune responses in most treated pts. However, the reduced ability of vax-induced Ag-specific CD8+ T cells to cross-recognize PCa cells, together with their low frequency in PBMC, could explain why PSA control was achieved only transiently and in strict dependence with vax administration. Anti- tumor vax represent a useful tool for controlling PCa biochemical recurrence in the absence of major side effects, but immunization protocols inducing efficient tumor cell killing still need to be identified.

No significant financial relationships to disclose.
Differential protein expression profiling by iTRAQ-2DLC-MS/MS of human bladder cancer EJ138 cells transfected with the metastasis suppressor KiSS-1 gene
Authors: Grau L. , Ruppen I. , Gil M. , Piulats J. M. , Bellmunt J. , Ashman K. , Ecke T. , Sanchez-Carbayo M.
Published: August 2020

e16043

Background: The use of isobaric tags for relative and absolute quantization (iTRAQ) followed by multidimensional liquid chromatography (LC) and tandem mass spectrometry (MS/MS) analysis is emerging as a powerful methodology for biomarker and drug target discovery. KiSS-1 is a metastasis suppressor gene reported to be involved in the progression of several solid neoplasias. The loss of KiSS-1 expression has been shown to be inversely correlated with increasing tumor stage and poor overall survival in bladder tumors. In order to identify the molecular pathways associated with the metastasis suppressor role of KiSS-1 in bladder cancer, we carried out a proteome discovery analysis using an iTRAQ approach. Methods: Bladder cancer cells (EJ138) were transiently transfected with a vector encompassing the full length KiSS-1 gene. Protein extracts collected after 24h and 48h transfection were fractionated, digested with trypsin and treated with iTRAQ reagents. The labelled peptides were separated through Strong Cation Exchange (SCX) and Reversed Phase LC and analysed by MALDI TOF/TOF MS. Several software packages were utilized for data analysis: ProteinPilot, Protein Center for gene ontology (GO) analysis and Ingenuity Pathway. Results: Comparative analysis among transfected, mock and empty vector exposed cells have identified more than 800 proteins with high confidence (>99%), showing high correlation rates among replicates (>70%). The involvement of the identified proteins in biological networks has served to characterize molecular pathways associated with KiSS-1 expression and to select critical candidates for validation analyses by Western Blot using independent transfected replicates. As part of complementary clinical validation strategies, inmunohistochemical analyses performed in metastatic bladder tumours spotted onto tissue microarrays (n = 175) have revealed the role of KiSS-1, ezrin and filamin in bladder cancer progression. Conclusions: Our proteomic study not only has served to reveal molecular mechanisms associated with the metastasis suppressor role of KiSS-1 in bladder cancer, but also to identify novel potential metastatic biomarkers for patients affected with bladder tumors.

No significant financial relationships to disclose.
Determination of efficacy of TIP combination (paclitaxel, ifosfamide, cisplatin) as first salvage therapy for patients with relapsed germ cell tumors in a poor prognosis group
Authors: Mardiak J. , Rejlekova K. , Mego M. , Rajec J. , Sycova-Mila Z. , Obertova J. , Salek T. , Reckova M.
Published: August 2020

e16049

Background: The efficacy of TIP appears to be suitable salvage therapy for patients with relapsed germ cell tumors (GCTs) with good prognostic features.The aim of our study was to determine the efficacy of TIP as first salvage therapy for patients with relapsed GCTs with poor prognostic features. Methods: Thirty seven patients with relapsed GCTs were treated with TIP as first salvage therapy. Sixteen (43%) patients had favorable prognostic features for response (testis primary tumor site and prior complete response to induction chemotherapy regimen) and 21 (57%) patients had poor prognostic features (either extragonadal site or incomplete response to induction chemotherapy regimen). Four cycles of paclitaxel (175 to 250 mg/m2), ifosfamide 6 g/m2, and cisplatin 100 mg/m2 were given 21 days apart with GC-SF support, followed by resection of resectable radiographic residua. Results: Ten (69%) out of 16 patients with good prognostic features achieved a favorable response to TIP, and all 10 (100%) patients achieved complete response (CR). Six (60%) of the favorable responses remain durable at a median follow-up of 50,6 months. 9 (43%) of 21 patients with poor prognosis achieved a favorable response to chemotherapy, from whom only 1 (10%) patient achieved CR, but 5 patients achieved durable response at a median follow-up duration of 60,6 months. Estimated 2-year overall survival rate (OS) for patients with good prognosis was 56% (95 % CI 54–100%) and 33% (95% CI 21–68%) for patients with poor prognosis. Despite this results, estimated 5-year OS was even more positive for patients with poor prognosis 19% (95% CI 15–61%) comparing to 13% (95% CI 23–80%) for patients with good prognosis. Conclusions: Demonstrated long-term survival of patients with poor prognosis in our nonrandomised study with limited number of patients refers to the TIP being suitable therapy also for patients with relapsed GCTs with poor prognosis. These results warrant the need to continue investigation of real effectiveness of TIP as a first salvage therapy even for patients with poor prognostic features.

No significant financial relationships to disclose.
Bortezomib therapy for prostate specific antigen (PSA)-only relapse after definitive local therapy
Authors: Turner J. S. , Chen C. S. , Butler W. , Bearden J. , Garrett-Mayer E. , Onicescu G. , Kraft A. S.
Published: August 2020

e16053

Background: We conducted a single arm, phase II trial of single-agent bortezomib, a proteasome inhibitor, in patients with prostate cancer with biochemical recurrence (PSA relapse) after definitive local therapy. Eligible patients had previous radical prostatectomy and/or radiation therapy (including brachytherapy), and a rising PSA over 1 ng/mL without bone scan evidence of metastasis. The primary goal of this study was to determine the PSA response to single agent bortezomib. Secondary goal was to identify the time to PSA relapse after bortezomib therapy defined as time from nadir to PSA >1ng/ml. Methods: Treatment was composed of bortezomib 1.3mg/m2 IV on days 1,4,8,11 then 10 days off for the first two cycles. The third cycle was comprised of weekly bortezomib therapy for three out of four weeks. Sixteen patients were enrolled and treated at 4 sites with13 evaluable patients. Results: Median baseline PSA was 12.0 ng/ml. 3 of 13 patients (23%) achieved complete responses and 1 a partial response (PR) for a response rate of 30% (95% CI: 0.09 –0.61). Median time to PSA relapse in these 3 patients was 6.0 months. Linear longitudinal modeling was used to compare the rate of increase in PSA prior to treatment versus during treatment with bortezomib and found that treatment significantly decreased the slope of log PSA during treatment, slowing PSA rise (p = 0.003). The major toxicity associated with bortezomib therapy was peripheral neuropathy (7 pts, grade 3 in 3 pts) requiring dose reductions in 3 cases and discontinuation of therapy in 4 patients. Other toxicities included non-neutropenic infections (shingles in 2 pts), 1 small bowel ileus (grade 3), and 1 case of thrombocytopenia (grade 3). Conclusions: In a small number of patients there was a 30% PSA response rate to single agent bortezomib therapy. Further investigations using bortezomib as a single-agent or in combination are warranted in this patient population.

No significant financial relationships to disclose.
Prognostic and predictive values of carbonic anhydrase IX (CAIX) and pathologic features in patients with metastatic clear cell renal cell carcinoma receiving targeted therapy
Authors: Choueiri T. K. , Regan M. , Oh W. , Clement J. , Amato A. , McDermott D. , Cho D. , Atkins M. , Signoretti S.
Published: August 2020

e16067

Background: Tumor Carbonic Anhydrase IX (CAIX) expression and histologic features can predict outcome in patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy. We sought to investigate the prognostic and predictive utility of such features in patients receiving VEGF-targeted therapy. Methods: We identified 118 patients with mRCC initiating first- line VEGF-targeted therapy including 94 with clinical data, clear cell histology and available tissue. Tumors were evaluated for specific histologic features and for CAIX expression by immunohistochemistry using the MN75 antibody. The relationship between these pathology findings and tumor shrinkage and other treatment outcomes was assessed. Results: Higher tumor clear cell component was independently associated with greater tumor shrinkage (p=0.02), response (p=0.02) and treatment duration (p=0.02). Patients with high vs. low tumor CAIX expression had mean tumor shrinkages of -12% vs. -5%, respectively (p=.38). There was heterogeneity in tumor responsiveness to sunitinib or sorafenib according to CAIX status (p=0.055 for interaction): mean shrinkage was -17% vs. -25% (mean difference +8%, 95% CI -14% to +31%) for sunitinib-treated patients with high vs. low tumor CAIX expression compared to -13% vs. +9% (mean difference -22%, 95% CI -42% to -1%) for sorafenib-treated patients. Conclusions: Patients with higher clear cell component in their tumors are likely to experience superior clinical benefit from VEGF-targeted therapy. Although CAIX expression was not found to be of prognostic value in patients with clear cell mRCC treated with VEGF-targeted therapy, it may be a predictive biomarker for response to sorafenib treatment.

[Table: see text]
Microvesicular-mediated gene transfer of prostate tumor markers
Authors: Renzulli J. F. , Dooner G. , Owens C. , Colvin G. , Dooner M. , Del Tatto M. , Goldstein L. , Quesenberry P.
Published: August 2020

e16076

Background: Microvesicles have been a subject of research for many years. Recent work has focused on the potential for cancer vaccines via microvesicles. It has also been demonstrated that various cell-specific phenotypes can be transferred from one cell type to another through microvesicle transfer. Studies in our laboratory have demonstrated that co-culture of murine lung tissue with marrow cells across a cell impermeable membrane can induce elevations in lung-specific mRNA expression in human donor marrow stem cells. Our objective is to determine whether there is transfer of genetic or transcriptional factors via microvesicles from human prostate cancer cells to fresh human marrow cells. Methods: Fresh prostate tissue was harvested from surgical specimens following radical retropubic prostatectomy. Samples were histologically confirmed to contain prostatic adenocarcinoma. Co-cultures were established using a transwell system in which 0.05–0.100 grams of prostate tissue was minced and co-cultured with 1–3 million normal, human donor marrow cells for 2–7 days. Marrow not co-cultured with tumorserved as a control. Target cells were collected and total RNA was analyzed for prostate-specific gene expression byReal Time RT-PCR. Fold differences in expression of the genes were analyzed, using TaqMan®, gene assays (Applied Biosystems) and were expressed in relation to the marrow control. Results: We have observed significant increases in gene expression in marrow cells co-cultured with prostate tumor cells (Gleason grades 6–9). Variable increases in expression were seen in 3 patient samples, as high as 7-fold for ERG, greater than 10-fold for ACPP and greater than 100-fold for STEAP, PART, TMPRSS2, PSCA and ETV1. Conclusions: These studies demonstrate that prostate specific genes are present in fresh human marrow cells after co-culture with tumor tissue. This establishes a base to begin evaluating the significance of microvesicle-mediated genetic transfer, mechanisms of transfer and therapeutic options for blocking or manipulating such transfer to influence the disease process.

No significant financial relationships to disclose.
A phase I/II trial of gefitinib given concurrently with radiotherapy in patients with nonmetastatic prostate cancer
Authors: Joensuu T. K. , Joensuu G. , Nokisalmi P. , Reddy C. , Isola J. , Ruutu M. , Kouri M. , Kupelian P. , Hemminki A.
Published: August 2020

e16079

Background: We estimated the safety and tolerability of 250 mg gefitinib q.d. given concurrently with three- dimensional conformal radiotherapy (3D-CRT) in patients with non-metastatic prostate cancer (PC). Methods: 42 patients with T2/T3N0M0 PC were treated in a single centre, non-randomized study (study code ZD1839/IL0118). PSA<20 and good performance status (WHO 0–1) were required. Adjuvant or neo-adjuvant hormonal treatments were not allowed. 250 mg gefitinib q.d. was started one week before and lasted for the duration of radiation therapy. 50.4 Gy (1.8 Gy/day) of 3D-CRT was administered to the tumor, prostate and seminal vesicles, followed by a 22 Gy booster (2 Gy/day) for a 72.4 Gy total dose. EGFR expression, presence of EGFRvIII and activated pEGFR were studied. Levels of serum TNF, IL-1 α and IL-6 were also evaluated. Results: Maximum tolerated dose was not reached in phase I (12 patients) and 30 additional patients were treated in phase II. Thirty (71.4%) patients completed trial medication and 12 (28.6%) prematurely discontinued because of adverse events. Dose-limiting toxicities were recorded in 16 (38.1%) patients, the most common of which was grade 3–4 transaminase increase (6 patients). After median follow-up of 38 months nobody had died of PC. The estimated PSA-free survival rate at 4 years (Kaplan-Meier) was 97%, hormone-free survival 91% and overall survival 87%. These figures compared favourably with matched, non-randomized patients treated with radiation only. Data on biochemical analyses will be presented. Conclusions: The combination of gefitinib and radiation is reasonably well tolerated and has promising activity in non-metastatic PC. A randomized study is being discussed for evaluating the efficacy of the approach.

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Sensitivity and specificity of osteopontin (OPN) versus prostate-specific antigen (PSA) in prostate carcinoma (PCa): A case- control study
Authors: Libener R. , Montefiore F. , Bonini F. , Ruggero L. , Maffezzini M. , Puntoni M. , Nanni L. , Paganuzzi M. , Puntoni R. , Betta P.
Published: August 2020

e16082

Background: OPN is a secreted adhesive glycoprotein overexpressed in human cancers. A stimulatory effect of OPN on human PCa cells in vitro has been demonstrated. This study intends to determine if measuring serum OPN and PSA levels can provide informative markers for the detection of PCa. Methods: Serum total PSA using a chemiluminescent immunoassay system (Hybritech PSA, DxI Beckman Coulter, Inc.) and plasma OPN using an ELISA technique (R&D Systems, Inc.) were measured in 263 male subjects referred for diagnostic prostate biopsy, including 167 control patients with benign prostate pathology (mean age: 65.30; median age: 66; SD: 6.80; range 46–83) and 96 PCa patients (mean age: 66.80; median age: 68; SD: 7.90; range 47–86). Sensitivity and specificity were determined for each marker. The relationship between sensitivity and specificity was profiled by receiver operating characteristic (ROC) curves of OPN and PSA. Results: Both markers levels were higher in PCa patients (OPN 51.98 ng/ml, SD 32.64, range 5.9–169.54; PSA 12.91 ng/ml, SD 14.73, range 1.69–90) than in controls (OPN 49.93 ng/m, SD 27.78, range 4.15–146.34; PSA 8.04 ng/ml, SD 5.94, range 0.46–45), although the elevation was significant (p<0.001) for PSA but not for OPN (p=0.59). The increase of serum OPN level paralleled the increase of the tumour size, defined by the T stage, and was more striking for T ≥2 PCa than for T1 PCa. The increase of PSA, related to the tumour size, was less evident and was observed only in high stage (T3) tumours. The ROC curve showed that OPN was not a marker that enabled the discrimination between PCa and non-cancer patients. For PSA, a cut-off value of 4 ng/ml had a sensitivity of 93% with a specificity of 13%. A cut-off value of 5 ng/ml resulted with a sensitivity of 85% and specificity of 26%. Conclusions: OPN and PSA are not correlated and therefore their combined evaluation in a larger study group could provide a novel insight into the natural history of PCa. A follow-up of the patients involved is ongoing in order to assess a possible prognostic role of the two markers. (The study was funded by the Alessandria branch of the Italian League against Cancer through a grant from the Cassa di Risparmio di Alessandria Foundation)

No significant financial relationships to disclose.
Protein profiling of tumor tissues by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to discriminate between localized and metastatic renal cell carcinoma
Authors: Kamai T. , Tomosugi N. , Abe H. , Yoshida K.
Published: August 2020

e16098

Background: We previously reported that mRNA of interferon-alpha receptor type 2 (IFNAR2) was upregulated in metastatic and IFN-a resistant renal cell carcinoma (RCC) in comparison to localized RCC or metastatic tumors with good response to IFN-a (BMC Cancer, 2007). We speculated potential different molecular mechanism between above two groups. Protein profiling using human tumor tissues may give insight into cellular pathways leading to carcinogenesis and metastasis in RCC. Methods: We examined mRNAs expression for IFNAR2 in paired tumor and non-tumor samples from the surgical specimens of Japanese patients with RCC using a real-time reverse transcription polymerase chain reaction. Then we selected representative five IFNAR2 upregulated clear cell carcinomas cases with metastatic tumor, five IFNAR2 upregulated metastatic sarcomatoid carcinomas, and five normal expression clear cell carcinomas with localized tumor. We investigated protein profiling in the tumor tissues of above three groups using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) coupled with IMAC-Cu chips. Results: For hierarchical clustering analysis, we used the 25 peaks which revealed significant differences in single-marker analysis in the range from 1,500 to 10,000 m/z. The heat map analysis based on the clustering distinguished completely metastatic tumors with IFNAR2 upregulated groups from localized tumors with IFNAR2 normal expression group. Furthermore, the heat map discriminated metastatic sarcomatoid carcinomas from metastatic clear cell carcinomas with a sensitivity of 100% and a specificity of 80%. Conclusions: SELDI-TOF MS profiling of tumor tissues can be applied to differentiate patients with three types of RCCs. Our findings may reflect different molecular mechanism between localized and metastatic carcinomas, and the different response to immunotherapy with IFN-α. This may shed light on the potential therapeutic strategy for IFN-α treatment. However, further investigation is required to verify the usefulness of this method in clinical practice.

No significant financial relationships to disclose.
Characterization of lymphoid infiltrates in prostatectomy specimens post neoadjuvant hormonal therapy using quantitative immunofluorescence and RNA FISH
Authors: Donovan M. J. , Khan F. , Powell D. , Capodieci P. , Gleave M. , Taylor I. , Gomez-Navarro J. , Cordon-Cardo C.
Published: August 2020

e16104

Background: Immunotherapy for advanced prostate cancer requires an understanding of the host response including lymphocyte subsets and cytokine expression. Using quantitative immunofluorescence (IF), image analysis and RNA FISH we examined a series of prostatectomy specimens from patients, ± neoadvjuvant hormonal therapy (NHT) and determined their baseline immune characteristics. Methods: CD4,8,25,45,68,69,86 and Foxp3 were evaluated by IF and IFNg with RNA FISH on prostatectomy specimens from 40 patients with T1c-T3 prostate cancer; 20 control and 20 post long-term NHT. Sections were analyzed with three multiplex IF assays, triplicate images acquired with spectral imaging, digitally masked and processed with IF image analysis software. IFNg RNA transcript localization was performed on all 40 patients using published protocols. Results: There was a predominance of CD8 in both control and NHT patients with a high but variable level of CD86 and 69 across the entire cohort, reflecting T cell activation. CD68 appeared reduced in NHT, but this change was not statistically significant. Number of Treg (CD4+/CD25+/Foxp3+) cells were similar between groups; however, in NHT an increased Treg population was associated with an elevated preoperative PSA compared with controls (p<0.05). IFNg transcript activity was low in the entire cohort and limited to tumor epithelial cells. Conclusions: The prominent CD8 expression and low level of IFNg in both control and NHT groups suggest an ongoing but not overly active immune response. Multiplex IF and in situ RNA FISH are useful tools for developing a disease phenotype and provide the necessary parameters for evaluating gene-protein expression especially in pharmacodynamic studies.

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Sequential and intermittent docetaxel (D) and imatinib (Im) in hormone-refractory prostate cancer patients (NYU 04–47)
Authors: Gómez-Pinillos A. , Ballard H. , Shelton G. , Reilly M. M. , Chachoua A. , Taneja S. , Ferrari A. C.
Published: August 2020

e16108

Background: Platelet-derived growth factor is frequently expressed in advanced prostate cancer (PC) lesions where it supports PC cell growth and neo-angiogenesis. Im. is a PDGF inhibitor that blocks cell cycle in G1-S due to MEK/erk inhibition. D blocks cell cycle progression in G2-M. Sequential block of the cell cycle progression in G2-M followed by G1-S may increase anti-tumor responses. The phase II study dose of sequential D on day 1 and Im started 24–36h later given daily for 14 d was established in a previous phase I. Methods: Eligibility: at least 2 prior hormone manipulations and up to one prior chemotherapy, PSA>5ng/ml, ECOG PS 0–2. Treatment schedule: D 70mg/m2 day 1 followed 24–36 hours later by Im 600mg PO daily × 14 days. Cycles were repeated every 21d until toxicity or progression. Pegfilgrastim was given each cycle for neutropenia prevention. A two steps design was planned to assess activity (PSA decline >50% and/or measurable or symptomatic response) and tolerance including interim analysis to determine if 37 patients (pts) should be enrolled. Results: Of 15 pts enrolled, 13 had metastasis and 5(33%) received prior chemotherapy. There were 98 cycles of trial therapy administered and 9 events (PSA or bone progression) registered at the time of analysis. Median baseline PSA 73,5ng/ml (2.1–1954.3). Median follow-up estimated by inverse Kaplan Meier: 308 days (CI95%, 133–482). Median of cycles administrated 6 (1–12). PSA decline >50% observed in 7/15pts (46.67%) of which 3 was >80% (20%). PSA decline <50%, observed in 6/15(40%). 2/15(15.3%) were non-responders. Pain scores improved in all symptomatic pts. Median duration of response was 162 days (42- 281). Estimated median progression free survival by Kaplan-Meier was 155 days (CI95%, 80–339). Toxicity: there was G1–2 fatigue, anorexia, weight change in 66% pts; nausea, vomiting, taste changes in 66% pts, anemia in 46% and neuropathy in 46% pts. G3 fatigue in 2 pts, neuropathy and CHF in 1 pt. No G4 toxicities were observed. Conclusions: Sequential and intermittent D every 21 days and Im for 14 days is tolerable and active by PSA decline and symptomatic improvement. Compared to previous report with weekly D and continuous Im, this alternative schedule appears to have similar activity with better tolerance.

[Table: see text]
Prognostic role of somatostatin receptor subtypes in human prostate cancer
Authors: Gernone A. , Pagliarulo V. , Trabucco S.
Published: August 2020

e16120

Background: Neuroendocrine differentiation (NED) in prostate carcinoma (PC) is frequently detected by immunohistochemistry as single cells in conventional adenocarcinoma. NED of PC correlates with poor prognosis and tumor progression during androgen-deprivation therapy. The aim of our study was to correlate the expression of somatostatin receptor (SSTR) 1, 2, 3, 4, 5 subtypes in primary PC with NED pattern and Overall Survival (OS). Methods. PC tissues were reviewed from 100 pts who had undergone biopsy or radical prostatectomy for previously untreated advanced or metastatic PC from 2002 to 2007. 24 samples expressed hystologically chromogranin A (CgA), a marker of NED expression. Patient characteristics included: median age 68 years (range 45–83), median baseline PSA: 70 ng/ml (range 0.3–200), median ECOG Performance Status: 1 (range 0–2), Gleason score ≥ 7, medium serum level of CgA was 56.2 nmol/L (range 0.5–120). Results: The expression of SSTR subtypes (1, 2, 3, 4, 5) were investigated and our data identified four histological features. SSTR1 was expressed in 4/24 samples, SSTR 5 was detected in 2/24 samples, both SSTR1 and SSTR5 were found in 6/24 samples. OS at last follow up on July 2008 was 60%. SSTR 1–5 were undetectable in 12/24 pts with more aggressive clinical course and the OS was < 10%. The PSA and CgA levels were not correlated with clinical outcome. SSTR subtypes 2, 3 an 4 were not expressed in all 24 samples. Conclusions: SSTRs expression significantly correlated with OS. The absence of SSTR 1 and 5 in more aggressive disease could represent a growth advantage in NED prostate cancer. SSTRs and somatostatin analogs are potential targets for prostate cancer treatment.

No significant financial relationships to disclose.