bluuebunny/crossref_metadata_2025 huggingface dataset:
Pancreatic neuroendocrine tumors: Single institution review over 10 years.
Authors: Asija Aakanksha , Milan Stacey , Prestipino Anthony , Yeo Charles , Pillai Madhavan V.
Published: March 2020

e15183

Background: Pancreatic neuroendocrine tumors(pNET) are rare tumors accounting for less than 5% of pancreatic cancer. They are functionally and biologically heterogeneous and have not been studied in great detail until recently. Methods: We conducted a retrospective review of 79 consecutive patients with pNET diagnosed and treated at Thomas Jefferson University Hospital between the years of 2000 and 2010. Results: Of the 79 patients whose records were reviewed, 32 were male and 47 were female. Median age at diagnosis was 61 years. Two cases were associated with MEN1 syndrome. Primary tumor arose in the head, body and tail of the pancreas in 15, 10 and 26 patients, resp. In 6 patients, the tumor was multifocal. The neuroendocrine tumor was accompanied by pancreatic adenocarcinoma in 1 patient and intraductal papillary mucinous neoplasm in 3. In 10 patients, distant metastasis was detected, involving liver only. Tumor was functional in 9 patients: 5 insulinoma, 2 gastrinoma,1 glucagonoma and 1 VIPoma. As per TNM staging, 28, 22 and 10 patients were Stage I, II and III, and IV at diagnosis. Treatment by surgical resection was undertaken in 54 patients. In 21 patients, the tumor was discovered incidentally; 21 patients presented with abdominal pain. Other symptoms were irregular bowel movements, weight loss and jaundice. 51 of the 79 (64.5%) patients were alive at last follow up. On univariate analysis, median survival for females was 137 months vs 114 months for male. Median survival for patients with functional tumors was similar to those with nonfunctioning tumors (118 and 115 months, resp). Median survival for patients with Stage I, II, and III and Stage IV patients were 234,112 and 40 months resp. Median survival for patients who underwent surgical resection was 130 months vs those who did not (30 months). Conclusions: Majority of pNET were located in the body and tail of pancreas; an area requiring thorough scrutiny with special imaging studies for diagnosis. Only a minority of patients presented with liver metastasis(12%) and a smaller number showed hormonal activity (11%). Prognosis improved markedly in patients who underwent surgical resection. Therefore, whenever appropriate, surgical resection should be the treatment of choice in patients with pNET.
Combination therapy with radiation and weekly paclitaxel/carboplatin as definitive treatment for locally advanced esophageal cancer.
Authors: Doherty Mark , Cowzer Darren , Kelly Ciara Marie , Battley Jodie Emma , Leonard Gregory D. , Power Derek Gerard
Published: March 2020

e15196

Background: Definitive chemoradiotherapy (CRT) is an established treatment option in localised esophageal cancer. While most patients are treated with cisplatin and fluorouracil, alternative chemotherapy regimens have been used. The combination of carboplatin and paclitaxel (CP) has been validated in a neoadjuvant CRT trial by the CROSS study. There has also been a phase II study (v. Meerten, ASCO 2010, e14508) showing efficacy and tolerability of this regimen in the definitive setting with radiation doses of 50.4Gy/28#. We report our experience using this strategy in two Irish centres. Methods: Patients treated with weekly CP and definitive radiation between Jan 2010 and Oct 2012 were identified from our pharmacy database. Clinicopathologic details were obtained from electronic medical records. The group contains patients with locally advanced unresectable disease, or those medically unfit for esophagectomy. Results: Between Jan 2010 and Oct 2012, we identified 22 patients. Thirteen patients had squamous histology, while 9 had adenocarcinoma. Staging was performed with CT, EUS, and PET/CT – 1 patient had T2 disease, while the remainder had T3/T4, and 10 patients had positive nodes. Reasons for not pursuing surgical resection were extent of disease and poor performance score. In total, 86% of patients received full dose treatment, with reasons for dose delay/reduction being grade 3 sepsis, grade 3 gastrointestinal toxicity, and decline in performance status. Overall 5 (23%) patients needed hospital admission during treatment. At a median follow up of 14 months (range 9-23months), 19 patients are alive with no evidence of disease, 2 patients have died of disease, and 1 patient is alive with relapsed disease. Our 1-year recurrence free survival rate is 86%. Conclusions: Definitive CRT with CP is a tolerable regimen that can be administered on an outpatient basis, and provides a treatment option in those who are unsuitable for surgical resection or Herskovic type CRT. Our results compare favorably with previous studies in this population. Further investigation is warranted in a prospective study to validate the efficacy of this approach.
Effect of the combination therapy of sorafenib and radiofrequency ablation on the survival time of advanced HCC.
Authors: Wang Nanya , Li Wei , Zhao Hengjun , Cui Jiuwei
Published: March 2020

e15198

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers in the worldwide. In China, accounts for 70% patients are in the advanced stage at the first diagnosis. Sorafenib is the only systemic therapy in adavanced HCC. Radiofrequency ablation (RFA) therapy is an new and effective minimally invasive method recent years and there are rare reports of the combination of RFA and sorafenib for the advanced HCC. This study was designed to observe the effect and security of the combination therapy with RFA and sorafenib for advanced HCC. Methods: Twenty-four advanced HCC patients treated with sorafenib for more than 3 months were divided into two groups: sorafenib alone (13 cases) and RFA/sorafenib (11 cases). The tumor status of these patients was evaluated with computed tomography (CT) every 1~2 months. Progression-free survival (PFS), Overall survival(OS) and adverse effects were observed. Results: The median PFS in sorafenib group was 3.9 (2.3-5.8) months, while median PFS in RFA/sorafenib group was 6.8 (2.5-12.8) months. The combination therapy got longer PFS than treated sorafenib only (P<0.05). And the mOS in sorafenib group and RFA/sorafenib group were 16.3 vs. 22.7months (P<0.05). The side effect of radiofrequency ablation are mainly included fever and pain in puncture location. And only 2 patients got pleural effusion post-operation. All the side effects are disappeared in 2 weeks. The most common adverse reactions observed in patients treated with sorafenib were: fatigue, weight loss, rash or superficial skin desquamation, hand-foot skin reaction, hair loss, diarrhea, anorexia, nausea and abdominal pain, only 3 patients got severe hand-foot skin reaction and diarrhea, but all of them continued the sorafenib oraled after symptomatic treatment. Conclusions: RFA combined with sorafenib prolonged the PFS and OS in advanced HCC. This combination therapy is safe and effective for patients with advanced HCC. This approach could be a new choice for advanced HCC.
Expression of HIF1a and HIF2a in bone metastatic clear cell renal cell cancer and use as prognostic markers.
Authors: Timar Jozsef , Szasz Attila Marcell , Kardos Magdolna , Tokes Annamaria , Kulka Janina , Szendroi Miklos , Szendroi Attila
Published: March 2020

e15523

Background: Bone metastasis is a frequent complication of ccRCC and predictors of this type of progression are scanty. The aim of this study was to analyse HIF and HIF regulated gene expressions in bone metastatic ccRCC. Methods: A pre-target therapy era cohort of 125 ccRCC patients with <100 month follow-up period have been collected with paraffin embedded primary tumors. 65 patients developed bone metastasis where 45 metastases were available for analysis. RNA was isolated from FFPE tissues and gene expression of HIF1A, HIF2A as well as HIF-regulated genes GLUT1, LDH5, GAPDH, CAIX, VEGF, VEGFR2 and EPOR were measured by RT-PCR using B2M as control. Protein product of these genes was measured on TMA arrays using standardized immunohistochemistry and an image analysis program (Mirax Viewer, 3DHistech). Results: Expression of HIF1A and HIF2A was significantly increased in bone metastatic primary ccRCC tumor tissues both at mRNA and protein levels. Significant upregulation of 3 out of 7 HIF-regulated genes (VEGFR2, EPOR and LDH5) in the primary tumor tissues of bone metastatic ccRCC was proved at mRNA levels and confirmed at protein level for VEGFR2 as well. In bone metastatic tissues a significant overexpression of HIF2A and VEGF mRNA was also detected compared to the primary site. Prognostic power of the protein expression in primary tumor was found for HIF1A (p= .001), HIF2A (p = .041), and VEGFR2 (p = .001) (confirmed at mRNA levels as well) for overall survival at time of surgical removal of primary renal tumor using Kaplan-Meier method and log-rank statistics. To further test the power of HIF1A and HIF2A as prognostic factors we have performed multivariate analysis considering available clinicopathological variables (gender, Fuhrman grade, stage) and found that HIF2A protein level outperformed all other factors in the model. Conclusions: These data indicate that HIF genes are overexpressed in bone metastatic ccRCC among which HIF2A expression at mRNA and protein levels can be used as a strong independent prognostic marker.
Correlation of stomatitis and cutaneous toxicity with clinical outcome in patients with metastatic renal cell carcinoma treated with everolimus.
Authors: Rossi Lorena , Santoni Matteo , Medri Matelda , Scarpi Emanuela , Burattini Luciano , Burgio Salvatore Luca , Savini Agnese , Berardi Rossana , Stanganelli Ignazio , Cascinu Stefano , Amadori Dino , De Giorgi Ugo
Published: March 2020

e15529

Background: We assessed the incidence and clinical presentation of stomatitis and cutaneous toxicity associated with everolimus in patients (pts) with metastatic renal cell carcinoma (mRCC). Correlation between these toxicities and clinical outcome was also determined. Methods: We retrospectively reviewed the clinical data of pts with mRCC treated with everolimus in two Italian Centers. Clinical evidence of stomatitis and/or cutaneous toxicity inducing a treatment discontinuation or a dose reduction were considered stomatitis-cutaneous toxicity events (SCTE). SCTE were evaluated and corresponding clinical data were reviewed for response and clinical outcome. Response was evaluated according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Results: The study population consisted of 79 mRCC pts treated everolimus (57 male, 22 female; median age 69 years, range 44–88). Fifty-two pts (66%) received everolimus as second-line therapy, while 27 (34%) as third-line. SCTE were seen in 20/79 pts (25%) at a median of 30.5 days on everolimus treatment (range 10–270 days). Tumor response was evaluable in 77 of 79 patients (19 of 20 SCTE pts and 58 of 59 non-SCTE). Partial response or stable disease was achieved in 15 of 19 pts with SCTE (79%) compared to 28 of 58 (48%) with no SCTE (p = 0.03). After a median follow-up of 19 months (range, 1 to, 39), the median progression-free survival (PFS) was 5.5 months (95% CI 3.4-7.7) and the median overall survival (OS) was 17.2 months (95% CI 13.2-24.4). A significant difference was found in the median PFS equal to 7.5 months (95% CI 3.4-24.4) in SCTE pts vs 3.7 months (95% CI 2.7-7.5) in non-SCTE, p = 0.047, and in the median OS equal to 30.6 months (95% CI 14.8-not reached) in SCTE pts vs 14.0 months (95% CI 9.9-17.7) in non-SCTE, p = 0.004. Conclusions: These data suggest that SCTE may be a predictive marker of favorable outcome in mRCC treated with everolimus. A prospective observational study with a dermatologic/stomatologic monitoring has been planned in mRCC pts treated with everolimus.
Association of a 2-weeks-on and 1-week-off schedule of sunitinib with decreased toxicity in metastatic renal cell carcinoma.
Authors: Najjar Yana George , Elson Paul , Wood Laura S. , Garcia Jorge A. , Dreicer Robert , Rini Brian I.
Published: March 2020

e15534

Background: Treatment of metastatic renal cell carcinoma (mRCC) with sunitinib can be associated with toxicity leading to dose reduction. Maintaining adequate sunitinib dosing and avoiding dose interruptions that lower drug levels are essential for optimizing clinical efficacy. Standard sunitinib schedule is 4 weeks of treatment and 2 weeks of rest (schedule 4/2). Empirically in clinical practice, several metastatic RCC patients at The Cleveland Clinic (CCF) have been changed from a 4/2 schedule to a 2 weeks on /1 week off (2/1) schedule after experiencing toxicity in an attempt to maintain daily dose but reduce toxicity. Methods: The medical records of mRCC patients who were changed to a 2/1 schedule of sunitinib at CCF were retrospectively reviewed. Patient toxicity on each schedule was recorded during routine clinic visits and graded according to the Common Toxicity Criteria, version 4.0. Results: 21 patients were identified: 71% male, 78% clear cell histology, and 29% prior systemic therapy. All but one had prior nephrectomy. 95% of patients on the 4/2 schedule had grade 3 or 4 toxicity which led to the schedule change to 2/1. No grade 4 toxicities were observed on the 2/1 schedule, and 33% of patients experienced grade 3 toxicity (p = 0.0001 for comparison of worst grade toxicity on 4/2 versus 2/1). Two of the most common toxicities, fatigue and hand-foot syndrome (HFS), were significantly less frequent on the 2/1 schedule than on the 4/2 schedule (fatigue 52% all grade/33% grade 3 on 4/2 versus 33%/14% on 2/1; HFS 33%/29% on 4/2 versus 14%/0% on 2/1; p =.04 for both). Median overall treatment duration on the 4/2 schedule was 13.5 months (range 1.1-60.6 months) and median overall treatment duration on the 2/1 schedule was 24.4 months (range 1.3 to 67.6+ months). Conclusions: Treatment with sunitinib on a 2/1 schedule is associated with significantly decreased toxicity in patients who initially experience grade 3 or greater toxicity on the 4/2 schedule and can extend treatment duration considerably. Prospective clinical trials are required to define the optimal schedule of sunitinib to balance efficacy and toxicity.
Antihypertensive therapy with ACE-inhibitors and clinical outcome in metastatic renal cell carcinoma (mRCC) patients.
Authors: Bianconi Maristella , Scartozzi Mario , Faloppi Luca , Giampieri Riccardo , Bittoni Alessandro , Del Prete Michela , Cecchini Luca , Burattini Luciano , Montironi Rodolfo , Cascinu Stefano
Published: March 2020

e15536

Background: Preclinical and clinical reports in various solid tumours, such as HCC, showed a potential enhancement of anti-angiogenic effect of TKIs treatment by the concomitant use of ACE-inhibitors. On the other hand hypertension is a common side-effect with the use of such therapeutic approach with an improved efficacy profile suggested in these patients. However data in metastatic renal cell carcinoma patients are lacking. The aim of our analysis was to evaluate the correlation between incidental use of ACE-inhibitors and clinical outcome in mRCC patients receiving first-line TKIs. Methods: 102 patients were eligible for our analysis. All patients received a TKI as a first-line treatment. ACE-inhibitors therapy was initiated prior or during the TKI administration. Results: Median OS was 32.13 months. 21 (21%) patients received ACE-inhibitors, while 81 (79%) did not. The OS was 37.5 months for patients treated with concomitant ACE-inhibitors and 17.8 months for those without such a treatment (p=0,005). No significant differences were found with other antihypertensive treatments or for the clinical variables considered. Conclusions: In our analysis the incidental use of ACE-inhibitors represents a relevant factor for clinical outcome in mRCC patients. If confirmed in larger case series the use of antihypertensive treatment, particularly ACE-inhibitors, could be considered a stratification factor.
Morphoproteomics of mTORC2 pathway as resistance signature and activated ERK and STAT3 prosurvival/antiapoptotic pathways in metastatic renal cell carcinoma (mRCC) progressing on rapalogs.
Authors: Yadav Swetha Siddappa , Buryanek Jamie , Brown Robert E , Ouyang Fangqian , Amato Robert J.
Published: March 2020

e15548

Background: Resistance to rapalog therapies (rapamycin, temsirolimus or everolimus) in mRCC may be due to adaptive switching from mammalian target of rapamycin complex (mTORC)1 to mTORC2. A preclinical study using an agent targeting both complexes demonstrated the combination is more effective than temsirolimus in vitro but not in xenograft models (Zhang 2013 PLos One). Methods: Morphoproteomic analysis of mRCC biopsies showed progression while the patients were treated with everolimus or temsirolimus at the time of biopsy. Constitutive activation evidenced by expression (≤3) of phosphorylated (p)-mTOR (Ser 2448) in the nuclear compartment coupled with concomitant expression of p-Akt (Ser 473) favors mTORC2 and constitutive activation by p-extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Tyr204) and p-signal transducer and activator of transcription (STAT)3 (Tyr705) in the nuclear compartments (≤3) indicates convergent signaling through prosurvival/antiapoptotic pathways. Results: Overexpression of mTORC2 with strong expression of p-ERK1/2 and p-STAT3 indicates adaptive switch from mTORC1 to mTORC2 pathway and constitutive activation of prosurvival/antiapoptotic pathways (Table). Overexpression of mTORC1 with strong expression of p-ERK 1/2 and p-STAT3 indicates adaptive resistance to everolimus. Equal expression of mTORC 1 and 2 with concomitant strong expression of p-ERK1/2 and p-STAT3 indicates resistance to everolimus and constitutive activation of the adaptive prosurvival/antiapoptotic pathways. Conclusions: Morphoproteomics confirms mTORC2 as resistance signature to rapalog therapy and uncovers constitutive activation of the prosurvial ERK and STAT3 pathways as additional adaptive mechanisms to such treatment, indicating the need for a combinatorial therapeutic approach in mRCC progressing on rapalogs. [Table: see text]
Renal cell cancer (RCC): Use of metformin in the setting of renal impairment.
Authors: Ochuwa Nwabugwu , Finkel Kevin , Ouyang Fangqian , Amato Robert J.
Published: March 2020

e15551

Background: Metformin is a biguanide that is widely used to treat type-2 diabetes and prediabetic syndromes. It has been found to inhibit RCC cell proliferation through activation of AMP-activated protein kinase (AMPK) and downstream inhibition of mammalian target of rapamycin (mTOR). Metformin is associated with potentially life threatening lactic acidosis (LA), but a clear link has not been established. We evaluated the occurrence of lactic acidosis in metformin-treated RCC patients with renal impairment. Methods: A retrospective study of 65 RCC patients treated with 250 to 2000 mg of metformin daily was conducted. Demographic data including age, gender, and ethnic background were collected. Data were collected on median metformin dose, eGFR, dialysis status, lactic acid, BUN, Na, K, Cl, and CO2 values. Results: Median metformin dose was 1000 mg daily in each group. Fifteen patients (23%) had elevated lactic acid >4. The mean eGFR for patients with elevated lactic acid of >4 vs. <4is comparable (p=0.98). The two populations were significantly different at the BUN baseline level: patients with lactic acids >4 have statistically significant smaller median baseline BUN level (median of 19.0 vs. 19.5; Wilcoxon two-sample p=0.03). Moreover, there is a marginally significant difference in age between these 2 groups (Mean of 58 vs. 62.8, Student's t-test p=0.07). Conclusions: Regardlessof lactic acid elevation, patients did not experience lactic acidosis. Complete data will be presented. [Table: see text]
Phase I clinical trial of external hyperthermia and intravesical mitomycin C to treat BCG-refractory bladder cancer.
Authors: Abern Michael , Vujaskovic Zeljko , Dewhirst Mark W. , Lan Lan , Craciunescu Oana I. , Stauffer Paul , Inman Brant Allen
Published: March 2020

e15560

Background: Patients with non-muscle-invasive bladder cancer (NMIBC) that fail intravesical bacillus Calmette-Guérin (BCG) are at high risk for progression. Radical cystectomy is an effective but morbid treatment option. We tested the safety and efficacy of combined intravesical mitomycin C (MMC) and external deep regional hyperthermia (HT) as a bladder-sparing approach for BCG-refractory NMIBC. Methods: Patients with BCG-refractory NMIBC were eligible for this phase I clinical trial. Treatment consisted of intravesical MMC (40 mg in 40 mL) with concurrent HT with target temperature of 42°C. MMC dwell time was 60-120 min and heating time was 40-60 min. HT was delivered using a BSD2000 device and temperatures monitored with skin, bladder and rectal probes. Treatment was given weekly for 6 weeks (induction) then monthly for 4 months (maintenance). The primary endpoint was toxicity which was assessed using CTCAE 3.0. Secondary endpoints included recurrence-free survival (RFS), progression-free survival (PFS), cystectomy, and overall survival (OS) which were assessed at 3 month intervals with cystoscopy and cytology for 2 years. Results: Fifteen patients were eligible and consented to the clinical trial. Median age was 66 years and 87% were male. Median follow-up was 2.85 years. One patient did not tolerate supine position, two completed induction but recurred prior to maintenance, one recurred after 3 maintenance treatments, and 11 patients received all 10 treatments. The 2 year RFS was 33% (median RFS = 15.4 mos). Six patients (40%) required cystectomy (median time = 20.1 mos). No patient had bladder progression but two patients developed ureteral tumors (not present on baseline imaging). Two patients died, one from ureteral cancer and one of cardiovascular disease, for a 3-year OS of 83% (median OS not reached). No grade III toxicities were observed. Common toxicities were abdominal pain (36%), cystitis (22%), pruritis and urinary tract infection (14%). Conclusions: The combination of MMC and HT for BCG refractory NMIBC was safe and associated with low grade toxicity. While recurrence was common, progression did not occur, and recurrent patients were safely salvaged with cystectomy. Clinical trial information: NCT00734994.
Body composition as a predictor of sunitinib toxicity in patients with renal cell carcinoma.
Authors: Cushen Samantha , Ryan Aoife M , Teo MinYuen , MacEneaney Peter , McLaughlin Patrick , Fitzpatrick Frances , Rozumna-Martynyuk Nataliya , McDermott Raymond S. , Power Derek Gerard
Published: March 2020

e15566

Background: Sunitinib is a standard first-line option for metastatic renal cell cancer (mRCC). Identification of biomarkers associated with outcome or toxicity is a challenge. Body composition is a prognostic factor in cancer and sarcopenia is associated with treatment toxicity and survival. We investigated if body composition by CT scan predicted dose limiting toxicity (DLT) from sunitinib in mRCC. Methods: Patients (pts) with mRCC receiving sunitinib 50mg as 1stline therapy between 2007-2012 were included. Ethical approval was obtained and prospectively maintained databases analysed. Skeletal muscle cross-sectional area at L3 was measured by CT. Sarcopenia was defined using published cut offs. Toxicity was assessed after 4 cycles of drug (CTCAE, v4.0). Results: 55 pts (43 male), mean age 64yrs (±10.6) were included. 67% were overweight/obese (BMI>25kg/m2). Sarcopenia was present in 33% (56% of normal BMI, 44% overweight group). Overall 40 pts (73%) experienced DLT (51% M, 100% F, p<0.016). DLT occurred in <6 months in 53% (44% M vs 83% F, p<0.016) and these pts were older (mean 68 yrs vs 60 yrs, p<0.01), had lower skeletal muscle mass (51.8 cm2/m2 vs 59.4 cm2/m2, p<0.012), and fat free mass (FFM) (51.4kg vs 57.7kg, p<0.03), and received higher drug dose in mg/kg FFM (1.01 vs 0.89, p<0.02). Common toxicities were GI (65%) and fatigue (47%). Of pts <25th percentile skeletal muscle mass 92% experienced DLT, higher than pts >75th percentile (p<0.05). Pts <25th percentile had an average of 5 toxicities vs 2 in those >75th percentile (p<0.003). All toxicities were more common in muscle wasted patients (p<0.05). 77% (n=10) of pts receiving a drug dose >75th percentile (1.105mg/FFM) experienced DLT in <6 months vs 44% (n=17) receiving a dose <75thpercentile (<1.099mg/FFM; p<0.037). Conclusions: Sarcopenia is prevalent in patients with mRCC, is easily measured, is an occult condition in pts with normal/high BMI, and is a significant predictor of DLT in pts receiving 1st line sunitinib. Our results highlight the potential use of baseline body composition to predict toxicity. The role of sarcopenia in targeted therapy is evolving and its potential to predict toxicity should be further studied.
Reversible posterior leucoencephalopathy syndrome (RPLS) associated with pazopanib.
Authors: Foerster Robert , Welzel Thomas , Debus Juergen , Gruellich Carsten , Jaeger Dirk , Potthoff Karin
Published: March 2020

e15574

Background: Tyrosine kinase inhibitors (TKI) are a relatively new modality for the therapy of metastatic renal cell carcinoma (MRCC). Although there are promising results, their use is often limited due to adverse reactions. We report on a case of malignant hypertension (HTN) and RPLS in a patient (PT) treated with pazopanib for MRCC. Methods: Case report. Results: A 62 year old woman with MRCC and since 8 weeks under 3rd-line therapy with pazopanib had suddenly developed headaches, grand-mal seizures, paresis of the left arm, gait instability and nausea during her vacation. The emergency physician measured blood pressure (BP) values >300 mmHG systolic and suspected a stroke. A CT without contrast agent in a local hospital only showed bone metastases. Suspecting cerebral metastases or meningeosis carcinomatosa (MC) the colleagues referred her to our radiooncologic department for diagnostics and treatment planning. At admission the PT was somnolent and unable to communicate because she had received larger quantities of diazepam as an anticonvulsive on the plane. The next day the PT was fully awake but showed significant anterograde amnesia from the onset of the headaches, psychomotoric deceleration and persistent gait instability. Brain metastases and MC were ruled out in an MRI which showed signs of RPLS in the form of band-like hyperintensities in the left parietal lob. HTN up to 220/120 mmHg persisted under 3x antihypertensive therapy and the PT reported that similar values were measured after the start of 1st-line sunitinib 1 year ago. We discontinued pazopanib. Within 1 week the neurologic findings vanished and we discharged her. An MRI 3 weeks later showed RPLS-typical cortical infarctions in the affected area. The PT remained without any neurologic symptoms but intermittent HTN persisted. Conclusions: Vascular endothelial growth factor (VEGF) inhibitors and TKI are associated with HTN. Currently the exact mechanism remains unknown. HTN is an indicator for improved outcome under TKI therapy. BP should be closely monitored under TKI therapy. RPLS clinically mimicking cerebral metastases should always be considered as the actual reason for neurologic findings in patients with known metastatic cancers under TKI therapy.
Testicular microlithiasis in Japanese male infertility patients: Clinical implications for predicting future testicular malignancy.
Authors: Arai Gaku , Okada Hiroshi , Sadaoka Yuko , Ohta Shigeyuki , Nishio Koujiro , Sato Ryo , Kawaguchi Makoto , Kobori Yoshitomo , Ashizawa Yshio , Yagi Hiroshi , Soh Shigehiro
Published: March 2020

e15579

Background: Testicular microlithiasis (TM) is commonly diagnosed by scrotal ultrasonography (US) in which it appears as multiple, small, uniform, echogenic foci without shadowing, scattered randomly throughout the testicular parenchyma. It is also prevalent in several urologic diseases including subfertility and testicular germ cell tumor. TM has been reported to be associated with carcinoma in situ (CIS) and the development of second testicular germ cell tumor (TGCT) after contralateral orchiectomy treatment for primary TGCT; however, no prospective studies have investigated the relationship between the detection of TM in patients without TGCT and future development of TGCT. In the present study, therefore, we investigated the prevalence of TM in the testes of male infertility patients and unilateral TGCT patients to determine if TM could be a predictor of future germ cell tumor in such patients. Methods: A total of 1,139 subfertile patients (296 with nonobstructive azoospermia, 58 with obstructive azoospermia, and 785 with oligozoospermia) and 22 unilateral testicular germ cell tumor patients were enrolled in the study. Prevalence of testicular microlithiasis according to testicular ultrasonography was compared between patients, and development of testicular germ cell tumors was monitored for at least 3 years. All patients were fully informed about the study, and their prior consent was obtained according to the recommendation of the institutional ethics committee. Results: The prevalence of TM was significantly higher in unilateral TGCT patients (40.9%) than in subfertile men (8.6%). No infertile patients without TM developed TGCT but one infertile patient with TM developed TGCT (seminoma) during follow up. One seminoma patient with TM in his remaining testis went on to developed testicular seminoma 3years after primary surgery. Conclusions: Testicular microlithiasis is more common in testicular germ cell tumor patients than in subfertile men. Since TM could be a surrogate marker for future TGCT in both patient populations, TM patients are recommended to perform careful self-checking of the testes and periodical testicular ultrasonography.
Prognostic analysis of Chinese patients with metastasic renal cell cancer (mRCC) receiving sorafenib: A multicenter retrospective study.
Authors: Guo Fang , Xie Xiaodong , Liu Zhaozhe , Song Xishuang , Zhang Qifu , Kong Xiangbo , Li Changfu , Li Zhenhua , Li Chengge , Qu Shuxian , Liang Xuefeng , Zheng Zhendong , Piao Ying
Published: March 2020

e15582

Background: This study was to investigate long-term efficacy of sorafenib and survival-related factors in Chinese patients with mRCC. Methods: 406 consecutive patients enrolled in this study between Oct. 2006 and Oct. 2009 from 6 comprehensive cancer centres in China. All cases were diagnosed as mRCC histopathologically without exception. 400mg sorafenib was orally taken twice daily until PD, death or intolerable toxic reaction. The primary endpoint was OS. The secondary endpoints were PFS and survival-related factors such as gender, age, ECOG PS, previous therapy and primary metastatic lesions. Data was analyzed using the SPSS statistical software. OS and PFS curves were output using the Kaplan-Meier method. Clinical parameters were included on univariate and multivariate analysis to evaluate associations with OS and PFS by the log-rank test and Cox proportional hazard models, P<0.05 (two-sided) was considered statistically significant. Results: 131 patients were available for survival analysis, including 96 males and 35 females. The median age was 60 years old. The median follow-up periods were 16.9 months. The median OS was 16.1 months. 1-year, 2-year and 3-year survival rates were 64.9%, 35.9% and 5.3%, respectively. The median PFS was 10.5 months. Univariate analysis demonstrated that OS was significantly associated with ECOG PS, metastatic lesions and previous therapy, whereas PFS was merely associated with ECOG PS and previous therapy. Multivariate analysis suggested that ECOG PS and previous therapy were independent prognostic factors for OS(P=0.004, P=0.019) and PFS (P=0.000, P=0.003), metastatic lesions was merely independent prognostic factor for OS (P=0.003). In the subgroup of patients with visceral metastasis, patients with lung metastasis alone had better prognosis than those with liver metastasis or dimerous metastasis. Conclusions: This long-term study demonstrated that sorafenib had good effects on Chinese patients with mRCC, especially for patients with lung metastasis alone. ECOG PS, metastatic lesions and previous therapy could be important parameters for survival and need attention in future.
A moncentric review of targeted therapy on overall survival in metastatic renal clear cell carcinoma.
Authors: Tadj Melanie , Arnoux Valentin , Mousseau Mireille , Descotes Jean Luc , Quesada Jean-Louis , Bensaadi Lamia , Laramas Mathieu
Published: March 2020

e15593

Background: Anti-angiogenic treatment had radically modified therapeutic strategy in metastatic renal cell carcinoma (mRCC). This study is aimed to determine the overall survival (OS) improvement in clinical practice. Methods: Retrospective, monocentric and non-interventional study in mRCC diagnosed since 2000 with 2 cohorts of patients determined according to the first line treatment (targeted therapy or others treatment). Results: Between 1 January 2000 and 31 December 2010, 98 patients were included. The 2 cohorts were balanced with regard to baseline disease and demographic characteristics in particular for prognosis profiles distribution. As first line, 58 patients received targeted therapy whose 21% were treated by bevacizumab, 71% by sunitinib and 8% by temsirolimus. In non-targeted therapy cohort (n=40), 37.5% were treated by cytokines, 15% by cytotoxic chemotherapy or hormonal therapy. Patients treated with targeted therapy had a significantly longer median OS (30 months versus 13 months; p<.003, log-rank test). The Hazard Ratio (HR) of death at 3 years was 0.53 (95% Confidence Interval, 0.33-0.85; p=.008, log-rank test). When adjusted to the prognosis profile, the HR of death was 0.43 (95%CI, 0.27-0.71). Conclusions: This retrospective study demonstrated the improvement of OS due to targeted treatments, for all prognostic risk groups. This result supported the complete change of care of mRCC patients with extension of therapeutic indications and efficient therapeutic lines.
Long-term response in a patient with urothelial cancer (UC) treated with AEZS-108.
Authors: Fernandez Gustavo L. , Schally Andrew V. , Koru-Sengul Tulay , Jorda Merce , Merchan Jaime R. , Flores Aurea M. , Block Norman L. , Manoharan Murugesan , Engel Juergen
Published: March 2020

e15596

Background: AEZS-108 (AN-152, zoptarelin doxorubicin) is an LHRH-cytotoxic hybrid drug consisting of a Luteinizing Hormone Releasing Hormone (LHRH) agonist coupled to the cytotoxic radical, doxorubicin. The binding permits AEZS-108 to accumulate on the surface of cells expressing LHRH receptors (LHRH-R) thus allowing drug uptake. This approach exploits LHRH-R to gain access to the targeted tumor cells. Once internalized, the cytotoxic properties of doxorubicin induce the anti-tumor response. Methods: This is a case report of a 66 year old male with a superficial bladder cancer history who was diagnosed in May 2009 with metastatic UC from the prostatic urethra. He presented with pelvic and retroperitoneal lymph nodes (LN). Patient had a partial response to cisplatin based chemotherapy and underwent radical cystoprostatectomy in Oct 2009. No residual UC in bladder or prostate was seen on pathology's examination. However he did have 11/24 removed LN positive for UC. The patient showed increased retroperitoneal LN by December 2009. He received 2 further lines of chemotherapy with no response and developed severe back pain, cervical LN, extensive liver metastases and a bulky retroperitoneal mass. The patient entered a Phase I clinical trial of AEZS-108, for “locally advanced unresectable or metastatic LHRH-R positive UC patients who failed platinum based chemotherapy“. He received AEZS-108 every 3 weeks for 9 cycles from May to October, 2011. Results: After 2 cycles of the investigational drug all pain and palpable lymph neck nodes disappeared; he stopped all narcotics and tolerated treatment very well. Mostly grade1-2 with few grade 3 toxicities were seen. CT scan pretreatment, and at 8, 22, 75 weeks post-treatment showed dramatic response at all disease sites. Twenty months after treatment start, the patient is symptom- free with no evidence of disease. Conclusions: This is the first case of a patient with LHRH-R positive Urothelial Carcinoma treated with AEZS-108 that is being reported. Considering the generally poor outcome of progressive UC and the short survival of these patients, the effect of this drug in this patient has been remarkable. The phase one study is ongoing.
An economic analysis of axitinib and sorafenib for second-line treatment of cytokine-refractory patients with advanced renal cell carcinoma in the United States (US).
Authors: Özer-Stillman Ipek , Ambavane Apoorva , Cislo Paul
Published: March 2020

e15601

Background: Cytokines are a first-line treatment option for a subset of advanced RCC patients in the US. After progression on cytokines, NCCN guidelines recommend targeted agents, such as axitinib and sorafenib. Subgroup analysis of post-cytokine patients in the phase III AXIS trial found that axitinib increased median progression free survival (PFS) compared with sorafenib (12.0 vs. 6.6 months, p<0.0001), while overall survival (OS) showed no difference (29.4 vs. 27.8 months, p=0.144). An economic analysis for this subgroup was conducted from a US healthcare payer perspective. Methods: A cohort partition model with monthly cycles was constructed to estimate direct medical costs and health outcomes, discounted at 3.0% per annum, over cohort lifetime. Patients were apportioned into 3 health states (progression-free, progressed and dead) based on OS and PFS Kaplan-Meier curves for the post-cytokine subgroup in the AXIS trial. Active treatment was applied until progression, followed by best supportive care (BSC) alone thereafter. The wholesale acquisition costs were based from RedBook. Adverse event (AE) management costs were obtained from published studies. AE rates and utility values were informed by the AXIS trial. Administrative claims data from MarketScan Database were analyzed to estimate costs for BSC and routine care of second-line advanced RCC patients. Results: The total per-patient lifetime costs were estimated to be $242,750 for axitinib and $168,880 for sorafenib and most of the cost difference (84%) was due to the higher total medication cost of axitinib. The cost difference was sensitive to dose intensity and length of treatment. The difference in quality-adjusted life-years (QALY) for axitinib versus sorafenib was minor (1.3 versus 1.2) and the incremental cost-effectiveness ratio (ICER) for axitinib compared with sorafenib was $683,209/QALY. Conclusions: For cytokine-refractory advanced RCC patients, axitinib resulted in an ICER > $650,000/QALY versus sorafenib due to high drug costs and lack of OS benefit, indicating that axitinib may not present good value for money as 2nd line treatment when compared to sorafenib in the US.
Response to sunitinib in patients with metastatic renal cell carcinoma: Experience of one center.
Authors: Jazvic Marijana , Radic Jasna , Soldic Zeljko , Bolanca Ante , Kusic Zvonko
Published: March 2020

e15603

Background: Five-years survival of patients with metastatic renal cell carcinoma (mRCC) is only 10%. A complete response (CR) to therapy is rare but has been achieved in minority of patients using high-dose interleukin-2. Sunitinib is an oral multitargeted receptor tyrosin kinase inhibitor and is currently considered the standard of care for first-line therapy of mRCC. CRs and long-term responders (LTR) to sunitinib have been documented in the literature. However, a detailed description and analysis of these patients is lacking. We report LTR, defined as patients achieving ongoing CR or remaining progression-free for ≥ 18 months on sunitinib. Methods: From 10/2008 till 12/2012, 48 patients were treated with sunitinib (50 mg/day, 4 weeks on/2 weeks off) as the first line therapy of clear cell mRCC. Tumor assessments were performed at baseline and every two cycles thereafter until the end of treatment, using RECIST criteria. Results: Nine patients were identified as LTR (18.8%). Retrospective data of these patients are reported in the Table. Conclusions: Sunitinib achieves LTR in a subset of patients with mRCC. Lung metastases and favourable MSKCC risk group may predict LTR. Maintaining full-dose sunitinib and management of therapy- related toxicity are crucial for treatment efficacy. [Table: see text]
Long-term outcome of sunitinib in metastatic renal cell carcinoma: Single center experience.
Authors: Maruzzo Marco , Basso Umberto , Zustovich Fable , Fiduccia Pasquale , Brunello Antonella , Roma Anna , Farina Patrizia , Bezzon Elisabetta , Banzato Alberto , Zattoni Filiberto , Zagonel Vittorina
Published: March 2020

e15606

Background: The multi-target tyrosine-kinase inhibitor sunitinib has been widely used in first or subsequent lines of treatment for metastatic renal cell carcinoma (mRCC). Since results of registrative clinical trials may be overestimated due to patient selection, outcome data of sunitinib in the routine clinical practice are warranted. Methods: We retrospectively reviewed clinical data of all consecutive mRCC patients starting sunitinib from March 2006 to September 2012 at our Institution. Results: Eligible were 106 pts, median age 63 years (range 27-89), 70% males, 89% clear cell histology, 87% prior nephrectomy. Sunitinib was prescribed either as first (70%) or second or further line of treatment after cytokines or targeted therapies. Patients received a median of 8 sunitinib cycles (1-49). Median PFS and OS in the first line were 15.0 mo (95% CI= 9.8-20) and 35 mo. PFS and OS in the second or further line were 15 mo (11.7-18.2) and 25 mo. Motzer risk score retained its prognostic relevance both in the first and in the second of further line. Patients who received at least 4 cycles at standard dose (50 mg/d 4 wks on/2wks off) had a significantly better PFS and OS compared to patients who did not (PFS 23.0 vs 12.0 mo p=0.012, OS 49.0 vs 16.0 mo p=0.006). First line pts progressing within three months from starting sunitinib were 18.9% (primary refractory), while 25.7% pts were treated for more than 24 mo (long term responders). Grade 3 or 4 toxicities have been recorded in 35% of pts but only 7 pts (6.6%) discontinued the treatment due to unacceptable toxicities. Conclusions: Sunitinib is active and feasible in a broader population of mRCC pts, with apparently superior PFS and OS results compared to pivotal trials. Better management of drug toxicities, less strict criteria for radiological progression, and availability of further sequential treatments may explain such results. Pts receiving at least 4 full dose cycles achieved statistically significant better outcomes.
Pazopanib in metastatic renal carcinoma (mRC): Experience of 31 centers in Spain in first, second, third, or subsequent lines in daily clinical practice.
Authors: Rodriguez Sanchez Angel , García Domínguez Rocio , De Velasco Guillermo , Pinto Alvaro , Puente Javier , Rubio Gustavo , Vazquez-Estevez Sergio , Juan Marta , Constenla Manuel , Lopez Brea Marta , Sereno Maria , Puertas Javier L. , Garrido Maria , Marrupe David , Villalobos Maria L , Cantos Blanca , de Portugal Teresa , Vilchez Rocio , Gonzalez-Larriba Jose-Luis , Arranz Arija Jose Angel
Published: March 2020

e15609

Background: In clinical trials pazopanib (P) was superior to placebo, noninferior to sunitinib, and very well tolerated as 1st-line for mRC, but there is limited information in daily clinical practice. Methods: We retrospectively reviewed 159 patients (p) who received P in in 31 centers in Spain during the first 18 month after P approval, to evaluate the timing of use and its efficacy. Results: Mean age was 66 y, 64.8% were males, 81.1% clear-cell, 12% non-clear cell, and 6.9% unspecified. At diagnosis of mRC 73.6% had nephrectomy, 78.6% and 71.7% of p were of good-intermediate risk (MSKCC and Heng criteria respectively). Metastatic sites were lung (59.7%), lymph nodes (26.4%), bone (22.6%), skin/soft-tissues (17.6%), liver (11.9%), CNS (2.5%), and 31.4% others (adrenal, pancreas, etc.). Median follow-up since diagnosis of mRC was 16 months (m). P was given as 1st systemic treatment in 81 p, (50.9%), as 2nd line in 32 p (20.1%, most after sunitinib, 17 due to intolerance), or as ≥3r line (46 p, 29%). Median follow-up after P was 7 m in 1st line, and 10 m in 2nd or ≥ 3rd line. Toxicity was as expected. No toxic deaths were registered. At the time of analysis, 85 p have discontinued P (progression: 73 p, toxicity: 10 p, other causes: 2 p), and 35 p have died. The table shows time to treatment failure due to progression or toxicity (TTF), and overall survival (OS) since the 1st dose of P. There were statistically significant differences in 1st line TTF and OS between MSKCC subgroups. Conclusions: In p with mRC and good-intermediate prognosis, P appears to be as effective in daily clinical practice as it was in 1st line trials. P also showed efficacy in p with poor risk, in 2nd-line (particularly progression or intolerance to sunitinib), and after 2 or more TKIs. Updated analysis will be available in June 2013. [Table: see text]
Multicenter observational study of temsirolimus use records conducted under conditions of routine medical practice.
Authors: Richardet Martin Eduardo , Sala Raul , Fein Luis , Richardet Eduardo Arnoldo
Published: March 2020

e15610

Background: Sometimes efficacy and toxicity reported in clinical trials differs from what is later found on everyday practice. Temsirolimus was approved in Argentine on 2009. We conducted a study to evaluate the safety profile in advanced renal cancer patients treated with Temsirolimus in everyday practice conditions. Methods: Descriptive, observational, retrospective study of medical records of patients treated with Temsirolimus from 2 Argentinian centers were analyzed at IONC and IOR from April to December 2010. All patients were high risk according to Memorial Sloan Kettering Cancer Center. 50 patients were included, 36% (18) women and 64% (32) men, average age 53.8 years old (20 - 78). Adverse events were assessed based on the NCI CTC v3. Results: No patient showed side effects during or immediately after the infusion, related with the administration of the drug. This study included patients with extensive metastatic disease and multiple factors of adverse prognosis together with short life expectancy. All centers used the standard premedication and dose and no serious adverse events were registered. The most frequent adverse events were anemia, asthenia and mucositis. In all cases adverse events were manageable with support measures or dose reduction. Although more than 80% of patients showed some type of adverse event, the quantity and severity of them were lower than the ones reported in the literature. Disease progression (67.3% of patients) was the most frequent cause of treatment discontinuation. All patients received a dose = 25mg. A total of 52 adverse events were registered. In Terms of efficacy, 46 patients were suitable for analysis. Our rate of clinical benefit (PR 13%+SD 47.8%) is 60.8% , higher than what was reported in the pivotal phase III study (32.1%), this difference could be attributed to our limited sample size. The ORR observed (13%) is similar to the rate reported in the pivotal phase III trial (8.6%. Range 4.8 – 12.4). Conclusions: The treatment with Temsirolimus in patients with advanced renal cancer with poor prognosis factors showed an acceptable safety profile and clinical benefit, taking into account the characteristics of the target population.