bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of the serine proteases inhibitor gabexate mesylate (GM) on the activity of gemcitabine (G) in cell lines of pancreatic cancer (PC)
Authors: Brandi G. , Paterini P. , Tavolari S. , Da Pozzo G. , Nobili E. , Di Cicilia R. , Di Marco M. , Pantaleo M. , De Rosa F. , Biasco G.
Published: August 2020

e15645

Background: Negligible advances for PC treatment have been done over the last decade and G remains the standard. Proteolitic degradation of extracellular matrix (ECM) is essential for early local invasion, metastasis and desmoplastic reaction characterizing PC. Differently from MMPs, the serine proteases (uPA and TAT) action is earlier and larger, degradating not only ECM, but also basement membrane, and activating trypsin, plasmin, angiogenesis via TGF-β1 and proliferation via PAR-2. GM is an inhibitor of u-PA,TAT, trypsin and plasmin, used in Italy and Japan for prophylaxis of acute pancreatitis after ERCP. In a previous study, GM demonstrated antinvasion and antimetastatic activity. Study aim: to evaluate if GM increases G efficacy on pancreatic cancer cell line. Methods: In vitro study of phenotypic effects of GM and G in poor differentiated PANC-1 PC cell line using:1) Cell vitality test (Trypan blu);2) Invasion test (Matrigel invasion assay);3) Cell cycle analysis (cytofluorimeter);4) Antiangiogenic test (tube formation assay in extracellular matrix using E.A.hy926 endothelial cells with matrigel). Different doses of G and GM (100,200,250,500 μM;1mM) alone or combined (concomitant or sequential) have been tested vs controls (PANC-1 without any treatment). All tests have been done in triplicate. Results: G alone (250 μM) decreases invasion by 40% (±5,6%) and cell vitality by 15% (±1,3%.). GM alone (100 μM) decreases invasion by 30% (±4,6%.) but 1mM is needed for similar vitality decrease. GM+G together are detrimental vs G alone while sequential treatment (GM before G with or without 24 hours of interval) enhances G activity. GM (200 μM) and G (250 μM) in immediate sequence show better results decreasing ability of invasion by 75% (±8,3%). Cell vitality is better inhibited from GM (100)/G (250) 24 h-delayed sequence by 28% (±3,8%). Combined treatment mainly blocks cells in G1 phase of cell cycle (5%±0,5%) vs controls. Concerning antiangiogenic assay, the administration of G alone is ineffective to inhibit angiogenesis, while pre-treatment with GM results in a strong anti-angiogenic effect. Conclusions: Association of GM to G could represent a new effective approach to inhibit invasion, angiogenesis and growth in pancreatic cancer.

No significant financial relationships to disclose.
The clinical significance of oophorectomy in gastric patients
Authors: Song H. , Kim J. , Do Y. , Lee W. , Ryu S. , Kim I. , Sohn S.
Published: August 2020

e15646

Background: The oophorectomy in isolated metastasis of ovary can lead to long term survival in patients with gastric cancer, but the clinical significance of oophorectomy in stage IV gastric cancer patients is not known well in this time. Methods: We reviewed the medical record of the 55 gastric cancer patients who were metastasis or recurrent in ovary at Dongsan Medical Center, Kimyung University School of Medicine, Daegu, Korea from 1985 to 2008. Results: Twenty-one patients were metastasis to ovary at the time of diagnosis of gastric cancer, and 34 patients were recurrent in ovary after the gastric resection. The mean age was 45.3 ± 11.6 years in metastatic cancer and 46.8 ±12.6 years in recurrent cancer patients. The stage at the time of gastric resection in 34 recurrent patients were I in 3, II in 1, III in 18, and IV in 10. Adjuvant chemotherapy were performed in 26 (76.5%) patients. Oophorectomy were performed in 33 (97.1%) of recurrent cancer, and 17 (81.0%) of metastatic cancer. The 1-year and 2-year survival rate of metastatic cancer were 14.7%, and 0%, and 1-year, 2-year, and 3-year survival rate of recurrent cancer were 47.2%, 18.1%, and 0%, respectively. The median survival duration of metastatic cancer were 8.9 ±1.0 months, and recurrent cancer were 11.4 ±2.3 months. Recurrent cancer were better survival than metastatic cancer patients (p=0.014). The long-term survival (over 2 years) was noted in 5 patients of recurrent cancer patients. The stage of gastric cancer was correlated to overall survival time in total patients (p=0.028). But, the relapse-free survival time after gastrectomy is the only factor to predict survival duration after oophorectomy in recurrent cancer patients (p=0.029). Age, stage of gastric cancer, extent of involvement of ovary, and systemic chemotherapy were not related to survival time of recurrent cancer patients. Conclusions: The survival time in patients with oophorectomy in recurrent gastric cancer was correlated to relapse-free survival time after gastric resection.

No significant financial relationships to disclose.
Therapeutic vaccination against advanced pancreatic cancer by autologous dendritic cells pulsed with a MUC1 peptide: Preclinical results of a clinical phase I trial
Authors: Jin D. , Rong Y. , Lou W. , Qin X. , Wu W. , Nin X. , Nin X. , Wang D. , Kuang T. , Qin Y.
Published: August 2020

e15652

Background: Pancreatic ductal adenocarcinoma has a particularly poor prognosis. Therefore, novel therapeutic strategies such as immunotherapy are required. The aim of the present phase I study was to evaluate the safety, immune responses and clinical activity of a vaccine based on autologous dendritic cells (DC) pulsed with a specific MUC1 peptide in advanced pancreatic cancer patients. Methods: Five patients who had pancreatic cancer ductal adenocarcinoma expressing MUC1 in stage of III/IV were enrolled to the clinical trial. Patients underwent leukapheresis to generate dendritic cells by culture in vitro with granulocyte macrophage colony-stimulating factor and interleukin-4 for 5 days. Dendritic cells were then pulsed overnight with MUC1 peptide (GVTSAPDTRPAPGSTAPPAH) and harvested for vaccination. Dendritic cells (3×106-6×106) were injected intradermally every 2 weeks for 3–4 times. Results: All patients remained with progressive disease. Four patients developed strong T-cell IFN-γ and Granzyme B Elispot responses to the vaccine. Most interestingly, the patient who was treated with the highest number of DC(6×106) had more number of CTL than other patients and showed delayed-type hypersensitivity responses at injection sites and this patient stopped application of the analgetics. Another patient with relapsed pancreatic cancer who had finished the 4 times of vaccination and then followed 6 times of chemotherapy with Gemcitabine had a surprisingly long term of survival of 12 month. No evidence of significant treatment related toxicity or auto-immunity was observed. Conclusions: This study showed the safety and clinical response of MUC1 peptide-pulsed dendritic cell therapy for patients with advanced pancreatic cancer. It confirms the capability of this DC vaccine to stimulate an immune response in patients with pancreatic cancer even in the presence of a large tumor burden. Dendritic cell therapy is recommended for further clinical studies in pancreatic cancer patients.

No significant financial relationships to disclose.
A comparison between treatment outcomes of stage III and stage IV esophageal squamous cell carcinoma without visceral or bone metastases
Authors: Wang Y. , Liu D. , Chang B. , Kao R. , Lai Y. , Hsu W.
Published: August 2020

e15659

Background: Although classified as end-stage, patients of stage IV esophageal squamous cell carcinoma (SCC) without visceral or bone metastases (nodal stage IV) often have good performance status and are medically fit for curative treatment. The objective of this study was to compare the prognosis of patients of stage III and nodal stage IV. Methods: The retrospective study included patients who were diagnosed esophageal squamous cell carcinoma at Tzu Chi General Hospital from Jan, 2005 to Aug, 2008. Eligible patients must meet the following criteria: (1) stage III or nodal stage IV; (2) underwent esophagectomy or chemoradiation with curative intent; (3) Eastern Cooperative Oncology Group performance status ≤2. The standard order-set of chemotherapy was two monthly cycles of fluorouracil (1,000 mg/m2/24 hours for 4 days) and cisplatin (75 mg/m2 bolus day 1). Radiotherapy dose was 59.4 Gy for concurrent chemoradiation (CCRT) or 54 Gy for adjuvant setting after esophagectomy. Results: Patients characteristics were listed in Table . The median follow-up was 8 months (range: 1∼42 months). In 38 patients underwent definitive CCRT, ten achieved complete response (CR) and 13 achieved partial response. Two-year disease-free survival rate in 28 patients who achieved CR or underwent esophagectomy was 29.9%. Median survival of stage III and nodal IV were 11.5 and 8 months. Two-year overall survival (OS) rate of stage III and nodal IV were 23.9% and 33% (p=0.814). The only significant poor prognostic factor in both univariate and multivariate analyses was tumor length longer than 5 cm. Conclusions: In our study, medically fit patients of nodal stage IV esophageal SCC could achieve OS similar to those of stage III after intensive treatment. The result may indicate the necessity of developing a selection criterion in deciding which nodal stage IV patient should undergo curative treatment. [Table: see text]

No significant financial relationships to disclose.
Diabetes mellitus (DM), serum glucose, and outcome in gastroesophageal (GE) cancer
Authors: Feilchenfeldt J. W. , Capanu M. , Farooki A. , Sully D. , Miron B. , Power D. G. , Jhawer M. , Ilson D. H. , Kelsen D. P. , Shah M. A.
Published: August 2020

e15661

Background: Diabetes mellitus (DM) and impaired glucose tolerance (IGT) are frequent comorbidities in cancer patients. Their diagnosis is predictive of early recurrence following resection of colorectal cancer and of increased treatment related toxicity in localized breast cancer. Impaired glucose tolerance is a risk factor for the development of GE cancer. As nutrition and performance status are key determinants of outcome, we hypothesized that DM would influence treatment outcome in GE cancer. Our primary objective was to analyze the role of serum glucose, DM, serum albumin and BMI on treatment outcome and toxicity amongst a cohort of uniformly treated patients with GE cancer. Methods: 211 patients with GE cancer enrolled on 3 localized (2 esophagus, 1 gastric) and 4 metastatic consecutive prospective clinical trials (3 gastric, 1 esophagus) were examined. The studies involved treatment with chemotherapy combinations of taxanes, platinum, irinotecan, 5-fluorouracil, bevacizumab and cetuximab. Diagnosis of DM was based on clinical data, random glucose or fasting-glucose levels. Study parameters were tested for their association to time to treatment failure (TTF), overall survival (OS) and toxicity using the X2 test. Results: 132 metastatic pts were included: median age 57(range 32–76), M/F 96/36, median BMI 25.3 (16.2–40.1), 19 diabetic / 113 non-diabetic; overall survival was 10.8 months. 79 patients had localized disease: median age 61(32–80), M/F=53/26, median BMI 25.8 (range 16.1–38.5), 10 diabetic/69 non-diabetic; overall survival was 23.2 months. There was no statistically significant association of random glucose (p=0.06), DM (p=0.9), or BMI(p=0.2) with survival or with treatment related toxicity. Low serum albumin was associated with reduced survival, hazard ratio 2.12 (95% CI1.5–3.2), p<0.001. Conclusions: In GE cancer patients on protocol therapy, we confirm the negative prognostic significance of serum albumin on patient survival. This is remarkable considering all patients were protocol eligible with adequate organ function and performance score. We did not observe a clinically relevant impact of IGT or DM on treatment outcome or toxicity.

No significant financial relationships to disclose.
A phase II clinical and biological study of lithium carbonate (Li) in patients with low-grade neuroendocrine tumors
Authors: Lubner S. J. , Chen H. , Holen K. , LoConte N. , Rikkers L. , Weber S. , Warner T. , Eickhoff J. , Fass T. , Schelman W.
Published: August 2020

e15662

Background: Low-grade neuroendocrine tumors (NETs), such as carcinoid, islet cell tumors, and medullary thyroid carcinomas, respond poorly to chemotherapy, and effective, less toxic therapies are needed. Glycogen Synthase Kinase (GSK)-3β, a multifunctional protein kinase, has been shown to regulate growth and hormone production in NETs. Use of lithium carbonate (Li) in murine models suppressed carcinoid cell growth, reduced GSK-3β levels and reduced expression of chromogranin A. This study assessed the efficacy of Li in patients with NETs. Methods: Eligible pts had pathologically-proven, measurable low-grade NETs. Prior treatment was allowed if completed >4wks prior to registration. Standard eligibility criteria were used, and use of medications affecting Li metabolism or levels were prohibited. A single-arm, open-label, two-stage Phase II design was used. Li was dosed at 300mg orally TID with meals, titrated to a target serum level of 0.8–1.0mmol/L. The primary endpoint was objective tumor response by RECIST. Secondary endpoints included overall survival, progression-free survival, decrease of serum tumor markers, toxicity, and quality of life. Results: 15 pts were enrolled between 10/3/07and 7/17/08; 6 men, 9 women. The median age was 58 (range 47–74). Patients’ diagnoses were carcinoid tumor for 8 subjects, islet cell tumor for 5 subjects, and 2 unknown primary sites. ECOG PS was 0 (6 patients) or 1 (9 patients). Two pts came off study due to side effects (tremor, dizziness/abdominal pain). There were no radiographic responses. Due to an early stopping rule requiring at least 1 objective response in the first 13 evaluable pts, the study was closed to further accrual. 13 patients had pre- and post-therapy biopsies. Evaluation of quality of life and GSK-3β levels in tumor tissue is ongoing. Conclusions: Li was ineffective at obtaining a radiographic response in our 13 evaluable patients who were treated as part of this study. We will determine from tumor biopsies whether Li was effective at phosphorylating GSK-3β in order to make conclusions about GSK-3β as a therapeutic target for future NET treatment strategies. Funded through NIH grant R21CA117117- 01A2 and CTRC grant 1ULRR025011.

No significant financial relationships to disclose.
Gemcitabine in combination with intraperitoneal cisplatin in advanced hepatobiliary cancers
Authors: Liu W. , Zhang H. , Liu D. , Xue Y. , Huang Y. , Si X.
Published: August 2020

e15666

Background: Standard chemotherapy for advanced hepatobiliary cancers remains undefined. This study was to observe the therapeutic effect of gemcitabine combined with intraperitoneal cisplatin for the treatment of advanced hepatobiliary cancers and analyze their toxicities. Methods: Patients with measurable hepatobiliary cancers were unrandomized into gemcitabine (GEM) + cisplatin (DDP) (GEM group) and epirubicin (EPI) + DDP (EPI group). GEM was used intravenously by infusion for 30 min with the dose to 1,000 mg/m2 on day 1 and 8; cisplatin was infused intraperitoneal with a dose of 25mg/m2 on day1, 3 and 5. Twenty-one days counted as one cycle. After 2 cycles, treatment efficacy and adverse events were evaluated according to WHO criteria. Results: A total of 76 patients were enrolled from May 2004 to May 2006, with 30 patients for EPI group and 46 patients for GEM group, and all the patients were eligible for effectiveness analysis. Among GEM group patients, there was no complete response. The partial response rate was 32.61% and clinical benefit response (CR+ PR +SD) was 67.39%. All those data mentioned above were significantly higher than that of EPI group. The main adverse re-ction was hematologic toxicity, while nonhematologic toxicity was mild. Conclusions: This study demonstrated that combination gemcitabine with intraperitoneal infusion of cisplatin was an effective and safety treatment for the patients with advanced hepatobiliary cancers.

No significant financial relationships to disclose.
Retrospective study of the patients with unresectable gastric cancer (UNGC) who underwent a gastrectomy after receiving S-1 or S-1 combination chemotherapy (S-1+α)
Authors: Kobayashi K. , Tsuji A. , Hata Y. , Morita S. , Horimi T.
Published: August 2020

e15668

Background: At the 2007 ASCO annual meeting, JCOG 9912 and the SPIRITS trial showed that S-1 (S) and CDDP/S-1 (S+P) therapy to now be an accepted standard chemotherapy for advanced and recurrent gastric cancer (ARGC). Today in Japan, S- 1+αincluding S+DTX, S+CPT-11 and S+PTX are the mainstay treatments for ARGC. There are some case reports of pts with UNGC who were operated on due to the good anti-tumor effect of S-1+α, however, no consensus for performing a gastrectomy after chemotherapy has yet been reached. This study aims to identify the factors which make it appropriate to perform a gastrectomy after S- 1+α and to examine the validity of this chemotherapeutic regimen in combination with surgery. Methods: Twenty-five chemo-naïve pts with UNGC who received S-1+α (excluding neo-adjuvant) between May 2005 and Dec. 2007 were retrospectively reviewed, using the RESIST, Kaplan-Meier method, and Japanese Classification of Gastric Carcinoma (Eng. ed.). Results: The characteristics were: mean age 62; sex: M/F=18/7; cancer status; locally advanced (L):11, distant metastasis (D):9, lymph node swelling ≥group 3 (N):12, and peritoneal dissemination (P):11. Treatment regimens; S:13, S+DTX:3, and S+P:9. The median number of courses was 5. RR was 56% (PR:14, SD:9, PD:2). MST was 780 days. Twelve pts underwent a gastrectomy. The reasons for performing an operation were downstaging (DOWN):8, and palliative (PAL):4 (anemia:2/passage disturbance:2). The features were DOWN (M/F=5/3/65 yrs/PR:8/L:6, D:0, N:4, P:3) and PAL (M/F=4/0/57 yrs/SD:4/L:1, D:3, N:1 P:1). The median PFS and mean OS were 445 days and 312 days, respectively. No significant difference was observed between DOWN and PAL regarding the PFS and OS. All PAL cases were free from painful symptoms. Three pts received a curative A resection. In addition, 8 pts experienced histological changes, in particular, one pt achieved Grade 3 (No viable tumor cells were found.). Ten pts received adjuvant chemotherapy. Nine pts are alive at this writing. Conclusions: The findings of this study suggest that the above described chemotherapeutic regimen combined with a second-look gastrectomy might therefore be a new potentially effective strategy for the treatment of UNGC.

No significant financial relationships to disclose.
Efficacy of laser capture microdissection plus RT-PCR technique in analyzing gene expression levels of human gastric cancer
Authors: Uetake H. , Shitara K. , Sugihara K.
Published: August 2020

e15669

Background: We reported the efficacy of laser capture microdissection plus RT-PCR (LCM+RT-PCR) technique in analyzing gene expression levels of human colon cancer (Makino, BMC cancer, 2008). In the present study, gene expression level of angiogenic factors, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP) and cyclooxygenase-2 (COX-2) in human gastric cancer was studies using LCM+RT-PCR methods. Methods: Gene expression level of VEGF, TP and COX-2 were separately quantified in cancer cells and in cancerous stroma of 51 gastric cancers specimen by LCM+RT-PCR methods (Danenberg Tumor Profile). Results: All the gene expressions were successfully estimated separately in cancer cells and cancerous stroma. VEGF and TP gene higher expressed in cancer cell than in cancerous stroma (P<0.0001, Wilcoxon), whereas COX-2 gene expression was higher in cancerous stroma (P=0.0004, Wilcoxon). Only in TP, positive correlation of gene expression was observed between in cancer cells and in cancerous stroma (rs=0.494, P=0.0014, Spearman). And a linear relationship was observed between VEGF and TP gene expression in cancerous stroma (rs=0.768, P<0.0001, Spearman). Conclusions: Gene expression level of angiogenic factor was different between in cancer cells and cancerous stroma. By using LCM+RT-PCR method, gene expression level of angiogenic factors can be separately estimated in cancer cells and cancerous stroma.

No significant financial relationships to disclose.
Study to see the efficacy and toxicity profile of docetaxel-based chemotherapy in advanced stomach cancer in Bangladeshi patient population
Authors: Hoque E. , Karim S. , Hossen M. , Ahmed T. U.
Published: August 2020

e15687

Background: Gastric cancer is the second most common cause of cancer death worldwide. In Bangladesh it is one of the major causes of cancer death. Advanced gastric cancer patients have a poor prognosis of 3 to 5 months. Docetaxel has shown activity against gastric cancer as monotherapy and in combination with other agents. The purpose of this study was to investigate the efficacy and toxicity profile of docetaxel based chemotherapy in advanced stomach cancer in Bangladeshi patient population. Methods: From January 2004 to December 2006, thirty patients with advanced inoperable gastric cancer (Gastric or esophagogastric adenocarcinoma) were included in the study. Patients received no prior chemotherapy. Patients were given docetaxel 75mg/m2 I/V in 1 hour infusion and Cisplatin 75mg/m2 (d1) plus 5-fluorouracil 750mg/m2/d (days 1 to 5) I/V with adequate hydration every 3 weeks. The primary end point was time to tumour progression. Secondary end point was overall survival and toxicity profile. Results: Among the 30 evaluable patients time to tumour progression was 11.5 months. Overall response rate was 87% (26 patients). Complete response rate was 20% (6 patients), 27% (8 patients) had stable disease, 7% (2 patients) had developed progressive disease. Two-year survival rate was 21%. Grade 3 to 4 treatment related adverse events occurred in 63%. Among the toxicities there were: neutropenia (80%), stomatitis (19%), and diarrhea (15%). There was no treatment related death. Conclusions: Adding docetaxel to CF regimen significantly improved time to tumour progression and survival rate in advanced gastric cancer patients. In context with the survival benefit the toxicities of this regimen are acceptable. Docetaxel in combination with Cisplatin and 5-fluorouracil is a very safe and active in patients of Bangladesh with advanced gastric cancer. Larger studies involving higher number of patients are needed to evaluate these results in case of Bangladeshi patient population.

No significant financial relationships to disclose.
Bone marrow recovery and subsequent chemotherapy following radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 in patients (pts) with metastatic castration-resistant prostate cancer (metCRPC)
Authors: Tagawa S. T. , Parmar S. , Pena J. , Petrillo K. , Matulich D. , Selzer J. , Vallabhajosula S. , Goldsmith S. J. , Bander N. H. , Nanus D. M.
Published: August 2020

e16004

Background: Reversible myelosuppression is the dose-limiting toxicity of radioimmunotherapy (RIT). Cases of marrow damage, including myelodysplasia and acute leukemia have been reported with the RIT most used to date (that targeting CD20 in Non- Hodgkin's lymphoma), though no statistically significant association exists. In addition, post-RIT chemotherapy (chemo) may theoretically be limited. We have treated metCRPC pts with anti-PSMA RIT since 2000 and analyzed post-therapy outcomes. Methods: Follow-up across 4 prospective phase I and II trials utilizing 177Lu-J591 and 90Y-J591 was performed. Quality of hematologic recovery from post-RIT myelosuppression was documented. Administration of pre- and post-RIT chemo was analyzed. Specific searches for subsequent myelodysplasia and/or leukemia were performed. Results: Median age of the 109 treated pts is 70 (range 47–88). Entry criteria for all trials included progressive metCRPC, PS < 2, normal baseline neutrophil and platelet counts, and hemoglobin > 10 g/dL. 80 received 177Lu-J591 at cumulative doses ranging from 10–120 mCi/m2 and 29 received 90Y-J591 at cumulative doses of 5–40 mCi/m2. 43% received at least 1 line of pre-RIT chemo, 53% received at least 1 line of post-RIT chemo, and 20% have never received chemo to date. All pts with adequate performance status received chemo except per pt choice. Excluding re-treated pts, 98% and 87% of assessable pts had full recovery of neutrophils and platelets respectively. Of the remaining, all but 4 recovered to Gr 1 neutropenia and/or thrombocytopenia. The most common reason for lack of complete hematologic recovery was CRPC progression in bone marrow (16 pts with persistent or recurrent myelosuppression underwent bone marrow biopsy). No cases of post-RIT myelodysplasia and/or leukemia were discovered. Conclusions: Anti-PSMA radioimmunotherapy is well-tolerated with efficacy previously reported. While follow-up is ongoing, reports of irreversible bone marrow damage appear unfounded and all patients with intact performance status willing to undergo post-RIT chemotherapy are able to receive it.

[Table: see text]
Micropapillary urothelial carcinoma of the urinary bladder: Early surgery or neoadjuvant chemotherapy?
Authors: Ghoneim I. , Stephenson A. , Gong M. , Campbell S. , Fergany A.
Published: August 2020

e16007

Background: Micropapillary bladder carcinoma is a rare variant of urothelial carcinoma (UC) of the urinary bladder. As a particularly aggressive variant, patients are often urged to undergo up-front radical cystectomy. Though data is scarce on the treatment outcomes of patients with this entity, we present the case for neoadjuvant chemotherapy as opposed to early cystectomy in the setting of clinically localized micropapillary UC. Methods: A review of records of all patients evaluated at our institution for UC was conducted to identify micropapillary UC of the bladder over the period from 2000–2007. A total of 24 cases were found, and were evaluated for preoperative pathology and clinical stage, treatment course, pathological stage and cancer specific survival. Results: Mean patient age was 67.9 years with 19 males and 5 females. Twenty-one (87.5%) patients had clinically organ confined micropapillary UC at the time of diagnosis, three had minimally enlarged lymph nodes on pelvic CAT scans. Half of our patients had BCG refractory high grade non-muscle invasive UC. Twenty-two patients (91.67%) were offered radical cystectomy as first line management. Extended lymph node dissection was performed in eleven patients (45.83%). Final pathologic examination diagnosed metastatic lymph node involvement in 20 patients (83.33%), with 4 patients (20%) having positive LN outside the standard (pelvic) template of dissection. A stage upgrade was noticed in 95.23% of cases. Median cancer specific survival was 13 months. Survival at one year was 44% and 50% at 2years, with only one patient alive at 5 years. Conclusions: Our results suggest that clinically localized micropapillary UC is often metastatic to LN at the time of presentation. This setting of frequent systemic disease should encourage standard neoadjuvant chemotherapy rather than early surgical management for these patients. Extended LN dissection is warranted in these cases due to the high incidence of nodal involvement outside the standard template.

No significant financial relationships to disclose.
Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in renal cell carcinoma
Authors: Sgambato A. , Camerini A. , De Luca F. , Valsuani C. , Siclari O. , Genovese G. , Boninsegna A. , Cecchi M. , Cittadini A. , Amoroso D.
Published: August 2020

e16008

Background: Deregulation of the normal cell cycle is a frequent event in human tumors and plays an important role in malignant transformation. p27kip1 is a negative regulator of the G1 phase, is frequently lost in tumor cells and, in some cases, its alteration is coupled with oxidative DNA damage. Methods: We evaluated the expression of p27kip1 and the extent of endogenous oxidative DNA damage (by means of 8-hydroxydeoxyguanosine [8-OHdG] levels) by immunostaining in a series of 125 (median age 64[range23–86]yrs) renal cell carcinomas (RCCs); furthermore, the prognostic significance of their alterations was tested. Median values of expression were used as cut-off. p27kip1 expression was also evaluated by Western Blot in a second series of 34 fresh-frozen RCCs. Results: to date, median follow-up is 29[range 4 - 104] months. p27kip1expression was lost in a significant fraction of tumors (55%) with a median percentage of positive cells of 20% [range 0–60%). Loss of p27kip1 staining correlated with higher tumor grade (p=0.049). Recurrence (p=0.007) and death (p=0.006) from RCCs were significantly more frequent in patients p27kip1-negative compared with positive ones. Kaplan-Meier analysis showed a significant separation between high vs low p27kip1 expression groups for both disease-free (p=0.011) and overall (p=0.002) survival. At multivariate analysis, loss of p27kip1expression was the only independent risk predictor for recurrence (HR=4.326, p=0.014) and death (HR=4.915, p=0.012) from RCCs when tumor size, tumor grade and stage were included. No significant correlation with clinical or pathological parameters and outcome was found for 8- OHdG. p27kip1 total protein levels showed a variable behaviour at WB analysis with a modest trend toward a global reduction but an elevation in some cases. Conclusions: loss of p27kip1 is frequent in human RCCs and is a powerful predictor of poor outcome. p27kip1 alteration are not related to endogenous oxidative DNA damage. The behaviour of p27kip1at WB analysis is probably related to the elevation of the cytoplasmatic (and inactive) fraction.

No significant financial relationships to disclose.
Somatic malignant differentiation in adult male germ-cell tumors (GCTs): Preliminary evidences from the INTera database (International Project for Teratoma with Malignant Transformation)
Authors: Necchi A. , Colecchia M. , Nicolai N. , Mego M. , De Giorgi U. , Mikuz G. , Sava T. , Di Nicola M. , Pastorino U. , Salvioni R.
Published: August 2020

e16013

Background: Malignant transformation (MT) is a rare phenomenon characterized by a neoplastic somatic differentiation within a GCT. Little is known concerning its clinical implications. An international registry (INTera Project) has been established to collect all past and new cases worldwide. Methods: Patients (pts) with a MT within GCT have been retrospectively identified from registries of contributing Institutions. Significant clinical and pathological data have been collected and data files gathered at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Results: 47 pts have been identified as well as a variety of 12 histologies. 25 pts had MT in primary tumor: 14 of them had no metastases (11 underwent primary retroperitoneal lymph-node dissection - RPLND), and 11 underwent chemotherapy (CT) ± surgery due to metastatic disease. All 14 pts with no metastases remain disease-free (DF) following a median follow-up (f-up) of 72 months (2–236+ months). 6 of 11 pts undergoing chemotherapy remain disease-free following a median f-up of 155 months (8–297+). 22 pts had MT in metastases only and 20 of them are evaluable. Following CT, 7 underwent radical surgery and 5 of them remain DF following a median f-up of 77 months (19–166+ months), while 13 could not undergo radical removal of disease, and 3 of them have been rescued by further CT and are DF at 37+, 41+ and 79+ months. So far, all 14 pts with no metastases as well as 7/9 (78%) who had radical removal of disease are alive and DF versus only 7/22 pts (32%) who could not receive a radical excision of residual masses. Median disease-free survival of pts with MT in primary only versus distant sites only was 54 (0–326+) and 2.5 (0–166+) months respectively (p=0.064 - at Log-rank test). No relevant outcome differences have been observed according to histology. Conclusions: Ongoing INTera project is a collaborative effort of MT case- collection worldwide. Stage of disease and radical surgery seem to associate with outcome. The growing number of cases and a centralized pathology review would help to increase knowledge on this rare disease.

No significant financial relationships to disclose.
Long-term effects of a program of bladder preservation using chemotherapy plus radiotherapy in muscle invasive bladder cancer (BC). Analysis of biologic predictive factors and health-related quality of life (QOL)
Authors: Passalacqua R. , Brighenti M. , Naldi N. , Potenzoni D. , Monica B. , Fumagalli M. , Lazzarelli S. , Caminiti C.
Published: August 2020

e16014

Background: Long-term effects of a combined approach of transurethral resection (TUR) plus chemotherapy (CT) and pelvic radiotherapy (RT) in terms of bladder preservation, survival, QOL are largely unknown. Moreover we investigated whether p53, Ki67, bcl-2, c-erbB-2 protein expression predict the achievement of a complete response (CR). Methods: From March 1994 to June 2000, 75 pts with muscle invasive BC were treated with a bladder sparing approach including an initial TUR, 3 cycles of CT (cisplatin + 5- FU) alternating with pelvic RT (40 Gy). At the response evaluation, pts with biopsy proven residual disease were considered incomplete responders (IR) and underwent immediate cystectomy. Pts with CR were treated with two additional CT cycles plus a bladder RT boost (20- 24 Gy). Paraffin embedded blocks of the primary tumors were collected and Ki67, p53, bcl-2 and c-erbB-2 protein expression were evaluated in a blind fashion. The Expanded Prostate Cancer Index Composite (EPIC) scores for urinary function, (especially storage, voiding symptoms and bowel function) was used to explore QOL in bladder preserved and compared with a group of matched patients treated by radical cystectomy only. Results: Median age was 67 yrs (range 42–80); T2a-T2b: 42%; T3a-T3b: 47%; T4a: 11%; G3: 88%; hydronephrosis: 32%. Overall, 56 (74.7%) pts achieved a CR and the achievement of a CR was significantly related to lower T stage (p= 0.002), high Ki67 (p=0.001), absence of hydronephrosis (p= 0.007) and high p53 overexpression (p=0.007). Multivariate analysis showed that only a low T stage (p=0.002) and high p53 expression (p=0.043) predict the obtaining of a CR. At 5 years of follow-up, 44 (59%) were alive and in 33 of them (75%) bladder was preserved; after 10-years 28 (37.3%) were alive and in 23 of them (82%) bladder was preserved. Analysis of QOL scores is ongoing. Conclusions: This approach induces a long term survival similar to radical cystectomy with a high rate of bladder preservation and represents a valid treatment for muscle invasive BC. Overexpression of p53 is a predictive marker for the obtaining of CR and for bladder preservation.

No significant financial relationships to disclose.
Identification of factors predicting loss of renal differential function on the operated kidney after laparoscopic partial nephrectomy
Authors: Pouliot F. , Pantuck A. J. , Calimlim B. , Dujardin T.
Published: August 2020

e16015

Background: Partial nephrectomy (PN) is now the gold standard for small renal mass of less than 4 cm since it prevents renal insufficiency that may occur with radical nephrectomy. The impact of warm ischemis time (WIT) on the operated kidney's renal differential function (RDF) have been poorly studied in the litterature, especially when WIT is less than 30 minutes. We evaluated the effect of WIT and other perioperative factors on RDF function assessed by pre- and post-operative renal scintigraphy. Methods: Between 2003 and 2008, 182 laparoscopic PN were performed by a single surgeon on patients with two kidneys. Among those, 56 had a MAG3-lasix renal scintigraphy pre- and post-operatively between 7 and 14 days. Data were collected prospectively. Loss in RDF is calculated as follow: Loss in RDF=(RDF preoperatively-RDF postoperatively/RDF preoperatively) × 100. Results: Medians for age, pre- op creatinine, pre-op GFR (Cockroft formula) and tumor CT-size were 61 years, 83 μM, 83,2 ml/min and 26 mm, respectively. Median WIT and pre-operative RDF were 30 minutes and 50%. Median loss of RDF after surgery was 24%. In multivariate analysis, low pre-operative RDF, WIT and intrarenal location of the tumor were associated with a statistically significant loss of RDF (p<0.05). Age, pre-op GFR, tumor CT-size, diabetes and HTN did not predict loss in RDF. Fitting the relative RDF loss versus WIT to a polynomial curve suggests that the rate of loss in RDF increase with WIT. The point of inflection of the polynomial curve (reflecting the maximal change in rates of loss in RDF) was estimated to be at 32 minutes. Linear regression curves show that loss in RDF rate is 0.8% per minute when WIT is less than 32 minutes and 1.3 % per minute when WIT is more or equal to 32 minutes. Conclusions: We show that a WIT of less than 32 minutes optimizes the chances of preserving RDF of the operated kidney and that the rate of loss in RDF is higher above 32 minutes. Finally, higher loss in RDF must be expected if the patient has a low pre-operative RDF and intrarenal location of the tumor.

No significant financial relationships to disclose.
Incidence and long term prognosis of papillary renal cell carcinoma
Authors: Schrader A. J. , Rauer-Bruening S. , Olbert P. J. , Hegele A. , Rustemeier J. , Hofmann R.
Published: August 2020

e16020

Background: Papillary renal cell carcinoma (pRCC) represents the largest subgroup of non clear-cell kidney cancer. In this study we assessed tumour characteristics and long-term prognosis of patients with pRCC in comparison with conventional clear-cell cancer (ccRCC). Methods: We evaluated 744 patients who had undergone renal surgery for RCC between 1990 and 2005. The mean follow-up was 5.6 years. Results: Both groups pRCC and ccRCC were alike concerning age, body mass index, and the incidence of regional lymph node or distant metastasis at diagnosis. The percentage of male patients was higher in pRCC than in ccRCC (73.8 vs. 60.3%, p = 0.006). Even though patients with pRCC presented more often with smaller (p = 0.039) and low grade tumours (p = 0.006), there was no statistically significant difference in tumour recurrence or tumour related death. Moreover, looking at the whole cohort Kaplan-Meier curves revealed no differences regarding tumour specific survival between pRCC and ccRCC (p = 0.94; 5-year survival 78% vs. 77%). However, we observed a trend towards an improved outcome for organ confined (pT1–2) cancer, but a significantly inferior prognosis for locally advanced stage (pT3–4) and/or metastatic papillary tumours at the time of renal surgery. However, applying multivariate analysis including age, sex, and tumour grade, histology could neither be retained as a significant independent prognostic marker in the metastatic setting (p = 0.068, cox regression analysis) nor in a subgroup analysis focussing on patients with advanced cancer (pT3–4 and/or N+/M+; p = 0.064, cox regression analysis). Conclusions: Even though pRCC and ccRCC differ significantly in many aspects including histology and genetic alterations, in all, their long term prognosis is comparable. As we could not confirm a favourable clinical course for pRCC in general, standardized aftercare programmes and - if necessary - systemic treatment, especially in the era of novel targeted drugs, are also needed for this common RCC subtype. In addition, routine histologic subtyping of pRCC is strongly recommended.

No significant financial relationships to disclose.
Association of estimated glomerular filtration rate (eGFR) with odds of a renal lesion
Authors: Hruby G. , Van Batavia J. , Wosnitzer M. , Benson M. , Desai M. , McKiernan J. , Newhouse J.
Published: August 2020

e16025

Background: Patients with ESRD on long term hemodialysis are known to be at an increased risk for renal cell carcinoma. We postulate that some component of chronic renal failure not corrected by dialysis might be the tumor-inducing factor. We sought to determine if chronic renal insufficiency is a risk factor for developing renal cell carcinoma. Methods: A case- control study was used to determine a relationship between renal carcinoma and glomerular filtration rate (MDRD) (eGFR) and using patients with prostate cancer as controls. 1,298 patients from the Columbia University Urologic Oncology Database were identified with either prostate or kidney cancer who had sufficient information to predict eGFR. eGFR calculations were performed for both groups. eGFR was divided into two groups based upon the cut-off value of ≥90. eGFR was also categorized according to the MDRD definitions of chronic kidney disease (CKD), CKD1–4 (values≥90, 60≤values<90, 30≤values<60, and values<30, respectively). Logistic regression techniques were used to quantify the association between pre-operative glomerular filtration rate and the presence of renal or prostate cancer. Results: The mean age of the prostate (n=713) and kidney (n=585) group was 59.9 and 61 years, respectively (p=0.041). The mean weight was 83.9 and 87 kg, respectively (p=0.005). The mean serum creatinine was 1.01 and 1.29 mg/dL, respectively (p<0.001). The mean eGFR was 85 and 73.8, respectively (p<0.001). Two models were fit to analyze the association of eGFR. The first model found eGFR <90 was significantly associated with the presence of a renal carcinoma when controlling for age and race (OR=1.93, CI=1.49–2.49). The second model investigated the eGFR-CKD categories while controlling for age and race and was able to predict the presence of renal cancer (p < 0.001). Patients with an eGFR value of 60≤X<90 had an OR of 1.47 (CI= 1.13–1.92) for renal cancer when compared to patients with normal eGFR levels. Patients with an eGFR value of 30≤X<60 and <30 had an OR of 6.26 (CI=4.10–9.55) and 21.11 (CI=4.87–91.42), respectively. Conclusions: Diminished renal function showed a significant association with the presence of renal cancer. Chronic renal insufficiency may be a risk factor for the development of renal carcinoma.

No significant financial relationships to disclose.
Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer
Authors: Fabbri F. , Montanari M. , Cruciani G. , Amadori D. , Zoli W.
Published: August 2020

e16026

Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m2) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (> 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of >10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation.

No significant financial relationships to disclose.
Phase II dose escalation study of sorafenib in patients with metastatic renal cell carcinoma (mRCC) who have had prior treatment with VEGFR-TKI antiangiogenic treatment
Authors: Mancuso A. P. , Donato De Paola E. , Catalano A. , Calabrò F. , Messina C. , Zivi A. , Cerbone L. , Vigna L. , Caristo R. , Sternberg C. N.
Published: August 2020

e16027

Background: Sorafenib is an orally active multikinase inhibitor (Raf kinase, VEGFR 1, 2, 3 and PDGFR inhibitor) for the treatment of advanced RCC. The purpose of this study was to assess the efficacy and toxicity of Sorafenib in mRCC patients (pts) previously treated with an anti-angiogenic VEGFR-TKI using escalating dose levels. Methods: Pts with mRCC, PS 0–2 and adequate organ function were eligible. Pts received Sorafenib 400 mg/BID/continuously in 4-wk cycles. Pts with no progressive disease (evaluated at 12 weeks) continued to receive Sorafenib at the standard dose, while progressive pts received an increasing dose (600 mg BID) with early disease restaging after 4 weeks. Pts who progressed at 600 mg BID were taken off study. Efficacy was assessed by RECIST criteria. Results: 18 pts were entered; baseline characteristics: PS 0–1: 94%; median age 62 years (41–82); nephrectomy: 100%; surgery for metastatic disease: 28%, clear-cell 78%, papillary-cell 16%, sarcomatoid 6%.≥ 2 metastatic sites: 84%. 10 pts were refractory to cytokine treatment and all progressed or experienced unacceptable toxicity after anti-angiogenic VEGFR-TKI treatment, Sunitinib (13 pts) or Pazopanib (5 pts). Median number of cycles was 7.5 (1–16). Overall, 72% of pts had disease control without significant correlations between response to prior therapy and hypertension. 14 pts had progression free survival (PFS) of 4.3 months (mos). 4 pts are still in treatment with a median PFS > 8 mos. Of 6 pts in which the dose was escalated, 3 benefitted with a PFS of > 3 mos. The most common toxicity (NCIC 3.0, all pts) was grade (g) ≥ 1 diarrhea in 10 pts, g2–3 hand-foot syndrome in 7 pts and g-3 mucositis in 1 pt. Other hematological and non-hematological toxicities were g1 with a frequency < 15%. Conclusions: Sorafenib at doses of 400–600 mg/BID/continuosly results in acceptable and well tolerated salvage treatment after VEGFR-TKI failure. In progressive patients, treatment with a higher dose could be a valid option. Final and mature data will be presented in combination with translational research evaluating biological characteristics on tissue and blood.

No significant financial relationships to disclose.