Assessment of interfraction dose variation in pancreas SBRT using daily simulation MR images.

Pancreatic Cancer is associated with poor treatment outcomes compared to other cancers. High local control rates have been achieved by using hypofractionated stereotactic body radiotherapy (SBRT) to treat pancreatic cancer. Challenges in delivering SBRT include close proximity of several organs at risk (OARs) and target volume inter and intra fraction positional variations. Magnetic resonance image (MRI) guided radiotherapy has shown potential for online adaptive radiotherapy for pancreatic cancer, with superior soft tissue contrast compared to CT. The aim of this study was to investigate the variability of target and OAR volumes for different treatment approaches for pancreatic cancer, and to assess the suitability of utilizing a treatment-day MRI for treatment planning purposes. Ten healthy volunteers were scanned on a Siemens Skyra 3 T MRI scanner over two sessions (approximately 3 h apart), per day over 5 days to simulate an SBRT daily simulation scan for treatment planning. A pretreatment scan was also done to simulate patient setup and treatment. A 4D MRI scan was taken at each session for internal target volume (ITV) generation and assessment. For each volunteer a treatment plan was generated in the Raystation treatment planning system (TPS) following departmental protocols on the day one, first session dataset (D1S1), with bulk density overrides applied to enable dose calculation. This treatment plan was propagated through other imaging sessions, and the dose calculated. An additional treatment plan was generated on each first session of each day (S1) to simulate a daily replan process, with this plan propagated to the second session of the day. These accumulated mock treatment doses were assessed against the original treatment plan through DVH comparison of the PTV and OAR volumes. The generated ITV showed large variations when compared to both the first session ITV and daily ITV, with an average magnitude of 22.44% ± 13.28% and 25.83% ± 37.48% respectively. The PTV D95 was reduced by approximately 23.3% for both plan comparisons considered. Surrounding OARs had large variations in dose, with the small bowel V30 increasing by 128.87% when compared to the D1S1 plan, and 43.11% when compared to each daily S1 plan. Daily online adaptive radiotherapy is required for accurate dose delivery for pancreas cancer in the absence of additional motion management and tumour tracking techniques.

Identifying the location of locoregional recurrences after definitive radiotherapy for head and neck cancer using metabolic parameters of baseline and mid-treatment 18F-FDG-PET scans.

INTRODUCTION: Tumour recurrences after treatment of head and neck squamous cell carcinoma (HNSCC) are more likely to originate from regions of high-baseline FDG-PET uptake. Mid-treatment functional imaging can potentially predict for higher risk of tumour recurrence. The aim of this study is to correlate the location of locoregional tumour recurrence with baseline FDG-PET metabolic volumes and mid-treatment FDG-PET metabolic volumes in patients with HNSCC following definitive radiotherapy. METHODS: A total of 23 patients with 26 local and/or regional recurrences underwent baseline (W0-PET) and mid-treatment (W3-PET) 18F-FDG PET scans as part of their radiotherapy. FDG-PET-based metabolic volumes (MTV20%, MTV40%, MTV60%, MTV80%, SUV2.5, SUVpeak and PET_EDGE) were delineated onto the FDG-PET scans. The recurrence nidus was identified on FDG-PET at the time of recurrence (REC-PET). DIR-based fusion was performed for REC-PET to W0-PET, and REC-PET to W3-PET. The location of the recurrence nidus was correlated with the FDG-PET volumes. Further analysis included a comparison of the recurrence density to FDG-PET metabolic volumes. RESULTS: Most recurrences occurred within the MTV20%, MTV40% and SUV 2.5 volumes. Sixty-nine per cent of recurrences (18 of 26) occurred within both the W0 MTV40% and W3 MTV40% volumes. A higher recurrence density was seen for iso-SUV contours closer to the maximum SUV for both W0 and W3. For a number of the FDG-PET volumes, including MTV20%, MTV40% and SUV2.5, the recurrence density was improved for W3 compared to W0, however, this improvement was small in magnitude. The average volume of MTV40% contours was considerably smaller than MTV20% and SUV2.5 contours. CONCLUSION: The metabolic parameters of SUV2.5, MTV20% and MTV40% delineated on the baseline and mid-treatment FDG-PET scans encompassed the majority of recurrences. The MTV40% is significantly smaller, hence, we prefer this volume for future dose escalation studies.

The delivered dose assessment in pancreas SBRT with the target position determined using an in-house position monitoring system.

Purpose: This study assessed the delivered dose accuracy in pancreas SBRT by incorporating the real-time target position determined using an in-house position monitoring system. Methods and materials: An online image-based position monitoring system, SeedTracker, was developed to monitor radiopaque marker positions using monoscopic x-ray images, available from the Elekta XVI imaging system. This system was applied to patients receiving SBRT for pancreatic cancer on the MASTERPLAN Pilot trial (ACTRN 12617001642370). All patients were implanted pre-treatment with at least three peri-tumoral radiopaque markers for target localisation. During treatment delivery, marker positions were compared to expected positions delineated from the planning CT. The position tolerance of ±3mm from the expected position of the markers was set to trigger a gating event (GE) during treatment. The dosimetric impact of position deviations and actual dose delivered with position corrections was assessed by convolving the plan control point dose matrices with temporal target positions determined during treatment. Results: Eight patients were treated within this study. At least one GE was observed in 38% of the treatment fractions and more than one GE was observed in 10% of the fractions. The position deviations resulted in the mean(range) difference of -0.1(-1.1 - 0.4)Gy in minimum dose to tumour and 1.9(-0.1- 4.6)Gy increase to Dmax to duodenum compared to planned dose. In actual treatment delivery with the patient realignment, the mean difference of tumour min dose and duodenal Dmax was reduced to 0.1(-1.0 - 1.1)Gy and 1.1 (-0.7 - 3.3)Gy respectively compared to the planned dose. Conclusions: The in-house real-time position monitoring system improved the treatment accuracy of pancreatic SBRT in a general-purpose linac and enabled assessment of delivered dose by incorporating the temporal target position during delivery. The intrafraction motion impacts the dose to tumour even if target position is maintained within a 3mm position tolerance.

Correcting rotational error in rectal cancer radiation therapy: Can planning target volume margins be safely reduced?

INTRODUCTION: The magnitude and impact of rotational error is unclear in rectal cancer radiation therapy. This study evaluates rotational errors in rectal cancer patients, and investigates the feasibility of planning target volume (PTV) margin reduction to decrease organs at risk (OAR) irradiation. METHODS: In this study, 10 patients with rectal cancer were retrospectively selected. Rotational errors were assessed through image registration of daily cone beam computed tomography (CBCT) and planning CT scans. Two reference treatment plans (TPR ) with PTV margins of 5 mm and 10 mm were generated for each patient. Pre-determined rotational errors (±1°, ±3°, ±5°) were simulated to produce six manipulated treatment plans (TPM ) from each TPR . Differences in evaluated dose-volume metrics between TPR and TPM of each rotation were compared using Wilcoxon Signed-Rank Test. Clinical compliance was investigated for statistically significant dose-volume metrics. RESULTS: Mean rotational errors in pitch, roll and yaw were -0.72 ± 1.81°, -0.04 ± 1.36° and 0.38 ± 0.96° respectively. Pitch resulted in the largest potential circumferential displacement of clinical target volume (CTV) at 1.42 ± 1.06 mm. Pre-determined rotational errors resulted in statistically significant differences in CTV, small bowel, femoral heads and iliac crests (P < 0.05). Only small bowel and iliac crests failed clinical compliance, with majority in the PTV 10 mm margin group. CONCLUSION: Rotational errors affected clinical compliance for OAR dose but exerted minimal impact on CTV coverage even with reduced PTV margins. Both PTV margin reduction and rotational correction decreased irradiated volume of OAR. PTV margin reduction to 5 mm is feasible, and rotational corrections are recommended in rectal patients to further minimise OAR irradiation.

γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival.

Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4+ or CD8+ T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (>20% DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2- γδ T cells. In the context of γδ T-cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T-cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti-PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T-cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions.See related Spotlight on p. 600.

The Gut Microbial Profile of Preclinical Crohn's Disease Is Similar to That of Healthy Controls.

BACKGROUND AND AIMS: It is unclear whether microbial dysbiosis plays an etiologic role in Crohn's disease (CD) or is the result of protracted inflammation. Here, we test the hypothesis that dysbiosis predates clinical CD in asymptomatic first-degree relatives (FDRs) of CD patients: normal (FDR1), with borderline inflammation (FDR2), and with frank, very early inflammation (FDR3). METHODS: The gut microbial diversity was tested in ileocecal biopsies through next generation sequencing of the 16S rRNA gene in 10 healthy controls (HCs), 22 patients with active, untreated CD, and 25 FDRs (9 FDR1; 12 FDR2; 4 FDR3). The metagenomic functions of 41 microbiome-related processes were inferred by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis. RESULTS: Compared with HCs, alpha diversity in CD patients was decreased, with an observed decrease in Faecalibacterium prausnitzii and increase in Bacteroides fragilis. In FDRs, microbial diversity was unchanged compared with HCs. In Operational Taxonomic Units and PICRUSt Principal coordinates and component analyses, the ellipse centroid of FDRs was diagonally opposed to that of CD patients, but close to the HC centroid. In both analyses, statistically significant differences in terms of beta diversity were found between CD and HC but not between FDR and HC. CONCLUSIONS: In FDRs (including FDR3-who bear preclinical/biologic onset disease), we found that the microbial profile is remarkably similar to HC. If confirmed in larger studies, this finding suggests that clinical CD-associated dysbiosis could result from the changed microenvironment due to disease evolution over time.

Comparison of four dimensional computed tomography and magnetic resonance imaging in abdominal radiotherapy planning.

BACKGROUND AND PURPOSE: Four-dimensional (4D) computed tomography (CT) is widely used in radiotherapy (RT) planning and remains the current standard for motion evaluation. We assess a 4D magnetic resonance imaging (MRI) sequence in terms of motion and image quality in a phantom, healthy volunteers and patients undergoing RT. MATERIALS AND METHODS: The 4D-MRI sequence is a prototype T1-weighted 3D gradient echo with radial acquisition with self-gating. The accuracy of the 4D-MRI respiratory sorting based method was assessed using a MRI-CT compatible respiratory simulation phantom. In volunteers, abdominal viscera were evaluated for artefact, noise, structure delineation and overall image quality using a previously published four-point scoring system. In patients undergoing abdominal RT, the tumour (or a surrogate) was utilized to assess the range of motion on both 4D-CT and 4D-MRI. Furthermore, imaging quality was evaluated for both 4D-CT and 4D-MRI. RESULTS: In phantom studies 4D-MRI demonstrated amplitude of motion error of less than 0.2 mm for five, seven and ten bins. 4D-MRI provided excellent image quality for liver, kidney and pancreas. In patients, the median amplitude of motion seen on 4D-CT and 4D-MRI was 11.2 mm (range 2.8-20.3 mm) and 10.1 mm (range 0.7-20.7 mm) respectively. The median difference in amplitude between 4D-CT and 4D-MRI was -0.6 mm (range -3.4-5.2 mm). 4D-MRI demonstrated superior edge detection (median score 3 versus 1) and overall image quality (median score 2 versus 1) compared to 4D-CT. CONCLUSIONS: The prototype 4D-MRI sequence demonstrated promising results and may be used in abdominal targeting, motion gating, and towards implementing MRI-based adaptive RT.

Recent Insights and Advances in the Management of Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy with a propensity for recurrence and a poor prognosis. Incidence of MCC is on the rise and is known to increase with advanced age, immunosuppression, and UV exposure. Merkel cell polyomavirus is implicated in the pathogenesis of virus-positive MCC and accounts for 80% of MCCs in the northern hemisphere and 25% in southern latitudes. In contrast, tumorigenesis of virus-negative MCC is linked to UV-induced DNA damage. Interplay between ubiquitous Merkel cell polyomavirus skin infections that commonly occur in healthy skin and other established risk factors, such as immunosuppression and UV exposure, remains poorly understood. Surgery and radiotherapy achieves excellent locoregional control; however, invariably, a significant proportion of patients develop disseminated disease that is incurable. Chemotherapy offers a high response rate for metastatic disease, but responses are short-lived and the impact on survival is not established. Recent advances in our understanding of the genetic landscape and immunobiology of MCC has led to investigation of novel treatments, including immune checkpoint inhibitors, which are likely to rapidly transform the way we manage these patients. We review epidemiologic, clinical, and histopathologic features of MCC; describe recent insights in MCC biology; and discuss novel therapeutic approaches.

Outcomes of cutaneous squamous cell carcinoma of the head and neck with parotid metastases.

INTRODUCTION: Cutaneous squamous cell carcinoma of the head and neck (cHNSCC) metastatic to the parotid has a moderate risk of recurrence despite multimodality treatment. Immunosuppression is associated with lower rates of long-term cure. Our aim was to review outcomes of current management in a tertiary centre with a view to targeting future strategies. METHODS: A retrospective review of clinico-pathological data and outcomes for patients with metastatic cHNSCC involving the parotid gland, undergoing radical surgery and adjuvant radiotherapy during 2000-2014 was conducted. The Kaplan-Meier method was used to determine time-to-event outcomes. RESULTS: One hundred and thirty-two patients met the inclusion criteria. Median follow-up was 5.0 years. Five-year overall (OS), cancer-specific (CSS) and progression free survival (PFS) were 44% (95% Confidence Interval (CI) 34-53%), 64% (95% CI 52-74%) and 37% (95% CI 28-47%) respectively. Locoregional control (LRC) was 68% (95% CI 55-77%) at 5 years. Immunosuppressed patients fared worse (compared with immune-competent) with five-year OS, CSS, and PFS of 14% versus 53% (HR = 3.19; 95% CI 1.91-5.34), 40% versus 71% (Hazard Ratio (HR) = 2.92; 95% CI 1.38-6.19) and 10% versus 46% (HR = 2.51; 95% CI 1.52-4.14) respectively. On multivariate analysis, immune status strongly predicted OS (P < 0.001), CSS (P = 0.003), DMFS (P < 0.001) and PFS (P < 0.001), but not LRC. Largest lymph node size was the only significant factor predictive for LRC on multivariate analysis (P = 0.02). CONCLUSIONS: Despite multimodality treatment metastatic cHNSCC involving the parotid shows moderate rates of recurrence. Immunosuppressed patients with this disease have a particularly poor prognosis, demonstrating lower rates of CSS with similar rates of LRC compared to their immunocompetent counterparts.

p16-positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high-risk human papillomavirus or prognosis and implications for the workup of the unknown primary.

BACKGROUND: The incidence of p16 overexpression and the role of human papillomavirus (HPV) in cutaneous head and neck squamous cell carcinoma (cHNSCC) are unclear. METHODS: One hundred forty-three patients with cHNSCC lymph node metastases involving the parotid gland were evaluated for p16 expression by immunohistochemistry. The detection of 18 high-risk HPV subtypes was performed with HPV RNA in situ hybridization for a subset of 59 patients. The results were correlated with clinicopathological features and outcomes. RESULTS: The median follow-up time was 5.3 years. No differences were observed in clinicopathological factors with respect to the p16 status. p16 was positive, weak, and negative in 45 (31%), 21 (15%), and 77 cases (54%), respectively. No high-risk HPV subtypes were identified, regardless of the p16 status. The p16 status was not prognostic for overall (hazard ratio, 1.08; 95% confidence interval [CI], 0.85-1.36; P = .528), cancer-specific (hazard ratio, 1.12; 95% CI, 0.77-1.64; P = .542), or progression-free survival (hazard ratio, 1.03; 95% CI, 0.83-1.29; P = .783). Distant metastasis-free survival, freedom from locoregional failure, and freedom from local failure were also not significantly associated with the p16 status. CONCLUSIONS: p16 positivity is common but not prognostic in cHNSCC lymph node metastases. High-risk HPV subtypes are not associated with p16 positivity and do not appear to play a role in this disease. HPV testing, in addition to the p16 status in the unknown primary setting, may provide additional information for determining a putative primary site.

Salivary duct carcinoma: Treatment, outcomes, and patterns of failure.

BACKGROUND: Salivary duct carcinoma is rare, with distinct morphology and behavior. We reviewed our institutional experience with salivary duct carcinoma, aiming to characterize clinical behavior and treatment outcomes. METHODS: All salivary duct carcinomas treated curatively between 1999 and 2010 were reviewed. Overall survival (OS), locoregional control, distant control, and patterns of failure were analyzed. Multivariate analysis identified predictors of OS. RESULTS: Fifty-four patients with salivary duct carcinoma (parotid gland = 49; submandibular gland = 5) were included in the analysis. Fifty-three patients underwent primary surgery, and 48 (89%) received postoperative radiotherapy (RT; median dose = 60 Gy). Median follow-up was 5.7 years. The 5-year OS, locoregional control, and distant control were 43%, 70%, and 48%, respectively. Nine local (6 involving facial nerve), 10 regional, and 28 distant failures were identified. Multiple pathologic involved lymph nodes (pN2b/N2c) predicted reduced OS (hazard ratio [HR] = 3.6; p = .02). CONCLUSION: Distant recurrence is common. Presence of pN2b/N2c disease is associated with reduced OS. Local recurrence frequently involves the facial nerves. © 2015 Wiley Periodicals, Inc. Head Neck 38: E820-E826, 2016.

UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas.

Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell-infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities.

Outcome analysis of 215 patients with parotid gland tumors: a retrospective cohort analysis.

BACKGROUND: To identify prognostic factors in patients with parotid gland carcinomas who were treated at the Princess Margaret Hospital. METHODS: Clinical outcome of two hundred fifteen patients with malignancies of the parotid gland was evaluated over a 16-year period. RESULTS: Two-hundred-fifteen patients with adenoid cystic carcinoma (n = 20), adenocarcinoma (n = 19), acinic cell carcinoma (n = 62), basal cell adenocarcinoma (n = 7), carcinoma-ex-pleomorphic adenoma (n = 18), mucoepidermoid carcinoma (n = 70) and salivary duct carcinoma (n = 19) have been included. The 5- and 10-year overall and disease-free survivals were 80.62%/69.48% and 74.37%/62.42%, respectively. Multivariable analysis showed that age greater than 60 years, advanced pN classification, histopathological grade and the presence of lymphovascular invasion significantly worsened overall and disease-free survival. Univariable analysis revealed periparotid lymph node involvement was associated with decreased overall (p < 0.0001) and disease-free survival (p < 0.0001). CONCLUSIONS: In addition to age, pN classification, histopathological grade, perineural invasion, and lymphovascular involvement, periparotid lymph node metastasis appears to be an important prognosticator in parotid gland malignancy.

Intensity-modulated radiotherapy using simultaneous-integrated boost for definitive treatment of locally advanced mucosal head and neck cancer: outcomes from a single-institution series.

INTRODUCTION: The study aims to report outcomes for patients treated using intensity-modulated radiotherapy (IMRT) with simultaneous-integrated boost and weekly cisplatin for American Joint Committee on Cancer stage III/IV mucosal head and neck squamous cell carcinomas (HNSCCs). METHODS: Records for 67 patients treated definitively with IMRT for HNSCC were reviewed. By including only those treated with weekly cisplatin, 45 patients were eligible for analysis. Treatment outcomes, effect of patient, tumour and treatment characteristics on disease recurrence were analysed. RESULTS: All patients completed IMRT to 7000 cGy in 35 fractions, with concurrent weekly cisplatin 40 mg/m(2) (median 6 cycles). Median follow-up was 28 months for living patients. Two-year loco-regional recurrence-free, metastasis-free and overall survival were 85.4, 81.0 and 87.4%, respectively. Local recurrence occurred in three patients, and distant recurrence in eight patients. CONCLUSIONS: Our results show efficacy of IMRT and weekly cisplatin in the treatment of stage III/IV HNSCC at our institution with respect to loco-regional control.

Perineural invasion and spread in head and neck cancer.

Perineural involvement is a well-recognized clinicopathologic entity found in head and neck (H&N) cancers, including mucosal epithelial carcinomas and salivary gland malignancies. Perineural disease remains a diagnostic, prognostic and therapeutic challenge for the multidisciplinary H&N oncology team. Nerves are important routes of tumor spread in H&N malignancies, yet the biology and prognostic implications of perineural tumor growth are not fully understood. On balance, the available evidence suggests that it is associated with an increased risk of locoregional recurrence but the impact on survival remains uncertain. Perineural involvement has implications for locoregional disease diagnosis and management. MRI is the best imaging modality to detect tumor extent. Advanced radiotherapy technologies such as intensity-modulated radiation therapy and image-guided radiation therapy have the potential for more accurate targeting and treatment of anatomically complex patterns of disease spread. This review is limited to nondermatologic H&N cancers.

Lower chance of pregnancy with repeated cycles with in vitro fertilization.

OBJECTIVE: To evaluate pregnancy outcomes in initial and replicate IVF cycles. STUDY DESIGN: A retrospective analysis of 2,167 fresh, nondonor IVF cycles performed in a large private practice from January 1, 2005, to March 1, 2006. Standard controlled ovarian hyperstimulation and laboratory protocols were followed. RESULTS: Patients undergoing multiple treatment cycles were significantly older. There was no difference in body mass index or percentage of cancelled cycles with increasing number of IVF attempts. The number of retrieved, mature and fertilized oocytes progressively declined as the number of treatment cycles increased. The number of embryos transferred increased with increasing number of treatment cycles. Implantation, pregnancy and clinical pregnancy rates decreased significantly with the second treatment cycle and more markedly with 3-5 treatment cycles. CONCLUSION: The likelihood of a successful outcome declined with each additional treatment cycle. The most notable decrease in clinical pregnancy rates occurred after the third cycle. Patients who fail to conceive after 3 cycles of IVF should be counseled to begin considering other options.

Therapeutic amenorrhea in patients at risk for thrombocytopenia.

To examine the need for and evaluate the method of menses suppression in women at risk for thrombocytopenia. A systematic review of the published literature in MEDLINE using the search terms thrombocytopenia, menorrhagia, therapeutic amenorrhea, progestin intrauterine device, combination oral contraceptive--extended and cyclic, gonadotropin releasing hormone agonist, danazol, and progestins. There are an increased number of reproductive age women at risk for thrombocytopenia who would benefit from menses suppression. A number of effective medical regimens are available. In patients who fail medical therapy, endometrial ablation appears to be effective in women with thrombocytopenia. As a result of the increased number of women at risk for thrombocytopenia, there is a need for therapeutic amenorrhea. The type of regimen selected depends upon the patients need for contraception and the ability to tolerate estrogen-containing medications. For women who fail medical therapy, there are surgical options, which are associated with less morbidity than hysterectomy.

Adding human menopausal gonadotrophin to antagonist protocols - is there a benefit?

The objective of this retrospective analysis was to compare the clinical outcomes of recombinant FSH (r-FSH) with combination r-FSH plus human menopausal gonadotrophin (HMG) protocols in a large private practice using a single IVF laboratory, from 2001 to 2003. Patients underwent ovarian stimulation by standard gonadotrophin-releasing hormone (GnRH) antagonist protocol using r-FSH or combination r-FSH plus HMG. When two or more follicles had attained a minimum mean diameter of 20 mm, follicular triggering was achieved with either recombinant HCG (r-HCG; Ovidrel, 250 microg s.c.) or urinary HCG (u-HCG; 10,000 IU i.m.). The main outcome measures were number of oocytes retrieved and clinical pregnancy rate. There was a lower percentage of cancelled cycles and an increased number of oocytes retrieved, mature oocytes, oocytes that fertilized, embryo that cleaved and a tendency towards higher clinical pregnancy rates in patients treated with r-FSH alone compared with those treated with r-FSH plus HMG. Patients treated with r-FSH plus HMG had lower miscarriage rates and the live birth rate was similar in both treatment groups. In conclusion, irrespective of age, using a treatment regimen consisting of a combination of HMG plus r-FSH was not beneficial compared with r-FSH alone in patients using a GnRH antagonist protocol.