Ignacio Duran

Assessment of procalcitonin as a diagnostic and prognostic marker in patients with solid tumors and febrile neutropenia.

Cancer patients with fever and neutropenia currently are assessed on clinical grounds only. The current study prospectively evaluated the efficacy of baseline procalcitonin (PCT) in the detection of bacteremia and in the prediction of outcome in patients with solid tumors and febrile neutropenia.

Non–Risk-Adapted Surveillance in Clinical Stage I Nonseminomatous Germ Cell Tumors: The Princess Margaret Hospital’s Experience

BACKGROUNDnSince 1981 Princess Margaret Hospital has used initial active surveillance (AS) with delayed treatment at relapse as the preferred management for all patients with clinical stage I nonseminomatous germ cell tumors (NSGCT).nnnOBJECTIVEnOur aim was to report our overall AS experience and compare outcomes over different periods using this non-risk-adapted approach.nnnDESIGN, SETTING, AND PARTICIPANTSnThree hundred and seventy-one patients with stage I NSGCT were managed by AS from 1981 to 2005. For analysis by time period, patients were divided into two cohorts by diagnosis date: initial cohort, 1981-1992 (n=157), and recent cohort, 1993-2005 (n=214).nnnINTERVENTIONnPatients were followed at regular intervals, and treatment was only given for relapse.nnnMEASUREMENTSnRecurrence rates, time to relapse, risk factors for recurrence, disease-specific survival, and overall survival were determined.nnnRESULTS AND LIMITATIONSnWith a median follow-up of 6.3 yr, 104 patients (28%) relapsed: 53 of 157 (33.8%) in the initial group and 51 of 214 (23.8%) in the recent group. Median time to relapse was 7 mo. Lymphovascular invasion (p<0.0001) and pure embryonal carcinoma (p=0.02) were independent predictors of recurrence; 125 patients (33.7%) were designated as high risk based on the presence of one or both factors. In the initial cohort, 66 of 157 patients (42.0%) were high risk and 36 of 66 patients (54.5%) relapsed versus 17 of 91 low-risk patients (18.7%) (p<0.0001). In the recent cohort, 59 of 214 patients (27.6%) were high risk and 29 of 59 had a recurrence (49.2%) versus 22 of 155 low-risk patients (14.2%) (p<0.0001). Three patients (0.8%) died from testis cancer. The estimated 5-yr disease-specific survival was 99.3% in the initial group and 98.9% in the recent one.nnnCONCLUSIONSnNon-risk-adapted surveillance is an effective, simple strategy for the management of all stage I NSGCT.

Systemic Therapy for Non–clear Cell Renal Cell Carcinomas: A Systematic Review and Meta-analysis

CONTEXTnClinical data supporting the use of targeted agents for the treatment of metastatic renal cell carcinoma (RCC) are based predominantly on patients with clear cell histology. Little is known about the efficacy of these drugs in non-clear cell variants.nnnOBJECTIVEnTo evaluate the efficacy of different clear cell RCC (ccRCC)-approved targeted agents among patients with non-ccRCC compared with ccRCC.nnnEVIDENCE ACQUISITIONnWe conducted a systematic review of electronic databases to identify publications evaluating the outcomes of patients with non-ccRCC treated with targeted agents approved for treatment of ccRCC. Patients with sarcomatoid variant RCC were excluded from the main analysis but were evaluated as an independent cohort. End points of interest were response rate, median progression-free survival (PFS), and median overall survival (OS). Where possible, data were pooled in a meta-analysis. For studies of unselected patients with RCC, the outcomes of patients with non-ccRCC histology were compared with ccRCC. In exploratory analyses, outcomes of non-ccRCC with nonapproved agents were assessed.nnnEVIDENCE SYNTHESISnA total of 49 studies comprising 7771 patients were included in the analysis. Of these, 1244 patients (16.0%) had non-ccRCC, 6300 (83.1%) had ccRCC, and 227 (2.9%) had sarcomatoid tumours. The overall response rate for non-ccRCC with targeted agents was 10.5%. In studies directly comparing non-ccRCC and ccRCC, there were significantly lower response rates for non-ccRCC (odds ratio for response: 0.52; 95% confidence interval, 0.40-0.68; p<0.001). For non-ccRCC treated with targeted agents, median PFS and OS were 7.4 and 13.4 mo, respectively; for patients with ccRCC, these were 10.5 mo and 15.7 mo, respectively (p value for difference<0.001 for both parameters).nnnCONCLUSIONSnPatients with non-clear cell renal cell carcinoma (non-ccRCC) have significantly lower response rates and poorer median progression-free survival and overall survival than those with ccRCC. The optimal treatment of patients with non-ccRCC remains unclear and warrants further study.nnnPATIENT SUMMARYnSystemic treatments for patients with renal cell carcinoma (RCC) tend to be significantly less effective for non-clear cell RCC, with lower response rates and worse progression-free survival and overall survival when compared with clear cell RCC. Optimal therapy remains unclear and warrants further study.

Chromophobe renal cell carcinoma: a review of an uncommon entity.

Renal cell carcinoma is the most common neoplasm of the kidney. It is a heterogeneous disease, comprised of different histological variants with a distinct clinical course, genetics and response to treatment. The various subtypes identified include clear cell, papillary and chromophobe, among others. Chromophobe renal cell carcinoma is a rare variant and accounts for 5% of all cases. These tumors are macroscopically larger when compared with other forms and are commonly diagnosed at an early stage. Despite significant advances in renal cell carcinoma therapeutics in the past decade, no standard treatment has been identified for advanced chromophobe renal cell carcinoma. Nevertheless, new molecular insights have recently become available. A familial form of renal cell carcinoma, the Birt–Hogg–Dubé syndrome, has been described and the knowledge obtained has opened research opportunities in the therapeutic arena of chromophobe renal cell carcinoma. The following manuscript will endeavor to provide an overview of this uncommon entity including pathology, epidemiology, genetics, clinical aspects, and current and future treatment options.

A Randomised Phase 2 Study Combining LY2181308 Sodium (Survivin Antisense Oligonucleotide) with First-line Docetaxel/Prednisone in Patients with Castration-resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) is partially characterised by overexpression of antiapoptotic proteins, such as survivin. In this phase 2 study, patients with metastatic CRPC (n=154) were randomly assigned (1:2 ratio) to receive standard first-line docetaxel/prednisone (control arm) or the combination of LY2181308 with docetaxel/prednisone (experimental arm). The primary objective was to estimate progression-free survival (PFS) for LY2181308 plus docetaxel. Secondary efficacy measures included overall survival (OS), several predefined prostate-specific antigen (PSA)-derived end points, and Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores. The median PFS of treated patients for the experimental arm (n=98) was 8.64 mo (90% confidence interval [CI], 7.39-10.45) versus 9.00 mo (90% CI, 7.00-10.09) in the control arm (n=51; p=0.755). The median OS for the experimental arm was 27.04 mo (90% CI, 19.94-33.41) compared with 29.04 mo (90% CI, 20.11-39.26; p=0.838). The PSA responses (≥ 50% PSA reduction), BPI, and FACT-P scores were similar in both arms. In the experimental arm, patients had a numerically higher incidence of grades 3-4 neutropenia, anaemia, thrombocytopenia, and sensory neuropathy. In conclusion, this study failed to detect a difference in efficacy between the two treatment groups.

Immunotherapy in prostate cancer: review of the current evidence

Prostate cancer is the most common male malignancy in the Western world. Once it metastasizes, it is incurable. The current gold standard for metastatic disease is the combined docetaxel/prednisone regimen. Prostate cancer shows several characteristics that make it a suitable candidate for immunotherapy, as recently exemplified by the approval of sipuleucel-T, the first vaccine to treat any malignancy. Here, we review different tumor-associated antigen immunotherapy strategies currently being investigated, from a humanized radiolabeled monoclonal antibody (J-591) that targets radiation into tumor cells, moving on to vaccines and through to immunomodulator agents such as anti-CPLA-4 and anti-PD-1 monoclonal antibodies that activate T-cell responses via immune checkpoint inhibition. We explore different opinions on the best approach to integrate immunotherapy into existing standard therapies, such as androgen-deprivation therapy, radiotherapy or chemotherapy, and review different combination sequences, patient types and time points during the course of the disease to achieve a lasting immune response. We present data from recent phase III clinical trials that call for a change in trial endpoint design with immunotherapy agents, from the traditional tumor progression to overall survival and how such trials should include immune response measurements as secondary or intermediate endpoints to help identify patient clinical benefit in the earlier phases of treatment. Finally, we join in the recent questioning on the validity of RECIST criteria to measure response to immunotherapeutic agents, as initial increases in the size of tumors/lymph nodes, which are part of a normal immune response, could be categorized as disease progression under RECIST.

Biological markers of cisplatin resistance in advanced testicular germ cell tumours

IntroductionGerm cell tumours (GCTs) of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10–20% of patients die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in advanced GCTs. The objective of the present study was to clarify the role of the expression status of proteins involved in the Rb and p53 tumour suppressor pathways in sensitivity and resistance of GCTs to cisplatinbased chemotherapy.Materials and methodsParaffin-embedded tumour tissues from 84 patients with advanced GCT treated with cisplatinbased chemotherapy were analysed. Immunohistochemical expression of proteins p53 and mdm2, and the G1-phase cyclins D1 and D2 (CD1 and CD2) was assessed and correlated with the clinical course.ResultsThe percentages of positive expression of p53, mdm2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, there was no significant association between p53, mdm2 or CD1 expression and outcome. Instead, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (PFS) (p=0.06). In multivariate analysis, none of the molecular markers retained statistical significance with treatment response or survival.ConclusionsTissular expression of p53, mdm2 and CD1 is not associated with prognosis or treatment response in patients with advanced GCT. Aberrant CD2 expression appears to further determine a shorter PFS. Larger and further studies are required to validate CD2 as a marker of cisplatin resistance.

Eyelid metastasis from mediastinal teratoma with malignant transformation

A 29-year-old Hispanic male with an unremarkable past medical history, was diagnosed with a mediastinal germ cell tumor (GCT) of mixed histology including choriocarcinoma, embryonal carcinoma and teratomatous components. At the time of diagnosis the human chorionic gonadotropin (HCG) was 287 IU/l [normal range 52], alphafetoprotein (AFP) 421 mgr/l [normal range 55] and LDH 215 IU/l [normal range 5190]. No testicular primary or other metastasic sites were observed. The patient received treatment with a combination of bleomycin, etoposide and cisplatin [BEP] for four cycles achieving a normalization of the tumoral markers but only a mild reduction of the tumor volume. Shortly afterwards due to radiological progression, an R0 resection of the mediastinal mass was performed. Pathologic examination revealed a mixed histology with mature teratoma, gastrointestinal adenocarcinoma and sarcoma components together with extensive areas of fibrosis and necrosis. Two months later, the patient relapsed presenting with multiple pulmonary nodules and one suspicious liver lesion. A hepatic biopsy confirmed the diagnosis of teratoma with malignant transformation in keeping with sarcoma. The patient was then treated with a combination of vinblastine, ifosfamide and cisplatin (VeIP) with no response after two cycles. During treatment course he presented with a painless small nodule on his left inferior eyelid measuring around 8 mm (Figure 1a and b). A biopsy of this nodule (Figure 2) revealed areas of normal conjunctiva (white arrow) along with sarcomatoid components (black arrow) in keeping with metastatic sarcoma. Further systemic treatment options were discussed with the patient who rejected any active approach. To date, four months after diagnosis of this metastasis, the patient remains clinically stable with no symptoms. Though GCTs account for only 1 2% of all human malignancies they are the most common tumors diagnosed in men ages 15 to 34 years [1]. Only 10% of GCTs present as extragonadal malignancies arising in the mediastinum, retroperitoneum and central nervous system in order of frequency. The biology of GCTs is unique having the capacity to display totipotential differentiation ranging from embryonal carcinoma to extraembryonic cell types (i.e. yolk sac tumor or choriocarcinoma) or to somatic cell types (i.e. teratoma) [2]. Teratomas are tumors that display somatic elements with diverse differentiation stages (i.e. mature and immature teratomas). On rare occasions the teratomatous component in a GCT may undergo malignant transformation leading to histology indistinguishable from a somatic malignancy. Examples of histologic transformed cell types include rhabdomyosarcoma,