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.

Androgen receptor expression is associated with adverse pathological features in ureteral but not in pelvicalyceal urothelial carcinomas of the upper urinary tract.

PURPOSE: This study aims to determine the significance of androgen receptor (AR) expression in urothelial carcinoma of the upper urinary tract (UTUC). METHODS: AR expression was assessed on tissue microarrays containing specimens of 737 patients with UTUC who underwent radical nephroureterectomy with curative intent. AR expression was correlated with clinical and pathological tumor features as well as recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). RESULTS: Overall, AR was expressed in 11 % of tumors. AR expression was significantly associated with tumor necrosis as well as sessile and multifocal tumor growth but not with RFS, CSS or OS. AR was detected nearly twice as often in tumors of the ureter than of the pelvicalyceal system (p = 0.005). Subgroup analyses showed that the significant associations of AR with unfavorable pathologic features were exclusively attributable to tumors located in the ureter. However, in both ureteral and pelvicalyceal tumors, AR status was independent of RFS, CSS and OS. CONCLUSIONS: In this cohort of patients treated with RNU, AR expression was found in approximately 10 % of UTUCs, twice as often in ureteral than in pelvicalyceal tumors. While AR expression had no impact on postoperative prognosis, it was significantly associated with unfavorable pathologic features in ureteral tumors. Steroid hormone signaling might be relevant for future investigations of differences between ureteral and pelvicalyceal tumors.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Clinical nodal staging scores for prostate cancer: a proposal for preoperative risk assessment.

BACKGROUND: Pelvic lymph node dissection in patients undergoing radical prostatectomy for clinically localised prostate cancer is not without morbidity and its therapeutical benefit is still a matter of debate. The objective of this study was to develop a model that allows preoperative determination of the minimum number of lymph nodes needed to be removed at radical prostatectomy to ensure true nodal status. METHODS: We analysed data from 4770 patients treated with radical prostatectomy and pelvic lymph node dissection between 2000 and 2011 from eight academic centres. For external validation of our model, we used data from a cohort of 3595 patients who underwent an anatomically defined extended pelvic lymph node dissection. We estimated the sensitivity of pathological nodal staging using a beta-binomial model and developed a novel clinical (preoperative) nodal staging score (cNSS), which represents the probability that a patient has lymph node metastasis as a function of the number of examined nodes. RESULTS: In the development and validation cohorts, the probability of missing a positive lymph node decreases with increase in the number of nodes examined. A 90% cNSS can be achieved in the development and validation cohorts by examining 1-6 nodes in cT1 and 6-8 nodes in cT2 tumours. With 11 nodes examined, patients in the development and validation cohorts achieved a cNSS of 90% and 80% with cT3 tumours, respectively. CONCLUSIONS: Pelvic lymph node dissection is the only reliable technique to ensure accurate nodal staging in patients treated with radical prostatectomy for clinically localised prostate cancer. The minimum number of examined lymph nodes needed for accurate nodal staging may be predictable, being strongly dependent on prostate cancer characteristics at diagnosis.

Assessing treatment response after induction Bacillus Calmette-Guerin for carcinoma in situ of the urinary bladder: can post-induction random bladder biopsies be avoided?

OBJECTIVES: Patients diagnosed with bladder carcinoma in situ (CIS) and treated with intravesical Bacillus Calmette-Guerin (BCG) often undergo post-induction random bladder biopsies to assess treatment response. We sought to determine the correlation between post-induction urinary cytology/cystoscopy and histopathological findings obtained by random bladder biopsies. METHODS: Patients who were treated with BCG between 2006 and 2010 for CIS, had surveillance cystoscopy and cytology, and subsequently underwent random bladder biopsies were selected for analysis. Patients with a history of or concomitant urothelial cell carcinoma (UCC) stage T1 or higher were excluded. Cystoscopic finings were characterized as follows: negative - no mucosal erythema, raised lesions or papillary tumours; suspicious - mucosal erythema, but no raised lesions or papillary tumours; and positive - sessile or papillary tumours. The accuracy of cytology in predicting the results of subsequent random bladder biopsies was analysed. RESULTS: Of 21 patients included, surveillance cystoscopy findings were characterized as negative in nine, suspicious in seven and positive in five. Of 16 patients with negative/suspicious cystoscopy, 13 had agreement between cytology and biopsy, nine of whom were negative and four positive. Three of 16 patients had positive cytology, but negative biopsies; on further investigation of these three, one had CIS and two subsequent UCC. In the positive cystoscopy group, four of five patients had agreement between cytology and biopsy, two of whom were negative and two positive. One of the five patients had negative cytology, but a positive biopsy. CONCLUSION: Our data suggest foregoing random bladder biopsies in patients with negative urine cytology and no evidence of intravesical recurrence on cystoscopy following an induction course of BCG for CIS of the urinary bladder.

Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) risk tables and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model are the two best-established predictive tools to help decision making for patients with non-muscle-invasive bladder cancer (NMIBC). The aim of the current study was to assess the performance of these predictive tools in a large multicentre cohort of NMIBC patients. METHODS: We performed a retrospective analysis of 4689 patients with NMIBC. To evaluate the discrimination of the models, we created Cox proportional hazard regression models for time to disease recurrence and progression. We incorporated the patients calculated risk score as a predictor into both of these models and then calculated their discrimination (concordance indexes). We compared the concordance index of our models with the concordance index reported for the models. RESULTS: With a median follow-up of 57 months, 2110 patients experienced disease recurrence and 591 patients experienced disease progression. Both tools exhibited a poor discrimination for disease recurrence and progression (0.597 and 0.662, and 0.523 and 0.616, respectively, for the EORTC and CUETO models). The EORTC tables overestimated the risk of disease recurrence and progression in high-risk patients. The discrimination of the EORTC tables was even lower in the subgroup of patients treated with BCG (0.554 and 0.576 for disease recurrence and progression, respectively). Conversely, the discrimination of the CUETO model increased in BCG-treated patients (0.597 and 0.645 for disease recurrence and progression, respectively). However, both models overestimated the risk of disease progression in high-risk patients. CONCLUSION: The EORTC risk tables and the CUETO scoring system exhibit a poor discrimination for both disease recurrence and progression in NMIBC patients. These models overestimated the risk of disease recurrence and progression in high-risk patients. These overestimations remained in BCG-treated patients, especially for the EORTC tables. These results underline the need for improving our current predictive tools. However, our study is limited by its retrospective and multi-institutional design.

Increased water intake as a prevention strategy for recurrent urolithiasis: major impact of compliance on cost-effectiveness.

PURPOSE: We evaluated the economic impact of preventing recurrent stones using a strategy of increased water intake and determined the impact of compliance on cost-effectiveness for the French health care system. MATERIALS AND METHODS: A Markov model was constructed to compare costs and outcomes for recurrent kidney stone formers with less than 2 L vs 2 L or more daily fluid intake. Model assumptions included an annual prevalence of 120,000 stone episodes in France, 14.4% annual risk of stone recurrence and a 55% risk reduction in subjects with adequate water intake. Costs were based on resource use as estimated by a panel of experts and official national price lists. Outcomes were from the perspective of the public health payer, and encompassed direct and indirect costs. RESULTS: The total cost of an episode of urolithiasis was estimated at €4,267 including the cost of treatment and complications. This corresponds to an annual budget impact of €88 million for recurrent stones based on 21,000 stone events. Assuming 100% compliance with fluid intake recommendations of 2 L daily, 11,572 new stones might be prevented, resulting in a cost savings of €49 million. Compliance with water intake in only 25% of patients would still result in 2,893 fewer stones and a cost savings of €10 million. Varying the costs of managing stones had a smaller impact on outcomes since in many patients stones do not form. Varying the incidence of complications did not change the incidence of stones and had a negligible effect on overall cost. CONCLUSIONS: Preventing recurrent urolithiasis has a significant cost savings potential for a payer as a result of a reduced stone burden. However, compliance is an important factor in determining cost-effectiveness.

Nomogram Predicting Bladder Cancer-specific Mortality After Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-invasive Bladder Cancer: Results of an International Consortium.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. OBJECTIVE: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. RESULTS AND LIMITATIONS: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. CONCLUSIONS: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.

Tissue-based molecular markers for bladder cancer.

Bladder cancer is the second most common genitourinary malignancy in the United States, and is a major cause of morbidity and mortality. Despite aggressive treatment, survival for patients with muscle-invasive urothelial carcinoma of the bladder remains poor. Cancer stage, grade, and other clinical and pathological characteristics provide only limited prognostic information, and there is significant heterogeneity in patient outcomes using current risk stratification. Recent research into the profiling of bladder cancer at the molecular level has begun to shed light on important mechanisms of pathogenesis, as well as providing a number of potential tissue markers. These may provide useful prognostic information and guide patient selection for therapeutic strategies. This review explores recent advances in tissue-based molecular markers in bladder cancer and their potential utility. We also discuss design and statistical consideration for development and validation of molecular markers. A combination of complementary and yet independent molecular markers will likely better capture the biologic potential of each individual bladder tumor resulting in improved clinical decision-making.

Screening for bladder cancer using urine-based tumor markers.

Bladder cancer screening differs from routine detection of bladder cancer in patients with symptoms, such as hematuria, or a history of bladder cancer. The ultimate goal of cancer screening is to decrease cancer-related mortality by detecting disease prior to the time that the disease would normally prompt evaluation from symptoms. There are several features of urothelial carcinoma of the bladder which make screening for this disease an attractive alternative to the current approach to this disease. The disease targets a defined population and survival for patients with this disease is strongly associated with disease stage at presentation. In addition, quick, easy, and painless screening tests are theoretically possible using tumor-related markers because of the direct exposure of cancer cells to urine. Indeed, recent insights into the biology of bladder cancer initiation and progression have resulted in the identification of several urine-based markers which have promise for detecting the presence of bladder cancer. Nevertheless, adoption of screening programs prior to establishing evidence of effectiveness and large-scale financial considerations has substantial damaging consequences. This article reviews the current literature regarding screening for bladder cancer using urine-based markers.

Urine-based biomarkers for the early detection and surveillance of non-muscle invasive bladder cancer.

Bladder cancer has a very high frequency of recurrence and therefore requires lifelong surveillance, traditionally consisting of serial cystoscopy and cytology. These tests are both invasive and expensive, with considerable inter-user and inter-institutional variability. In addition, the sensitivity of cytology in detecting low-grade tumors is low. Therefore, there has been active investigation into urinary biomarkers that can either supplement or supplant these tests. At this point there are only six urine-based tests that are FDA-approved in bladder cancer surveillance, but a wide variety of other biomarkers are being studied. In this review, we examine the natural history of bladder cancer as well as the rationale and performance of an ideal urinary biomarker. The authors describe the FDA-approved biomarkers such as Bladder Tumor Antigen, ImmunoCyt, Nuclear Matrix Protein-22, and Fluorescent In Situ Hybridization, as well as the most promising investigational tests (i.e., Urinary bladder cancer test, BLCA-1, BLCA-4, hyaluronic acid, hyaluronidase, Lewis X antigen, microsatellite analysis, Quanticyt, soluble Fas, Survivin, and telomerase). The biological foundation, methodologies, and diagnostic performance of the biomarkers are discussed. The characteristics of the biomarkers are compared to urine cytology. At this time, urine biomarkers are utilized in a variety of clinical situations but their role is not well defined. The goal of identifying an optimal marker that will replace cystoscopy and/or cytology is still ongoing.

Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies.

Targeted therapies using small-molecule inhibitors (SMIs) are commonly used in metastatic renal cell cancer (mRCC) patients; patients often develop drug resistance and eventually succumb to disease. Currently, understanding of mechanisms leading to SMIs resistance and any identifiable predictive marker(s) are still lacking. We discovered that DAB2IP, a novel Ras-GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. Loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin (mTOR) inhibitors). Mechanistically, loss of DAB2IP results in the activation of extracellular signal-regulated kinase/RSK1 and phosphoinositide-3 kinase/mTOR pathway, which synergizes the induction of hypoxia-inducible factor (HIF)-2α expression. Consequently, elevated HIF-2α suppresses p21/WAF1 expression that is associated with resistance to mTOR inhibitors. Thus combinatorial targeting both pathways resulted in a synergistic tumor inhibition. DAB2IP appears to be a new prognostic/predictive marker for mRCC patients, and its function provides a new insight into the molecular mechanisms of drug resistance to mTOR inhibitors, which also can be used to develop new strategies to overcome drug-resistant mRCC.

Differential expression of nuclear retinoid receptors in normal and malignant prostates.

PURPOSE: To determine (1) whether nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are differentially expressed in normal and in cancerous human prostate tissues and (2) whether oral fenretinide therapy impacts the expression of these receptors in prostate cancer. PATIENTS AND METHODS: In situ hybridization with antisense riboprobes was used to probe for RAR and RXR transcripts in prostate tissues in a two-phased study: (1) expression of retinoid receptors in eight normal prostates was compared with their expression in 10 randomly picked radical prostatectomy specimens (group A); (2) expression of retinoid receptors was determined in 22 radical prostatectomy specimens from participants in a clinical study (group B). Twelve patients received oral fenretinide 200 mg/d, and 10 received placebo pills for 28 days before surgery. RESULTS: RARalpha, RARgamma, RXRalpha, and RXRgamma mRNAs were detected in most normal and cancerous prostates. In group A, RARbeta mRNA was expressed in only four of 10 malignant prostates but was present in seven of eight benign prostates (P =.05). RXRbeta mRNA was expressed in four of eight benign prostates and in zero of 10 malignant prostates (P =.023). In group B prostates, RARbeta and RXRbeta mRNAs were markedly reduced in all cancers and in the adjacent, nonmalignant tissue. There were no differences between receptor expression in the fenretinide-treated group and the placebo group. CONCLUSION: RARbeta and RXRbeta mRNAs are selectively lost in both prostate cancer and adjacent morphologically normal prostatic tissue, supporting the concept of a field of carcinogenesis. One month of oral fenretinide (200 mg/d) did not influence the expression of retinoid receptors in prostate cancer.

Perioperative outcomes and hospital reimbursement by type of radical prostatectomy: results from a privately insured patient population.

BACKGROUND: With the increasing use of robotic surgery in the United States, the comparative effectiveness and differences in reimbursement of minimally invasive radical prostatectomy (MIRP) and open prostatectomy (ORP) in privately insured patients are unknown. Therefore, we sought to assess the differences in perioperative outcomes and hospital reimbursement in a privately insured patient population who were surgically treated for prostate cancer. METHODS: Using a large private insurance database, we identified 17,610 prostate cancer patients who underwent either MIRP or ORP from 2003 to 2010. The primary outcomes were length of stay (LOS), perioperative complications, 90-day readmissions rates and hospital reimbursement. Multivariable regression analyses were used to evaluate for differences in primary outcomes across surgical approaches. RESULTS: Overall, 8981 (51.0%) and 8629 (49.0%) surgically treated prostate cancer patients underwent MIRP and ORP, respectively. The proportion of patients undergoing MIRP markedly rose from 11.9% in 2003 to 72.5% in 2010 (P<0.001 for trend). Relative to ORP, MIRP was associated with a shorter median LOS (1.0 day vs 3.0 days; P<0.001) and lower adjusted odds ratio of perioperative complications (OR: 0.82; P<0.001). However, the 90-day readmission rates of MIRP and ORP were similar (OR: 0.99; P=0.76). MIRP provided higher adjusted mean hospital reimbursement compared with ORP (US $19,292 vs. US $17,347; P<0.001). CONCLUSIONS: Among privately insured patients diagnosed with prostate cancer, robotic surgery rapidly disseminated with over 70% of patients undergoing MIRP by 2009-2010. Although MIRP was associated with shorter LOS and modestly better perioperative outcomes, hospitals received higher reimbursement for MIRP compared with ORP.

Clearance rates of total prostate specific antigen (PSA) after radical prostatectomy in African-Americans and Caucasians.

Racial differences in serum prostate specific antigen (PSA) values in men with and without prostate cancer have been observed but have yet to be explained. We aimed to determine if ethnic variations in the rate of metabolism of PSA could explain the different levels of PSA found in African-American and Caucasian men. In a prospective fashion, patients diagnosed with biopsy-proven clinically localized adenocarcinoma of the prostate and scheduled for radical prostatectomy were selected for the study. Eleven patients (six Caucasian, five African-American) were enrolled in the study. All patients demonstrated normal liver and renal function. Sera for total PSA were obtained at the following time intervals: preoperative (within 3 months of operation), time 0 (at time of prostate removal), 1, 4, 8, 24, 48, 72, 168 and 336 h after removal of the prostate. A log-linear regression model was then used to determine the metabolic clearance rate and half-life of serum total PSA. There were no statistically significant differences between Caucasian and African-American patients with regard to age, PSA prior to surgery, prostate weight, Gleason sum and PSA half-life. The metabolic clearance of total PSA followed first order kinetics. When comparing serum PSA levels expressed as a fraction of the baseline PSA, Caucasian and African-American patients demonstrated similar rates of metabolism. This study found similar rates of elimination of serum total PSA between African-Americans and Caucasians. These findings suggest that the rate of metabolism of PSA is similar for these groups. Further studies are needed to explain racial differences of serum PSA in patients with and without prostate cancer.

The value of simple tests in the detection of human ovulation.

Cervical mucus viscosity (CMV) and fern test (FT), leukocyte alkaline phosphatase (LAP) activity, basal body temperature (BBT) and serum luteinizing hormone (LH) levels were determined during 31 normal menstrual cycles of 29 volunteers. The day of the serum LH surge was taken as a reference point in evaluating the reliability and sensitivity in predicting ovulation of the other tests studied. Serum LH surge was accompanied by a sudden decrease in CMV, an increase in LAP activity, a gradual increase in FT and biphasic changes of BBT. In about 95% of cycles studied, the lowest values of CMV and peak values of LAP activity appeared on the day of the serum LH surge or one day before or one day after. The lowest point of the BBT coincided with the LH surge in only 26% of cycles. In 53% of cycles, the span was greater than one day before or after the LH peak. The FT corresponded to the LH surge in only 33% of the cycles, while in an additional 33% the preovulatory FT response occurred more than one day before or after the LH surge. The results indicate that CMV and LAP tests are rapid, simple and reliable for monitoring follicular maturation and the timing of ovulation when carried out daily, and may be of value in monitoring treatment during the induction of ovulation.