bluuebunny/crossref_metadata_2025 huggingface dataset:
Dystroglycan expression correlates with tumor grade and with outcome in renal cell carcinoma patients
Authors: Sgambato A. , Camerini A. , De Luca F. , Genovese G. , Valsuani C. , Tartarelli G. , Garrone O. , Cecchi M. , Cittadini A. , Amoroso D.
Published: March 2020

15554

Background: The dystroglycan (DG) complex is a transmembrane glycoprotein that forms a continuous link from the extracellular matrix to the actin cytoskeleton. Deregulated expression of DG has been reported in a variety of human malignancies and related to tumor differentiation and aggressiveness. Methods: In this study, the expression of the a-subunit of DG was evaluated by immunostaining in a series of 125 renal cell carcinomas (RCCs) and its relation with disease progression and cancer-specific survival was evaluated. Results: to date, median follow-up is 19 months (range 1–96). We found that a-DG expression was lost in a significant fraction of tumors (66%) with 18% being the mean percentage of positive cells (median = 0; range = 0–80%). Loss of DG staining correlated with higher tumor grade (p=0.039) but not with tumor stage or size. Recurrence (p=0.014) and death (p=0.041) from RCCs were significantly more frequent in patients whose tumors displayed reduced staining for DG compared with patients whose tumors were positive for a-DG expression. Kaplan-Meier analysis showed a significant separation between high vs low a-DG expression for both disease-free (p=0.0094) and overall (p=0.0023) survival. In a multivariate analysis, loss of a-DG expression was the only independent risk predictor for recurrence (HR=6.509, p=0.0012) and death (HR=4.701, p=0.012) from RCCs when tumor size as well as tumor grade and stage were included in the model. Conclusions: These findings demonstrate that loss of a-DG expression, which correspond to loss a functional DG complex, is a frequent event in human renal tumorigenesis and is associated with an aggressive phenotype of the disease. They also suggest that evaluation of DG expression has the potential to offer important prognostic information and warrant further studies to better understand the role(s) of this molecule in term of renal cancer development and as a new prognostic marker for RCC patients.

No significant financial relationships to disclose.
Adjuvant multimodality treatment in patients with high-risk prostate cancer following radical prostatectomy: Results of a prospective clinical phase-II trial
Authors: Thüer D. , Ohlmann C. , Pfister D. , Engelmann U. , Heidenreich A.
Published: March 2020

15557

Background: High risk prostate cancer (PCA) is associated with a high frequency of PSA relapse. Even with adjuvant androgen deprivation therapy about 50% of patients experience systemic recurrences within 5 years. Docetaxel has demonstrated significant activity in men with metastatic androgen independent PCA, zoledronic acid has been shown to significantly inhibit the development of osseous metastases. It was the aim of the current prospective clinical phase-II trial to evaluate safety and clinical efficacy of early multimodality treatment in high risk PCA after radical prostatectomy (RPE). Methods: Between 3/2004 and 12/2005 25 patients with high risk PCA following RPE were recruited. High risk PCA was defined by a risk of biochemical progression > 70% according to the postoperative Kattan nomograms. Adjuvant therapy consisted of androgen deprivation with LHRH analogues for 12 months, zoledronic acid at 4mg every 3 months and docetaxel at 75 mg/qm for six consecutive cycles. Adjuvant treatment was initiated 4 to 6 weeks after surgery. Follow-up examination were undertaken every 3 months with PSA serum determinations; in case of PSA increase 2 consecutive measurements at 4 weeks intervals were performed. Time to progression defined the time interval between initiation of therapy and first PSA relapse. Results: The mean follow-up is 20.5 (6–31) months. Adjuvant multimodality treatment was well tolerated in all patients with grade 3/4 hematotoxicity in 3 (12%) and gastrointestinal toxicity in 5 (16%) patients; 2 (8%) developed significant oncolysis with surgical intervention. In none of the patients the dosage of docetaxel or the number of cycles had to be reduced. Currently, 4 (16%) patients have developed PSA relapse with 2 exhibiting osseous metastases and 2 having died. Median time to progression was 14.5 (10–16) months. Conclusions: The clinical efficacy appears to be lower than expected with a 16% progression rate and a 8% mortality rate after only 20 months of follow-up. Adjuvant multimodality treatment of high risk PCA after RPE can be applied without significant treatment-associated side effects. Currently ongoing clinical phase-III trials have to further validate the concept of adjuvant chemotherapy.

No significant financial relationships to disclose.
Phase II trial of the anti-prostate specific membrane antigen (PSMA) monoclonal antibody (mAb) J591 plus low-dose interleukin-2 (IL-2) in patients (pts) with recurrent prostate cancer (PC)
Authors: Jeske S. J. , Milowsky M. I. , Smith C. R. , Smith K. A. , Bander N. H. , Nanus D. M.
Published: March 2020

15558

Background: The de-immunized mAb J591 recognizes the extracellular domain of PSMA and was engineered to induce antibody-dependent cellular cytotoxicity (ADCC). Low-dose IL-2 results in the clonal expansion of NK cells and may enhance ADCC. We conducted a phase 2 trial to determine the efficacy and toxicity of mAb J591 plus low-dose subcutaneous (SC) IL-2 in pts with recurrent PC. Methods: 17 pts with recurrent PC (2 groups: 11 with PSA relapse only; and 6 with progressive castrate metastatic disease) received continuous low-dose SC IL-2 (1.2 x 106 IU/m2/day) daily for 8 weeks with mAb J591 (25 mg/m2 IV) weekly on weeks 4, 5 and 6 (1 cycle). Pts could receive a maximum of 3 cycles. Results: 16 evaluable pts received up to 3 cycles of therapy (16 pts, one cycle, 9 two cycles and 2 three cycles). Toxicity was mild and limited to fatigue and injection site reactions. At the end of cycle 1, PSA was stable (-50%<change in PSA<25%) in 9 of 16 patients, with PSA declines up to 34%. No PSA decline >50% was observed. A post-hoc analysis of PSA kinetics showed 5 patients had a reduction in their PSA slope of =25%; 8 of the remaining 11 patients demonstrated PSA stabilization (- 25%<change in PSA slope<25%). PSA response was most commonly observed during weeks 4–6 of the cycle correlating with mAb administration. Flow cytometric analysis of peripheral blood mononuclear cells revealed an average increase in absolute NK cell count of 107% at week 4 and 117% at the end of cycle 1. Conclusions: The combination of mAb J591 with low-dose IL-2 was well tolerated and inhibited PSA kinetics in some patients, however no responses were seen. Repetitive dosed mAb J591 is a viable strategy for use in combination with immune modulatory or other therapies in recurrent prostate cancer.

No significant financial relationships to disclose.
A phase II study of IV gemcitabine (G) and oral capecitabine (C) in patients (pts) with advanced renal cell cancer (RCC): Results of Southwest Oncology Group study 0312
Authors: Van Veldhuizen P. J. , Hussey M. , Lara P. N. , Gumerlock P. H. , Clark J. , Lange M. K. , Crawford E. D.
Published: March 2020

15562

Background: Previous reports have suggested benefit of GC in a modest number of patients with RCC but with concerns regarding toxicity. We subsequently evaluated an adjusted dose regimen in pts with advanced unresectable or metastatic RCC. Methods: Pts who had not received prior chemotherapy where treated with G at 900mg/m2 days 1,8,15 and C at 625mg/m2 BID day 1- 21 of a 28 day cycle. Pts must have had adequate performance status, organ function and may have received prior immunotherapy. The primary endpoint was probability of response, confirmed and unconfirmed complete (CR) and partial responses (PR). A one-stage design for accrual was used and regimen would not be considered of interest if the true probability of response was <=5%. Results: 43 patients were enrolled of which 1 was ineligible and 2 were not analyzable. Median follow-up was 11.2 months (range: 1.3 to 18.5). One confirmed complete response (CR) and three unconfirmed partial responses (PR) were observed, for an overall response probability of 10% (95% CI: 3% to 24%). Four of the eligible patients had inadequate disease assessment and were assumed to be non-responders. 19 pts (48%) had stable disease (SD). The 6-month probability of being free from treatment failure was 20% (95% CI: 8% to 32%). The probability of survival at 6 months was estimated to be 75% (95% CI: 62% to 88%). Median survival was estimated to be 13 months (lower limit of 95% CI is 7 months, upper limit not estimable). One patient each experienced Grade 4 neutropenia, fatigue, thrombocytopenia and hemolysis/renal failure. Most common Grade 3 toxicities were neutropenia (12 pts), fatigue (5 pts), and leucopenia (4 pts). Conclusions: GC at this dose and schedule benefits a small percentage of pts with RCC with an acceptable toxicity profile. Given the RR and SD, GC may serve as a base regimen for combination therapy with targeted agents.

No significant financial relationships to disclose.
Global proteome analysis of germ cell tumor (GCT) cell lines under treatment with cisplatin (CDDP)
Authors: Honecker F. U. , Glaesener S. , Venz S. , Walther R. , Brummendorf T. H. , Balabanov S. , Bokemeyer C.
Published: March 2020

15567

Background: GCTs are the most common malignancy in young Caucasian males aged 20–40. With CDDP-based chemotherapy, highly effective treatment has been developed for the majority of patients with GCT. However, the molecular mechanisms underlying treatment response remain elusive. Therefore, we used a global proteomics approach to screen for changes induced in GCT cell lines by CDDP. Material and Methods: Global protein expression analysis of three GCT cell lines, NTERA2, 2102EP, and NCCIT, both untreated and treated with CDDP for 48 hours at the IC50, was performed using 2-dimensional gel electrophoresis. Differentially expressed proteins were analyzed using matrix-assisted laser desorption/ionization - time of flight (MALDI TOF) and Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. Identification of proteins was performed using peptide mass-fingerprinting and NCBI/SwissProt and The Global Proteome Machine database search. Results: In total, 66 proteins were found to be differentially expressed comparing untreated and treated cells. Numbers of proteins showing upregulation under CDDP were 18 in NTERA2, 10 in NCCIT, and 9 in 2102EP, whereas 17 proteins were downregulated in NTERA2, 5 in NCCIT, and 7 in 2102EP. Identification of corresponding proteins was successful in 44 out of 66 spots (67%). Differential expression of 5 proteins was found in more than one cell line. One protein (Enolase 1) was consistently up-regulated in all three cell lines under CDDP. The identified proteins can be grouped into different categories: 15 are involved in DNA-binding/transcription, 8 in metabolism, 8 in protein folding/binding/chaperone, 6 in cell signaling/differentiation, 4 in apoptosis, and 3 in cytoskeleton/cell movement. Conclusion: The results of this screening approach identify factors differentially regulated during response to CDDP in GCTs, and reveal a specific response pattern for each cell line. This knowledge can help to identify therapeutic targets and factors potentially involved in treatment sensitivity and resistance.

No significant financial relationships to disclose.
A population-based study evaluating metastatic renal cell cancer (mRCC) patients treated with interferon (IFN) alone, first-line IFN then second-line sunitinib, or sunitinib alone
Authors: Kollmannsberger C. K. , Heng D. Y. , Murray N. , Chi K. N.
Published: March 2020

15572

Background: Previously, immunotherapy agents such as IFN were the only treatments available for mRCC. Sunitinib has demonstrated prolonged progression free survival in a phase III trial but overall survival benefit has yet to be determined and few patients (pts) with poor MSKCC prognostic profiles were included. Methods: The province-wide BC Cancer Agency Registry was cross-referenced to the central pharmacy database to identify all pts with the diagnosis of mRCC who were treated with IFN and/or sunitinib. Sunitinib became available after October 2005 under an expanded access program or as standard treatment. Three groups of pts were identified: Group A consisted of pts who received IFN alone between January 2003 to October 2005, Group B was all pts who progressed on first-line IFN after October 2005 and subsequently were treated with second-line sunitinib and Group C was all pts treated with first-line sunitinib. Baseline characteristics and overall survival were collected on all patients. Results: A total of 75 patients were identified with 36 patients in Group A, 23 patients in Group B, and 16 patients in Group C. Data are reported from the initiation of IFN in Group A and the initiation of sunitinib in Groups B and C. Median follow-up was 6.0 months in group A, 7.6 months in group B, and 6.2 months in group C. Median age of treatment initiation (62y vs. 60y vs. 62y), number of metastatic sites (>1 site in 63% vs. 61% vs. 56%), and Karnofsky performance status (79 vs. 86 vs. 81) were similar between groups A, B and C, respectively. The MSKCC prognostic profiles were favorable, intermediate and poor in 26%, 51% and 23% in group A, 17%, 65% and 17% in group B and 31%, 38% and 31% in group C, respectively. The estimated 6-month overall survival in groups A, B and C was 56%, 72% and 100%, respectively (log rank A vs C p=0.009; log rank B vs C p=0.042). Conclusion: With the limitations of retrospective analysis and preliminary follow-up, the introduction of sunitinib as standard treatment into the general population of patients with mRCC appears to be associated with a longer overall survival compared to patients treated with IFN alone. Population-based analysis on the impact of the introduction of sunitinib therapy is ongoing.

No significant financial relationships to disclose.
University of Chicago Consortium phase II study of ispinesib (SB-715992) in patients (pts) with advanced renal cell carcinoma (RCC)
Authors: Beekman K. W. , Dunn R. , Colevas D. , Davis N. , Clark J. , Agamah E. , Thomas S. , Nichols K. , Redman B. , Stadler W.
Published: March 2020

15573

Background: Ispinesib is a novel kinesin spindle protein inhibitor that has significant antitumor activity in multiple tumor models and has demonstrated preliminary clinical activity in early phase I and II trials. A phase II study of Ispenisib in patients with metastatic RCC who had received at least one prior therapy was thus conducted. Methods: The primary objective was to assess the RECIST based overall response rate (RR) with optimal Simon two-stage design utilizing 10% and 30% RR as the null and alternative hypotheses, respectively. Eighteen pts were to be accrued during the first stage; if 3 or more responses (PR or CR) were seen, an additional 17 pts would be accrued. Further study would be recommended if 7 or more of the 35 total pts had a response. Secondary objectives included toxicity, time to progression, and overall survival. Pts were treated with 7 mg/m2 over one hour on days 1, 8, and 15 every 28 days with radiologic disease re- evaluation every 8 weeks. Results: 19 pts were accrued in 6 months. Baseline characteristics included clear cell histology in 74%, papillary in 11%, and unclassified in 11%; 1 or =2 prior therapies in 37% and 63%; prior immunotherapy in 53%, and prior sunitinib, sorafenib or bevacizumab in 79%; ECOG performance status 0 in 58% and 1 in 42%. 4 patients are too early for radiologic assessment. None of the 15 patients evaluable responded to treatment (95% CI: 0 - 21.8%). Seven patients (47%) experienced stable disease after 8 weeks. One patient experienced grade 3 neutropenia. No other grade 3 or 4 toxicities were attributable to drug. Grade 1 and 2 toxicities included: fatigue (28%), anemia (28%), leukopenia (33%), elevated alkaline phosphatase (18%), anorexia (11%), hyponatremia (11%), dyspnea (11%), headache (11%), and hypoalbuminemia (11%). Conclusions: Treatment with weekly Ispenesib in metastatic RCC is well tolerated but does not lead to objective responses. Under the hypothesis that Ispenesib is a cytotoxic rather than cytostatic agent, further evaluation in patients with metastatic RCC at this dose and schedule is not indicated. Supported by: NCI #N01-CM-62201

No significant financial relationships to disclose.
Macrocytosis in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKI's)
Authors: Khasawneh M. F. , Unnithan J. , Choueiri T. , Rini B. , Dreicer R. , Garcia J. , Wood L. , Elson P. , Bukowski R.
Published: March 2020

15583

Background: Sunitinib and sorafenib are TKIs with inhibitory activity against a variety of kinases including VEGFR, PDGFR, and cKIT, as well as significant clinical activity in mRCC. Off target toxicity is frequently seen, and in pts treated with these TKIs the development of anemia ± macrocytosis was noted. Further studies were conducted to clarify the frequency and etiology of these findings. Methods: A retrospective review of mRCC patients treated with sunitinib or sorafenib for = 3 months was undertaken. Complete blood count data including RBC indices was recorded at baseline, 3 months, and at the end of treatment. Thyroid function tests (TFTs) were collected, and in selected patients, bone marrow examination was undertaken. Results: Ninety eight pts were evaluated (61 sunitinib-treated, 37 sorafenib-treated). In sunitinib-treated mRCC patients, median MCV levels increased significantly at 3 months compared to baseline (97.1 fL vs. 90.2 fL; p<0.001) and median Hgb levels decreased from 13.4 to 12.8 (p =0.31). In patients receiving sunitinib >12 months, MCV continued to increase throughout treatment. There was no association between increasing MCV and the development of hypothyroidism. In 10 patients discontinuing sunitinib, MCV returned to baseline within 2 to 4 months. The number of patient receiving sunitinib with an MCV > 100 at the beginning, 3 months, and end of treatment were 2, 14 and 40 respectively. Bone marrow examinations performed during sunitinib therapy (n=3) demonstrated hypocellularity (5–10%) with normal trilineage hematopoiesis and no evidence of dysplastic changes. In contrast, sorafenib- treated mRCC patients showed no effects at 3 months on MCV levels (90.7 fL vs. 90.6 fL) but an increase in hemoglobin level (14.0 g/dL vs. 13.2 g/dL p=0.02) . At the beginning of treatment 2 patients had MCV values more than 100, but at 3 months and 12 months none of the patients had MCV values more than 100. Conclusions: Macrocytosis commonly develops in sunitinib-treated, but not sorafenib- treated mRCC pts. The etiology of this finding is unclear, but studies suggest direct effects on bone marrow precursors. Sunitinib-induced macrocytosis appears reversible with drug discontinuation.

[Table: see text]
Combination of bevacizumab (B) plus immunotherapy, with interleukin-2 (IL-2) and interferon-α (IFN-α) plus chemotherapy (BIC) in patients with metastatic renal cell cancer (mRCC): Dose-finding phase II trial
Authors: Buti S. , Lazzarelli S. , Simonelli C. , Venturini S. , Spazzapan S. , Lo Re G. , Mattioli R. , Dalla Chiesa M. , Brighenti M. , Passalacqua R.
Published: March 2020

15586

Background: Treatment with IL-2 and IFN-a is considered as an effective immunotherapy (IT) for mRCC. Bevacizumab (B) proved to have efficacy with different mechanism as regards as IL-2 + IFN-a, and had at least an additive effect with chemotherapy (Ch) in many tumors. On this basis, it is reasonable to search for a synergism between B, IT and Ch. Methods: This is a multicenter dose- finding/phase II study aimed at to investigate: 1) safety, tolerability, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the BIC combination; 2) antitumor activity. Dose-finding study comprised 5 escalation dose levels of Ch: Gemcitabine (G) (initial dose 600 mg/m2 to 1,000 mg/m2) followed by 5FU bolus (initial dose 400 mg/m2 to 600 mg/m2) each one on days 1 and 8 every 28 days, associated with fixed doses of B (10mg/kg on days 1 and 15), IL-2 (1 MUI/m2 bid sc on days 8, 9, 15, 16 and 1 MUI/m2/day sc from days 10 to 12 and from 17 to 19) and IFN-a (3 MUI sc on days 10, 12, 17, 19). Three patients were enrolled at each dose level according to Fibonacci statistical method. Phase II study used the reached MTD and was conducted according to two stage Minimax Simon design. Treatment was repetead for a maximum of 6 cycles followed by a maintenance therapy with B and IT until progressive disease (PD). Results: 32 patients were enrolled (male 75%); median age 58 years (range: 28–75): of these, 23 was assessable for toxicity, 14 were pre-treated and 9 not; there was 1 case of DLT (2° level) due to a transitory grade 3 transaminases rising; phase II used the highest dose level of Ch. Grade 3–4 toxicity during all cycles included: neutropenia non febrile (11/23) and 1 febrile, fever in 5; grade 3 toxicity included: thrombocytopenia in 7, asthenia in 4, hypertension in 2, anemia in 2; no bleeding of grade 3–4. So far there are 20 assessable patients for response: 6 (30%) partial response, 8 (40%) stable disease and 6 (30%) PD for an overall disease control rate of 70%. Conclusion: This is the first study that explored the synergy between antiangiogenic therapy, IT and Ch in mRCC. The BIC combination is generally well tolerated and shows promising activity. The Phase II study is currently ongoing and accrual is still open.

No significant financial relationships to disclose.
Phase I study of CNTO 95, a fully human monoclonal antibody to αv integrins, docetaxel, and prednisone in hormone refractory prostate cancer patients (HRPCP)
Authors: Chu F. M. , Picus J. , Mata M. , Kopacynski C. , Foster B. , Lang Z. , Beckman R. A. , Dreicer R.
Published: March 2020

15595

Background: CNTO 95 has demonstrated preclinical antitumor activity through binding to multiple av integrins, resulting in growth inhibition indirectly through anti-angiogenic effects as well as directly by inhibiting tumor cell proliferation. The target, av integrins, has been demonstrated by immunohistochemistry in a large proportion of human prostate cancer tissues. Docetaxel and prednisone have become a standard of care for HRPCP. The primary objective of this study was to evaluate the safety of combining CNTO 95 with this standard. Methods: Patients received day 1 infusions of 75 mg/m2 docetaxel together with twice daily oral prednisone in every 3 week cycles, with weekly infusions of either 5 or 10 mg/kg of CNTO 95 for 7 weeks beginning with the second docetaxel cycle, then CNTO 95 on the days of docetaxel thereafter. Patients were monitored for safety and PSA. Radiologic tumor assessments were performed at least every 4 cycles. Results: Six patients have received docetaxel and prednisone with CNTO 95 at either 5 mg/kg (n=3) or 10 mg/kg (n=3). In the 5 mg/kg group, 1 received 8 cycles then withdrew consent because of fluctuating PSA levels; 1 received 9 cycles then had soft tissue disease progression; and 1 has completed 9 cycles and remains on study treatment. In the 10 mg/kg group, all patients remain on study and have received 7, 6, and 6 cycles of treatment, respectively. There were no unexpected toxicities and only one Grade 3 toxicity (febrile neutropenia) attributed to docetaxel. A 50% decline in PSA occurred in 1 patient treated in the 10 mg/kg group. Conclusions: The combination of standard dose docetaxel and prednisone with 10 mg/kg of CNTO 95 was well tolerated and 3 new patients are planned to be treated with these doses on this study. Further study is warranted.

[Table: see text]
Preservation of erectile function after permanent radioactive seed implantation for treatment of prostate cancer
Authors: Steinmetz R. D. , Barrett W. L.
Published: March 2020

15596

Purpose: Assess erectile function before and after prostate brachytherapy. Materials and Methods: A total 241 patients were treated with permanent I-125 prostate brachytherapy for T1 and T2 adenocarcinoma of the prostate. A retrospective chart review was undertaken to assess erectile function before and after treatment using the scoring system of, 1- complete inability to have erections, 2 - can sometimes have erections sufficient for intercourse with or without medication, and 3 - has normal erectile function. Pretreatment testosterone levels were reviewed for correlation with pretreatment erectile function. Results: The median age was 68. At presentation, the median age of patients with erectile scores of 1, 2 and 3 was 70, 67 and 67 respectively. The median time of follow-up was 48 months. Pretreatment erectile function assessment revealed scores of 1 in 28%, 2 in 27% and 3 in 45% of patients. Median pretreatment testosterone levels were 296 ng/dl in the patients with pretreatment score of 1 compared to 360 ng/dl in patients with a score of 2 and 370 ng/dl in patients with a score of 3. The normal testosterone range for this age group is 165 ng/dl to 830 ng/dl. After 12 months erectile function assessment revealed scores of 1 in 29%, 2 in 42% and 3 in 29% of patients. After 24 months erectile function assessment revealed scores of 1 in 30%, 2 in 41% and 3 in 29% of patients. After 36 months erectile function assessment revealed scores of 1 in 32%, 2 in 45% and 3 in 23% of patients. After 48 months erectile function assessment revealed scores of 1 in 39%, 2 in 36% and 3 in 25% of patients. After 48 months, the median age of patients with erectile scores of 1, 2 and 3 was 75, 69 and 66 respectively. After 60 months erectile function assessment revealed scores of 1 in 32%, 2 in 47% and 3 in 21% of patients. After 72 months erectile function assessment revealed scores of 1 in 24%, 2 in 52% and 3 in 24% of patients. 49% of patients were given sildenafil, vardenafil, or tadalafil to improve erectile function. Conclusion: The rate of potency preservation in this cohort declined in an expected manner after permanent brachytherapy for prostate cancer.

No significant financial relationships to disclose.
The impact of varying rectal contours on rectal dose in prostate cancer patients treated with hypofractionated radiation
Authors: Joshua B. B. , Faria S. , Patrocinio H. , DeBlois F. , Duclos M. , David M. , Shenouda G. , Souhami L.
Published: March 2020

15598

Background: In curative radiation treatment of prostate cancer,the advent of 3DCRT has made a reduction in the incidence of normal tissue toxicities while optimizing tumor control. To optimize 3DCRT, the ICRU has published standard definitions of target volumes and organs at risk such that the tumor can receive the optimal dose with as little as possible dose to the organs at risk. However, the definition of the rectum as an organ at risk in radiation treatment of the prostate varies widely among institutions and so does the report of toxicities. We studied the effect of varying rectal contouring on rectal dose obtained from DVHs in a homogenous group of prostate cancer patients treated with hypo fractionationed radiation. Methods: 71 patients with favorable risk prostate cancer treated with a total of 66Gy in 3Gy/day fractionation.18 MV photons in a 5-field technique was used. None of the patients received hormonal therapy. Their treatment plans were archived and the rectum was re-contoured by a single investigator. 4 different contours were drawn to compare the rectal dose: i) the whole rectum from the anal verge to the recto sigmoid junction (WR); ii) the rectum from 1cm below the PTV to 1cm above (RPTV); iii) the rectal wall (i.e. the inner and outer rectal wall) from the anal verge to the recto sigmoid junction (RW); iv) the rectal wall from 1cm below the PTV to 1cm above (RWPTV) Results: There were significant differences in the median volume, minimum, mean rectal doses and dose to 50% of the volume, (p=0.0001). The whole rectum (WR) is having the lowest and the rectal wall with 1cm above and below the PTV (RWPTV) having the highest in all the parameters. The only parameter not significantly different among the 4 contours is the maximum rectal dose. Conclusion: the varied rectal contouring across different institutions is a possible reason for the broadly different reports of rectal toxicity after prostate irradiation. Our results suggest significant differences in rectal doses with varied contouring. Contouring the rectal wall only and limiting the volume to 1cm above and below the PTV confers the highest mean rectal dose. Comparison of rectal toxicity between institutions can only be meaningful if a consensual volume definition of the organ at risk is agreed upon.

No significant financial relationships to disclose.
Planned nerve preservation modifications to reduce positive surgical margins during robotic-assisted laparoscopic radical prostatectomy
Authors: Zorn K. , Gofrit O. N. , Lin S. , Steinberg G. D. , Zagaja G. , Shalhav A. L.
Published: March 2020

15599

Background: Robotic-assisted laparoscopic radical prostatectomy (RLRP) is increasingly being utilized for the treatment of localized prostate cancer at many centers. The main objective of RLRP is cancer control and preservation of erectile function with reduced positive surgical margin (PSM) rates. We evaluated the effect of a side-specific nerve preservation (NP)protocol which was implemented in June 2006 to help further reduce PSM rates. Methods: Between June-November 2006, 150 consecutive RLRPs were performed using select ipsilateral, NP techniques (interfascial, extrafascial and wide resection) based on pre-operative risk factors (clinical stage, biopsy Gleason score (GS), percentage of core number positive and maximal core cancer percentage). Prior to June 2006, only interfascial and wide resection were performed. The NP protocol, included ipsilateral extrafascial dissection in all patients with GS=7 with non-palpable disease. All patients with GS≤6, non-palpable disease and whose biopsy pathology demonstrated <33% of ipsilateral cores positive for cancer were offered interfascial dissection. Wide resection was performed for patients with palpable disease, GS≥8 and ≥66% of all ipsilateral biopsy cores positive for cancer. Pathological outcomes were compared with the 245 consecutive RLRP cases performed prior to June 2006, where more liberal interfascial NP was performed. Results: Relative to the modified NP group, mean patient age (60 vs 59, p= 0.21), PSA (6.7 vs 6.8, p=0.77), clinical stage (p=0.93), biopsy Gleason score (p=0.51), pathologic Gleason score (p=0.32) and stage (p=0.65) were similar to the control group. Mean total number of positive cores involved with cancer were also comparable between groups (3.5 vs 3.3, p=0.31). Overall PSM rate was significantly lower in the modified NP group (12.6% vs 20.4%,p=0.04). Specific pT2-PSM rates were significantly lower (8.3% vs 15%, p=0.04) while only a trend was observed for pT3-PSM rates (34.5% vs 40.4%, p=0.60) in the modified NP group. Conclusions: Modifying ipsilateral nerve preservation for patients undergoing RLRP, based on specific pre-operative variables has significantly helped further reduce overall and pT2-specific PSM rates.

No significant financial relationships to disclose.
Safety and activity of sorafenib in advanced renal cell cancer: A single institution experience
Authors: Bajetta E. , Procopio G. , Verzoni E. , Mancin M. , Pusceddu S. , Bajetta R. , Galassi M. , Gevorgyan A.
Published: March 2020

15604

Background: Sorafenib is an oral multitargeted tyrosine kinase inhibitor of RAF-kinase and VEGFR2, with antiangiogenic and antitumor activity in pretreated advanced renal cell cancer (RCC). Methods: In our institution, from December 2005 to November 2006, 131 consecutive patients(pts) with advanced RCC received sorafenib 400mg/bid/continuously. Main patient characteristics were: clear-cell cancer 106 pts, papillary-cell 15 pts, cromophobe-cell 3pts, collecting duct carcinoma 3pts, other histotypes 4pts. Previous nephrectomy was performed in 122 pts with median relapse free survival of 23 months (range 3–180 mos). The most common site of disease was lung, whereas 94 pts had 2 or more secondary disease locations. According to Motzer’s prognostic score 85 pts were at low risk, 36 pts and 10 pts at intermediate and high risk respectively . 12 pts were treatment naïve for metastatic disease. 68 and 51pts received one or at least two systemic treatments respectively. Results: Currently, 106 pts are evaluable for safety and objective response. According to the RECIST criteria, the activity of sorafenib in terms of tumor shrinkage was observed in 32 pts(31%) with 10 partial response (9.5%) and 22 minor response (21%) respectively. Stable disease was seen in 42 pts (41%) and progressive disease in 28 pts (26%), 4 pts were not evaluable for response. Overall, 74 pts (72%) had disease growth control. Median duration of response was 8 months and median time to progression was 6.5 mos, median overall survival has not been reached yet. The most common treatment-emergent adverse effects seen in 78% of pts, were grade (G) 1/2 (NCI-CTC) and included hand foot syndrome, rash, diarrhea, fatigue, hypertension and mucositis. Dose modification due to G3–4 adverse event, such as skin toxicity and cardiovascular events, was performed in 35 pts(32%). Conclusion: sorafenib is effective in terms of tumor growth control in untreated as well as in pretreated patients and in different hystotypes of renal cell cancer. Particularly, in heavily pretreated patients the number and severity of drug related toxicity suggests the dose reduction as possible standard therapy. The Authors would like to thank (I.T.M.O) Italian Trials in Medical Oncology for editorial assistance.

No significant financial relationships to disclose.
Background variables for the patients with invasive bladder cancer suitable for bladder-preserving therapy
Authors: Miyanaga N. , Akaza H. , Hinotsu S. , Joraku A. , Oikawa T. , Sekido N. , Kawai K. , Shimazui T.
Published: March 2020

15610

Background: The present study was undertaken to identify the patients suitable for bladder preservation by analysis of our previous studies. Methods: The subjects of this study were all 72 patients with T2–3N0M0 bladder cancer who underwent bladder- preserving therapy in our institute. The therapy involved intra-arterial chemotherapy with MTX and CDDP and concomitant radiotherapy. Results: Of the evaluable 70 cases, complete response was confirmed in 57 cases (81.4%). The median follow-up was 45.3 months. The 5-year cause-specific survival rate was 81 % and the 5-year overall survival rate was 66%. Based on the results of univariate analysis, variables contributing to complete response were selected. In T2 cases, tumor size of 3 cm or less was scored 0 and tumor larger than 3 cm was scored 1, while single tumor was scored 0 and multiple tumors were scored 1. In T3 cases, tumor size of 3 cm or less was scored 0 and tumor larger than 3 cm was scored 1, while G2 was scored 0 and G3 scored 1. The CR rates were 93.8% and 92.6% for total scores of 0 and 1, respectively, and 62.9% for a total score of 2 (P = 0.003; score 0 or 1 vs 2). The overall survival rate was significantly higher in the former group (P = 0.003). Conclusion: Bladder-preserving therapy can be acceptable for cases of single T2N0M0 tumor with a size of =3 cm and for T3N0M0 cases with a tumor size of =3 cm.

No significant financial relationships to disclose.
Secular trends in survival in prostate cancer (PC) (1992–2005) in a public hospital in Barcelona: Impact of PSA implementation and hormone-radiotherapy (HT+RT) treatment introduction—An observational study
Authors: Malmusi D. , Carles J. , Bellmunt J. , Macià F. , Llorente J. A. , Serrano S. , Foro P. , Gelabert A. , Albanell J. , Castells X.
Published: March 2020

15615

Background: There are reports of declines in mortality in several series and countries following introduction of PSA test. With routinely collected data we explore changes over time in PC survival, its correlation with PSA implementation and with the introduction of HT+RT. Methods: From the Hospital del Mar Cancer Registry we selected patients with histological confirmation of PC diagnosed between 1992 and 2005. Clinical and pathological stage, grade, PSA at diagnosis, type of treatment and follow-up until 2005 were available, and patients were grouped in three-years periods. Results: Out of 1,185 registered, 897 patients were evaluable. Median age at diagnosis decreased from 72 in 1992–96 to 70 in 2003–05 (p<.001). Median PSA at diagnosis decreased from 35 μg/ml to 14 μg/ml after 1996. Patients being diagnosed as metastatic changed from 67% before 1997 to 29% in 1997–99. A trend towards lower pathological stage has been observed, although in stage II and III no significant changes in risk group distribution were observed throughout the study period (χ2 =.318). Since 1999 there is a progressive increase in HT+RT indication in stages II and III with a significant decrease in the indication of surgery. There is an improvement in overall relative survival at 5 years before and after 1999, from 67,3% (CI: 60,2–75,2) to 92,9% (CI: 87,3–98,9).The same tendency was found in patients with localized tumour with intermediate and high risk coincidentally with the implementation of HT+RT. Conclusions: An increase in survival of patients with PC has been observed, coinciding with a shift towards lower stages and PSA levels at presentation, suggesting an influence of early detection by PSA. The increase in survival among localized tumors since 1999 could be explained by secular variations in the treatment of PC, as the implementation of HT+RT in patients with intermediate and high risk localized PC.

No significant financial relationships to disclose.
Immunodetection of androgen and estrogen a,b receptors in human urinary bladder cancer
Authors: Gómez Pinillos A. , Bueno Serrano G. , Sacristán López S. , García González R. , Varona Crespo C. , Fernández Fernández E. , Moyano Jato A. , Arenas Jiménez M. , Toledo Lobo M.
Published: March 2020

15616

Background: Bladder cancer predominates in males. Loss of androgen receptor (AR) has been associated with invasive and undifferentiated tumors but little is known about the role of hormonal receptors in this type of cancer. Methods: We evaluated samples from 41 nonconsecutive patients treated for bladder transitional cell carcinoma between 2001–2003. Immunohistochemistry was performed using anti-AR and anti-ER a,b antibodies on paraffin-embedded tumors from transurethral resections, nuclear expression was assessed. Western blotting for AR and pAKT were performed in 22 transurethral resections from nonconsecutive bladder cancer patients treated between 2004–2006. Chi-square and U Mann-Witney tests were performed. Results: Immunohistochemistry study: the male/female ratio was 9/1; 61% were noninvasive tumors (pTa, is,1) and 32% were invasive (pT2,3); 22% were G1 and 75% were G2,3. 95% were AR(+), 40% ERa(+) and 94% ERb(+). Significant differences in AR expression were observed between G1 78% and G2,3 tumors 100%, with a high grade tumor prevalence in the AR(+) tumors 81.6% p=0.046. No differences between ERa,b and differentiation were found. G2,3 tumors were predominantly ERb(+). AR was found in 92% noninvasive and in 100% invasive tumors p=0.53. No significant differences were found between invasiveness and ERa,b. Noninvasive tumors showed higher ERa,b expresión (54%, 95% respectively) than invasive tumors (20%, 91% respectively). Western blotting group: 54.5% were primary tumors and 45.5% were recidives. The noninvasive/invasive rate was 59/32%, the G1/G2,3 rate was 4.5/95.5%. 112, 250 and 160 kDa bands were found. AR/pAKT rate was 86.4/100%. 100% of invasive tumors and 86% G2,3 tumors were AR(+). No differences between pAKT, invasiveness, differentiation or AR expression were observed but recidivated tumors had a slight higher median expression level. Conclusions: AR is positively related to tumor grade and might be involved in bladder cancer progression. The profile of AR bands suggest covalent modifications, due to ubiquitin-mediated degradation or to activation mechanisms mediated by SUMO. Nuclear AR and the absence of bands under 90kDa suggest that activated protein is present in bladder cancer. pAKT/AR inhibitors could play a role for bladder cancer therapy.

No significant financial relationships to disclose.
Is the blood-brain barrier relevant in metastatic germ cell tumors?
Authors: Azar J. M. , Einhorn L. H. , Schneider B. P.
Published: March 2020

15618

Background: Metastatic germ cell tumors (GCT) are highly curable. Central Nervous System (CNS) recurrence can terminate a complete remission in other chemosensitive tumors such as small cell lung cancer due to the blood brain barrier (BBB). We document that the BBB can also be relevant in GCTs despite dramatic chemosensitivity. Methods: We present five cases of CNS only relapse in GCTs. None of these five patients had CNS metastases at the start of chemotherapy. Results: We have identified five unique patients from our large series of metastatic testicular cancer patients treated with chemotherapy. These patients were rendered free of disease with cisplatin- based chemotherapy only to relapse in the brain alone ( Table 1 ). This included one patient with good risk disease by the International Germ Cell Collaborative Group staging system (Patient #5). All patients had pulmonary metastases at diagnosis and a component of embryonal carcinoma. Three patients are alive without evidence of disease (NED) at 19, 32 and 8 months. One patient died of his disease (DOD) and one patient is alive with disease (AWD). Conclusion: The blood brain barrier is relevant in metastatic testicular cancer.

[Table: see text]

No significant financial relationships to disclose.
The value of PET-CT (positron emission tomography) in the treatment of metastatic renal cell carcinoma with sorafenib
Authors: Stierner U. , Boijsen M. , Suurküla M. , Lundstam S.
Published: March 2020

15621

Background: Sorafenib is a new potent multikinase inhibitor directed against both tumour proliferation and angiogenesis. Clinical benefit has been shown in 75% of patients with metastatic renal cell carcinoma. The aim of this study was to evaluate this new treatment with PET-CT with fluorodeoxyglucose (FDG), since the use of only CT measurements has been questioned. Methods: 10 patients (8 male, 2 female, 49–72 years) with metastatic renal cell carcinoma (9 clear cell, 1 chromophobe). All had progressive disease (8 after interferon). Sorafenib 400 mg b.i.d was given orally. FDG-PET-CT scan was performed from head-proximal thigh before treatment and after one month. Up to 6 target lesions in each patient were studied. The sum of the largest diameters was calculated from CT images for each patient. To evaluate the glucose uptake, a region of interest (roi) was designed for each leasion on the initial PET on the transverse section where the lesion appeared to be largest and/or most intense. Using the same roi for subsequent examinations the mean glucose uptake/mean cerebellar uptake was calculated. For each patient the mean change from baseline was calculated. Results: After one month of treatment the sum of tumour diameters measured by CT was mean 85% (53–110%) of the initial value. Measured by PET the mean glucose uptake at one month was mean 73% (29–100%) of the initial value. Seven patients had skeletal lesions. These were often difficult to measure on CT and only small changes were detected. Using PET the mean uptake in skeletal lesions was 77% (62–104%) at one month. Conclusions: Early effects of sorafenib treatment in metastatic renal cell carcinoma can be detected and quantified by PET-CT. Especially in skeletal lesions PET-CT exhibits considerable benefits over CT by visualizing responses otherwise missed. Future studies will reveal if a decrease in tumour glucose uptake at one month correlates with the more clinically relevant endpoints PFS and OS.

[Table: see text]
Retrospective analysis of patients with nonseminomatous testicular germ cell tumor and resection of postchemotherapy residual lung and mediastinal masses
Authors: Assad D. X. , Dienstmann R. , Metzger Filho O. , Rodrigues A. N. , Olmedo D. B. , Small I. A. , Herchenhorn D.
Published: March 2020

15633

Background: Treatment of nonseminomatous testicular germ cell tumor (NSGCT) involves surgery of postchemotherapy (PC) residual masses. The resection of immature teratoma or viable cancer prolongs disease-free and overall survival. Discordance of histology among different sites of residual masses has been reported to occur in one-third of the patients and therefore, all identified masses must be removed. This study aims to evaluate the histology of residual masses in patients submitted to thoracic surgery for NSGCT and estimate time to progression after surgery and overall survival. Methods: Retrospective analysis of all patients with NSGCT and PC residual lung and mediastinal masses treated at the Brazilian National Cancer Institute between 1997 and 2006. Results: Of the 16 patients included, 10 patients had residual lung masses, 5 had both lung and mediastinal masses and 1 had mediastinal mass. Median age at diagnosis was 26.5 years. Embryonal carcinoma plus yolk sac tumor was the most frequent testicular histology (31%). Nine (56%) had stage IIIC disease and 7 (44%) were high-risk at the IGCCCG score. All patients received platinum-based chemotherapy (one had platinum-refractory disease). Of the 15 patients who had lung masses, 8 had bilateral disease. Histology of residual lung masses was necrosis in 8 patients (53%) and teratoma in 7 (47%). There was 100% concordance in the histology of bilateral lung masses. Ten patients (62%) had concomitant retroperitoneal masses. In only 3 of these patients (33%) there was concordance between retroperitoneal and lung histology. Median follow-up after surgery was 21.5 months. Five of the 16 patients (31%) had disease progression. One patient died (this patient had platinum-refractory disease). Median time to progression was 10 months and median overall survival was not reached. Conclusions: These data confirmed the small concordance between the histology of PC residual masses in the lung/ mediastinum and retroperitonium in NSGCT. There was concordance in the histology of bilateral lung masses. These findings suggest that all sites of residual masses should be resected and the presence of necrosis in residual lung masses indicates no need for contralateral resection.

No significant financial relationships to disclose.