Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. PATIENTS AND METHODS: Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. RESULTS: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. CONCLUSIONS: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

Is orthorexia nervosa a feature of obsessive-compulsive disorder? A multicentric, controlled study.

PURPOSE: The term orthorexia nervosa (ON) was coined to describe altered thoughts and behaviours related to healthy eating. The prevalence of ON was found to scale up to almost 90% among high-risk populations (ballet dancers, athletes, and health workers). ON seem to share psychopathological aspects with both Eating Disorders (ED) and Obsessive-Compulsive Disorder (OCD). The aim of the study was to analyse the frequency and intensity of ON symptoms among subjects diagnosed with OCD, hypothesising that they would be higher than in two control groups (subjects with anxiety-depressive disorders and general population). METHODS: We conducted a multi-centre, observational, controlled study. Subjects filled in a socio-demographic questionnaire including questions related to life-style and two psychometric instruments: ORTO-15, for ON symptoms, and OCI-R, for OCD symptoms. Post hoc analysis of the dataset was performed using the revised version of ORTO-15, the ORTO-R. RESULTS: In the final sample of 328 subjects, the overall prevalence of ORTO-15-ON was 59.5%, mean score 37.9 ± 4.2. The mean score at the ORTO-R was 16.6 ± 4.6. No statistically significant differences were found in the prevalence of ON or in the mean ORTO-15 score among OCD patients and the two control groups, and this was confirmed by the multiple regression analysis. At the ORTO-R re-scoring, OCD patients scored significantly lower than the two clinical subgroups (p = .0005) and a lower ORTO-R score was associated to positivity at the OCI-R, confirming the initial hypothesis of the study. CONCLUSIONS: ON symptoms do seem to be more prevalent among subjects suffering from OCD. The psychometric properties of tools available to calculate ON symptoms, namely ORTO-15 vs. ORTO-R, play a relevant role in explaining such finding. ORTO-R seems to be a valid alternative able to overcome such difficulties, though further studies are needed to confirm this.

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. PATIENTS AND METHODS: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. RESULTS: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the 'CIS' versus 'no-CIS' groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63-1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01-1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23-2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34-0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82-1.35; p = 0.70). CONCLUSION: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

Impact of perioperative chemotherapy on survival in patients with advanced primary urethral cancer: results of the international collaboration on primary urethral carcinoma.

BACKGROUND: To investigate the impact of perioperative chemo(radio)therapy in advanced primary urethral carcinoma (PUC). PATIENTS AND METHODS: A series of 124 patients (86 men, 38 women) were diagnosed with and underwent surgery for PUC in 10 referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank testing was used to investigate the impact of perioperative chemo(radio)therapy on overall survival (OS). The median follow-up was 21 months (mean: 32 months; interquartile range: 5-48). RESULTS: Neoadjuvant chemotherapy (NAC), neoadjuvant chemoradiotherapy (N-CRT) plus adjuvant chemotherapy (ACH), and ACH was delivered in 12 (31%), 6 (15%) and 21 (54%) of these patients, respectively. Receipt of NAC/N-CRT was associated with clinically node-positive disease (cN+; P = 0.033) and lower utilization of cystectomy at surgery (P = 0.015). The objective response rate to NAC and N-CRT was 25% and 33%, respectively. The 3-year OS for patients with objective response to neoadjuvant treatment (complete/partial response) was 100% and 58.3% for those with stable or progressive disease (P = 0.30). Of the 26 patients staged ≥cT3 and/or cN+ disease, 16 (62%) received perioperative chemo(radio)therapy and 10 upfront surgery without perioperative chemotherapy (38%). The 3-year OS for this locally advanced subset of patients (≥cT3 and/or cN+) who received NAC (N = 5), N-CRT (N = 3), surgery-only (N = 10) and surgery plus ACH (N = 8) was 100%, 100%, 50% and 20%, respectively (P = 0.016). Among these 26 patients, receipt of neoadjuvant treatment was significantly associated with improved 3-year relapse-free survival (RFS) (P = 0.022) and OS (P = 0.022). Proximal tumor location correlated with inferior 3-year RFS and OS (P = 0.056/0.005). CONCLUSION: In this series, patients who received NAC/N-CRT for cT3 and/or cN+ PUC appeared to demonstrate improved survival compared with those who underwent upfront surgery with or without ACH.

Risk stratification of pT1-3N0 patients after radical cystectomy for adjuvant chemotherapy counselling.

BACKGROUND: In pT1-T3N0 urothelial carcinoma of the bladder (UCB) patients, multi-modal therapy is inconsistently recommended. The aim of the study was to develop a prognostic tool to help decision-making regarding adjuvant therapy. METHODS: We included 2145 patients with pT1-3N0 UCB after radical cystectomy (RC), naive of neoadjuvant or adjuvant therapy. The cohort was randomly split into development cohort based on the US patients (n=1067) and validation cohort based on the Europe patients (n=1078). Predictive accuracy was quantified using the concordance index. RESULTS: With a median follow-up of 45 months, 5-year recurrence-free and cancer-specific survival estimates were 68% and 73%, respectively. pT-stage, ge, lymphovascular invasion, and positive margin were significantly associated with both disease recurrence and cancer-specific mortality (P-values ≤ 0.005). The accuracies of the multivariable models at 2, 5, and 7 years for predicting disease recurrence were 67.4%, 65%, and 64.4%, respectively. Accuracies at 2, 5, and 7 years for predicting cancer-specific mortality were 69.3%, 66.4%, and 65.5%, respectively. We developed competing-risk, conditional probability nomograms. External validation revealed minor overestimation. CONCLUSION: Despite RC, a significant number of patients with pT1-3N0 UCB experience disease recurrence and ultimately die of UCB. We developed and externally validated competing-risk, conditional probability post-RC nomograms for prediction of disease recurrence and cancer-specific mortality.

Evolution in management of testicular seminoma: population-based outcomes with selective utilization of active therapies.

BACKGROUND: In this article, we report the evolution of treatment with increased use of active surveillance for stage I disease as well as risk-adapted chemotherapy for disseminated disease and associated outcomes of testicular seminoma in a contemporary population-based cohort. METHODS: All patients with histologically confirmed seminoma referred from 1999 to 2008 to the British Columbia Cancer Agency or Providence Cancer Center were retrospectively reviewed. Both institutions manage 90% of testicular cancers in their respective area. RESULTS: A total of 649 patients were included. Clinical stage (CS) distribution: CSI/II/III n=545/87/17. For CSI, there was a progressive and marked decrease in the utilization of prophylactic radiation (RT), and corresponding increase in the use of active surveillance. No deaths related to seminoma were reported in CSI patients. CSII or CSIII patients received RT or International Germ Cell Cancer Collaborative Group (IGCCCG) risk-appropriate chemotherapy with 101 of 104 patients being in long-term remission and 3 patients dying from treatment complications. For the entire seminoma population, <1% of patients died of seminoma or treatment after a median follow-up of 47 months (range 2-130 months). CONCLUSIONS: Progressive application of policies of active surveillance and earlier initiation of IGCCCG risk-adapted chemotherapy result in nearly universal control for all patients presenting with seminoma while reducing the burden of treatment.

Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: diminishing treatment-related morbidity while maintaining efficacy.

BACKGROUND: With treatment leading to nearly uniform cure in clinical stage I nonseminomatous testicular cancer (CSI-NSGCT), diminishing treatment-related morbidity has become the primary concern. This study examined feasibility and outcome of active surveillance as treatment in an unselected CSI patient population. MATERIALS AND METHODS: All patients with CSI-NSGCT referred from 1998 to 2007 to the British Columbia Cancer Agency and the Oregon Testis Cancer Program were retrospectively reviewed. A total of 233 patients were identified, of which 223 chose active surveillance. RESULTS: Vascular invasion (VI) was absent, present and unknown in 66%, 27% and 7% of cases, respectively. Overall, 49% of patients had embryonal predominant disease. Fifty-nine patients (26%) relapsed, all but one with good prognosis disease. VI was present in 30 relapsed patients. Most patients relapsed within 2 years (88%). Only 7 of 223 patients (3%) relapsed beyond 2 years. All relapses were in long-term remission following chemotherapy with or without retroperitoneal lymph node dissection (RPLND). Only 17 of 223 patients (8%) required postorchiectomy surgery. Disease-specific survival is 100% after a median follow-up of 52 months (3-136). No patient has required second-line chemotherapy. CONCLUSIONS: Active surveillance for all CSI-NSGCT patients is associated with excellent outcomes comparable with the best results reported with primary RPLND or adjuvant chemotherapy. Nearly 75% of patients are spared any therapy after orchiectomy.

The role of pelvic lymphadenectomy for prostate cancer--therapeutic?

PURPOSE: The incidence of metastatic lymph node involvement in prostate cancer has decreased with the advent of prostate specific antigen testing. Various algorithms have been designed to assess the probability of lymphatic involvement, resulting in the omission of lymph node dissection in many cases. However, recent reports suggest an underestimation of lymph node involvement. Meticulous lymph node dissection may provide a survival benefit by addressing micrometastatic disease. We analyzed the current literature on extended pelvic lymphadenectomy in prostate cancer. MATERIAL AND METHODS: The pelvic lymphadenectomy literature was reviewed using a MEDLINE search, focusing on the prevalence of positive nodes, staging vs extended lymphadenectomy and therapeutic benefits. RESULTS: Staging pelvic lymphadenectomy provides valuable prognostic data and it may be therapeutic. Extended lymph node dissection increases the detection of positive nodes. The number of positive or negative nodes resected may increase survival. The observed survival benefits may be due to the elimination of micrometastatic disease. CONCLUSIONS: The role, indications and extent of lymphadenectomy remain controversial. Extended lymph node dissection should be performed in all patients at high risk to increase staging accuracy and provide a potential survival benefit. Detailed, meticulous dissection of the internal iliac lymph tissue is required. The benefit of extended lymph node dissection in patients at low risk remains to be determined.

Targeted mid-trimester ultrasound examination: how does fetal anatomic visualization depend upon the duration of the scan?

OBJECTIVE: To determine the relationship between visualization of key fetal anatomic structures during mid-trimester ultrasound examination with gestational age and duration of examination. METHODS: One hundred ultrasound examinations at 16-22 weeks' gestation were reviewed to determine the times at which key fetal anatomic features were seen. Scans were terminated at 30 min or when a comprehensive anatomic survey was complete. Exclusion criteria included multiple gestation, maternal weight>77 kg, abdominal wall scarring, and suspected fetal anomalies. RESULTS: Visualization of cranial anatomy including lips, face, midline, ventricles, choroid plexus, and cerebellum was achieved in 98% of patients within 30 min. The corresponding figures for spine, cardiac screening (four-chamber, aortic, and pulmonary outflow views) and for abdominal anatomy (stomach, kidneys, bladder, ventral wall, and three-vessel cord) were 91%, 91%, and 99%, respectively. A complete anatomic survey including each of the above elements was obtained by 10, 15, 20, 25, and 30 min in 8%, 31%, 53%, 72% and 81% of the subjects. Rates of complete anatomic surveys within 30 min improved by gestational age interval, from 20/30 (67%) at 16-18 weeks, to 36/44 (82%) at 18-20 weeks, and 25/26 (96%) at 20-22 weeks; this rise was primarily due to improvements in visualization of the spine and heart. CONCLUSIONS: A comprehensive anatomical survey can be completed in 10 min or less in a minority of patients. For each 5-min time increment up to 30 min, the rate of complete surveys improves. Rates of completed anatomic surveys rise with gestational age.

Molecular prognostication in bladder cancer--a current perspective.

The optimal management of bladder cancer depends on the accurate assessment of the tumour's biological potential. Advances in molecular biology and cytogenetics have spurred intense research in identifying and characterising prognostic markers for patients with transitional cell carcinoma (TCC) of the bladder. The molecular changes that occur can be categorised into (1) chromosomal alterations leading to carcinogenesis, (2) cellular proliferation as a result of dysregulation of cell cycle control, and (3) growth control processes such as angiogenesis leading to metastasis. The accumulation of these changes ultimately determines a tumour's clinical behaviour and response to therapy. As the understanding of bladder cancer evolves, novel molecular markers for prognostication will make their way from the research laboratory to the clinical setting with the promise to improve patient care and outcomes.

Quantitative grading of a human blastocyst: optimal inner cell mass size and shape.

OBJECTIVE: To investigate the predictive value of quantitative measurements of blastocyst morphology on subsequent implantation rates after transfer. DESIGN: Prospective observational study. SETTING: Private assisted reproductive technology center. PATIENT(S): One hundred seventy-four IVF patients receiving transfers of expanded blastocyst-stage embryos on day 5 (n = 112) or day 6 (n = 62) after oocyte retrieval. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Blastocyst diameter, number of trophectoderm cells, inner cell mass (ICM) size, ICM shape, and implantation and pregnancy rates. RESULT(S): Blastocyst diameter and trophectoderm cell numbers were unrelated to implantation rates. Day 5 expanded blastocysts with ICMs of >4,500 microm(2) implanted at a higher rate than did those with smaller ICMs (55% vs. 31%). Day 5 expanded blastocysts with slightly oval ICMs implanted at a higher rate (58%) compared with those with either rounder ICMs (7%) or more elongated ICMs (33%). Implantation rates were highest (71%) for embryos with both optimal ICM size and shape. Pregnancy rates were higher for day 5 transfers of optimally shaped ICMs compared with day 5 transfers of optimally sized ICMs. CONCLUSION(S): Quantitative measurements of the inner cell mass are highly indicative of blastocyst implantation potential. Blastocysts with relatively large and/or slightly oval ICMs are more likely to implant than other blastocysts.

Dramatic declines in implantation and pregnancy rates in patients who undergo repeated cycles of in vitro fertilization with blastocyst transfer after one or more failed attempts.

OBJECTIVE: To compare the outcome of second and third cycles of in vitro fertilization with blastocyst transfer to the outcome of first attempts at IVF with blastocyst transfer. DESIGN: Retrospective study. SETTING: Private ART center. PATIENT(S): Three hundred and four patients undergoing treatment with in vitro fertilization with blastocyst transfer, 87 of which underwent at least one cycle of re-treatment after failing to achieve pregnancy in their first cycle. INTERVENTION(S): Bipronucleate oocytes were grown for up to 144 hours and subsequently transferred when at least one embryo attained the expanded blastocyst stage. MAIN OUTCOME MEASURE(S): Pregnancy and implantation rates. RESULT(S): Pregnancy rates per retrieval were significantly higher for patients undergoing their first cycle of in vitro fertilization with blastocyst transfer (36%) compared to those undergoing their second (19%) or their third (9%) cycles of treatment. Implantation rates per embryo were also higher for first cycles of in vitro fertilization with blastocyst transfer (30%) compared to second (18%) or third cycles (8%). CONCLUSION(S): Pregnancy and implantation rates decline dramatically in repeated cycles of in vitro fertilization with blastocyst transfer following one or more unsuccessful cycles of in vitro fertilization with blastocyst transfer.

A comparison of day 5 and day 6 blastocyst transfers.

OBJECTIVE: To compare implantation and pregnancy rates according to the day of embryo transfer (day 5 or 6 after oocyte retrieval) when transfer was postponed until expanded blastocysts developed. DESIGN: Retrospective clinical study. SETTING: Private ART center. PATIENT(S): One-hundred and eighty-three women undergoing blastocyst-stage embryo transfer following in vitro fertilization. INTERVENTION(S): Bipronucleate oocytes were grown for up to 144 hours and subsequently transferred only when at least one embryo attained the expanded blastocyst stage. MAIN OUTCOME MEASURE(S): Implantation and pregnancy rates. RESULT(S): Blastocysts transferred on day 5 implanted at nearly twice the rate of blastocysts transferred on day 6 (36.3% vs. 19.0%). Pregnancy rates were also almost twice as high among the day 5 transfer patients (59.3% vs. 32.3%). In addition, more blastocysts developed (3.6 vs. 2.4), and more were transferred (2.7 vs. 2.3) to the day 5 transfer patients, although the proportion of expanded blastocysts among the blastocysts that were transferred was the same for the two groups (91.7% vs. 93.6%). CONCLUSION(S): Embryos that develop to the expanded blastocyst stage and are transferred on day 5 after retrieval are approximately twice as likely to implant compared to those for which expansion and transfer are delayed until day 6.

Placental pathology casebook. Complete hydatidiform mole with coexistent term twin pregnancy.

A case of twin pregnancy consisting of a complete hydatidiform mole with a coexistent, viable fetus is presented. The case is distinctive for its presentation on ultrasound, its unusually low levels of serum hCG, its remarkable histology, and its term delivery.

The prognostic significance of S-phase analysis in stage Ta/T1 bladder cancer. A Southwest Oncology Group Study.

OBJECTIVES: An intergroup study (SWOG 8795) comparing two forms of adjunctive therapy (immuno and chemo), bacillus Calmette-Guerin (BCG) and mitomycin C (MMC), furnished preregistration index tumors for 244 patients with superficial, papillary stage Ta/T1 TCC. These were examined by flow cytometry to learn whether DNA ploidy or proliferation (low vs high S-phase fraction (SPF) helped to predict disease recurrence or progression. METHODS: Cell cycle analysis using commercially available (Multicycle) programs was performed on 249 Ta/T1 bladder cancers. Tumor grade, available for 223 cases, was assigned by a single study pathologist. The SWOG statistical office reviewed follow-up information and other data and performed statistical analysis. RESULTS: Disease recurrence occurred in half the cases studied. The most parsimonious model predictive of recurrence included only treatment arm and tumor grade, with the MMC arm and tumor grade greater than I indicating worse prognosis (p = 0. 014). Neither ploidy nor SPF predicted recurrence-free survival or contributed prognostic information that was additive to tumor grade. Within 5 years of follow-up, disease progression or death from bladder cancer occurred for 29/223 (13%) of patients. The most parsimonious model for progression-free survival included only grade greater than I (p<0.001) and high SPF (p = 0.029) (relative risk: tumor grade, 4.3, high SPF, 1.9). CONCLUSIONS: Knowledge of tumor proliferation (low versus high SPF) contributes prognostic information about tumor progression that is additive to tumor grade.