The Wabar impact craters, Saudi Arabia, revisited

The very young Wabar craters formed by impact of an iron meteorite and are known to the scientific community since 1933. We describe field observations made during a visit to the Wabar impact site, provide analytical data on the material collected, and combine these data with poorly known information discovered during the recovery of the largest meteorites. During our visit in March 2008, only two craters (Philby-B and 11 m) were visible; Philby-A was completely covered by sand. Mapping of the ejecta field showed that the outcrops are strongly changing over time. Combining information from different visitors with our own and satellite images, we estimate that the large seif dunes over the impact site migrate by approximately 1.0–2.0 m yr␣1 southward. Shock lithification took place even at the smallest, 11 m crater, but planar fractures (PFs) and undecorated planar deformation features (PDFs), as well as coesite and stishovite, have only been found in shock-lithified material from the two larger craters. Shock-lithified dune sand material shows perfectly preserved sedimentary structures including cross-bedding and animal burrows as well as postimpact structures such as open fractures perpendicular to the bedding, slickensides, and radiating striation resembling shatter cones. The composition of all impact melt glasses can be explained as mixtures of aeolian sand and iron meteorite. We observed a partial decoupling of Fe and Ni in the black impact glass, probably due to partitioning of Ni into unoxidized metal droplets. The absence of a Ca-enriched component demonstrates that the craters did not penetrate the bedrock below the sand sheet, which has an estimated thickness of 20–30 m.

TEMOZOLOMIDE AND BEVACIZUMAB THERAPY IN ADVANCED HEMANGIOPERICYTOMA/ SOLITARY FIBROUS TUMOR

Tumors comprising the spectrum of hemangiopericytoma/ malignant solitary fibrous tumor (HPC/SFT) are thought to arise from fibroblasts and represent a small subset of soft tissue sarcomas. Surgery is typically the treatment of choice for localized disease, with reported 10-year overall survival rates of 54-89% after complete surgical resection. However, for the approximately 20% of HPC/SFT patients who eventually develop local recurrences and/or distant metastases, options for effective treatment are limited and are poorly defined. Alternative therapeutic options are therefore needed for improved palliation and disease control. We hypothesize that HPC/SFT are a spectrum of soft tissue tumors with unique clinical, pathological, and molecular makeup and clinical behavior. HPC/SFT respond to unique therapeutic agents that specifically target aberrations specific to these tumors. We retrospectively reviewed the characteristics and the clinical outcomes for all HPC/SFT patients whose tumor specimens have been reviewed at the MD Anderson Cancer Center from January 1993 to June 2007 by a MD Anderson pathologist and were treated at the institution with available electronic medical records. We identified 128 patients, 79 with primary localized disease and 49 with recurrent and/or metastatic disease. For the 23 patients with advanced HPC/SFT who received adriamycin-based, gemcitabine based, or paclitaxel chemotherapy as first- or second-line therapy, the overall RECIST response rate was 0%. Most patients achieved a brief duration of disease stabilization on chemotherapy, with median progression-free survival (PFS) period of 4.6 months. For the 14 patients with advanced HPC/SFT who received temozolomide and bevacizumab systemic therapy, the overall RECIST response rate was 14%, with the overall Choi response rate of 79%. The median PFS for the cohort was 9.7 months with a median 6-month progression free rate of 78.6%. The most frequently observed toxic effect of temzolomide-bevacizumab therapy was myelosuppression. We have designed a phase II study to evaluate the safety and efficacy of temozolomide-bevaciumab in locally advanced, recurrent, and metastatic HPC/SFT in a prospective manner. Combination therapy with temozolomide and bevacizumab may be a potentially clinically beneficial regimen for advanced HPC/SFT patients.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial

BACKGROUND No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. METHODS In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. FINDINGS Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). INTERPRETATION Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. FUNDING AstraZeneca.

Patient Characteristics and Outcomes of Gastrointestinal Stromal Tumor Patients Undergoing Imatinib Plasma Level Testing

Although gastrointestinal stromal tumor (GIST) is effectively treated with imatinib, there are a number of clinical challenges in the optimal treatment of these patients. The plasma steady-state trough level of imatinib has been proposed to correlate with clinical outcome. Plasma imatinib level may be affected by a number of patient characteristics. Additionally, the ideal plasma trough concentration of imatinib is likely to vary based on the KIT genotype (genotype determines imatinib binding affinity) of the individual patient. Patients’ genotype or plasma imatinib level may influence the type and duration of response that is appreciable by clinical evaluation. The objectives of this study were to determine effects of genotype on the type of response appreciable by current imaging criteria, to determine the distribution of plasma imatinib levels in patients with GIST, to determine factors that correlate with plasma imatinib level, to determine the incremental effects of imatinib dose escalation; and to explore the median plasma levels and outcomes of patients with various KIT mutations. We therefore obtained KIT mutation information and analyzed CT response for size and density measurement of GISTs at baseline and within the first four moths of imatinib treatment. In 126 patients with metastatic/unresectable disease, the KIT genotype of patients’ tumor was significantly associated with unique response characteristics measurable by CT. Furthermore, hepatic and peritoneal metastases differed in their response characteristics. A subgroup of patients with KIT exon 9 mutation, who received higher doses of imatinib and experienced higher trough imatinib levels, experienced improved progression-free survival similar to that of KIT exon 11 patients. Therefore, we have found that imatinib plasma levels were higher in patients with elevated Aspartate amino transferase, were women, were older, or were being treated concomitantly with CYP450 substrate drugs. As expected, CYP450 inducers correlated with a lower plasma imatinib levels in GIST patients. Renal metabolism of imatinib accounts for <10%, so it was not included in the analysis but may affect covariates. Interestingly, there was a trend for low imatinib levels and inferior progression-free survival in patients who had undergone complete gastrectomy. Patients with KIT exon 9 mutation in our cohort received higher imatinib doses, experienced higher trough imatinib levels, and experienced a PFS similar to that of KIT exon 11 patients. In conclusion, imatinib plasma levels are influenced by a number of patient characteristics. The optimal imatinib plasma level for individual patients is not known but is an area of intense investigation. Our study confirms patients with KIT exon 9 mutations benefit from high-dose imatinib and higher trough imatinib levels.

Prognostic factors for advanced-stage human immunodeficiency virus-associated classical Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine, and dacarbazine plus combined antiretroviral therapy: A multi-institutional retrospective study.

BACKGROUND The treatment and outcomes of patients with human immunodeficiency virus (HIV)-associated Hodgkin lymphoma (HL) continue to evolve. The International Prognostic Score (IPS) is used to predict the survival of patients with advanced-stage HL, but it has not been validated in patients with HIV infection. METHODS This was a multi-institutional, retrospective study of 229 patients with HIV-associated, advanced-stage, classical HL who received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus combination antiretroviral therapy. Their clinical characteristics were presented descriptively, and multivariate analyses were performed to identify the factors that were predictive of response and prognostic of progression-free survival (PFS) and overall survival (OS). RESULTS The overall and complete response rates to ABVD in patients with HIV-associated HL were 91% and 83%, respectively. After a median follow-up of 5 years, the 5-year PFS and OS rates were 69% and 78%, respectively. In multivariate analyses, there was a trend toward an IPS score >3 as an adverse factor for PFS (hazard ratio [HR], 1.49; P=.15) and OS (HR, 1.84; P=.06). A cluster of differentiation 4 (CD4)-positive (T-helper) cell count <200 cells/μL was associated independently with both PFS (HR, 2.60; P=.002) and OS (HR, 2.04; P=.04). The CD4-positive cell count was associated with an increased incidence of death from other causes (HR, 2.64; P=.04) but not with death from HL-related causes (HR, 1.55; P=.32). CONCLUSIONS The current results indicate excellent response and survival rates in patients with HIV-associated, advanced-stage, classical HL who receive ABVD and combination antiretroviral therapy as well as the prognostic value of the CD4-positive cell count at the time of lymphoma diagnosis for PFS and OS. Cancer 2014. © 2014 American Cancer Society.

Relationship between survival and increased radiation dose to subventricular zone in glioblastoma is controversial.

To test the hypothesis on prolonged survival in glioblastoma cases with increased subventricular zone (SVZ) radiation dose. Sixty glioblastoma cases were previously treated with adjuvant radiotherapy and Temozolamide. Ipsilateral, contralateral and bilateral SVZs were contoured and their doses were retrospectively evaluated. Median follow-up, progression free survival (PFS) and overall survival (OS) were 24.5, 8.5 and 19.3 months respectively. Log-rank tests showed a statistically significant correlation between contralateral SVZ (cSVZ) dose > 59.2 Gy (75th percentile) and poor median PFS (10.37 [95% CI 8.37-13.53] vs 7.1 [95% CI 3.5-8.97] months, p = 0.009). cSVZ dose > 59.2 Gy was associated with poor OS in the subgroup with subtotal resection/biopsy (HR: 4.83 [95% CI 1.71-13.97], p = 0.004). High ipsilateral SVZ dose of > 62.25 Gy (75th percentile) was associated with poor PFS in both subgroups of high performance status (HR: 2.58 [95% CI 1.03-6.05], p = 0.044) and SVZ without tumoral contact (HR: 10.57 [95% CI 2.04-49], p = 0.008). The effect of high cSVZ dose on PFS lost its statistical significance in multivariate Cox regression analysis. We report contradictory results compared to previous publications. Changing the clinical practice based on retrospective studies which even do not indicate consistent results among each other will be dangerous. We need carefully designed prospective randomized studies to evaluate any impact of radiation to SVZ in glioblastoma.

Consolidation of first remission using radioimmunotherapy with yttrium-90-ibritumomab-tiuxetan in adult patients with Burkitt lymphoma

The addition of anti-CD20 antibodies to high intensity polychemotherapy regimens has improved response and survival rates in newly diagnosed patients with Burkitt lymphoma (BL). However, the role of additional anti-CD20 directed radioimmunotherapy for consolidation of first remission (CR1) has not been reported so far in BL patients receiving rituximab during first-line treatment. We compared five BL patients receiving Y-90-IT radioimmunotherapy consolidation in CR1 to 22 consecutive BL patients without consolidation. We observed that Y-90-IT treatment was associated with clinically relevant myelosuppression. After a median follow-up of 50 months, none of the patients with Y-90-IT treatment relapsed, and no patient died. In contrast, one patient (4.5%) in the non-Y-90-IT group relapsed (50 months-PFS 95.5%; p = 0.6336), and one patient died (50 months-OS 95.5%; p = 0.6171). In conclusion, our data suggest that survival rates are excellent and equal in rituximab pretreated BL patients with or without Y-90-IT consolidation in first remission.

Zevalin and BEAM (Z-BEAM) versus rituximab and BEAM (R-BEAM) conditioning chemotherapy prior to autologous stem cell transplantation in patients with mantle cell lymphoma.

Early relapse is common in patients with mantle cell lymphoma (MCL) highlighting the unmet need for further improvement of therapeutic options for these patients. CD20 inhibition combined with induction chemotherapy as well as consolidation with high-dose chemotherapy (HDCT) is increasingly considered cornerstones within current therapy algorithms of MCL whereas the role of radioimmunotherapy is unclear. This retrospective single center study compared 46 consecutive MCL patients receiving HDCT in first or second remission. Thirty-five patients had rituximab and BEAM (R-BEAM), and 11 patients received ibritumomab tiuxetan (Zevalin®), an Yttrium-90 labeled CD20 targeting antibody, prior to BEAM (Z-BEAM) followed by autologous stem cell transplantation (ASCT). We observed that the 5-year overall survival (OS) in the R-BEAM and Z-BEAM groups was 55% and 71% (p = 0.288), and the 4-year progression free survival (PFS) was 32% and 41%, respectively (p = 0.300). There were no treatment related deaths in both groups, and we observed no differences in toxicities, infection rates or engraftment. Our data suggest that the Z-BEAM conditioning regimen followed by ASCT is well tolerated, but was not associated with significantly improved survival compared to R-BEAM. Copyright © 2015 John Wiley & Sons, Ltd.

Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09

Treatment allocation by epidermal growth factor receptor mutation status is a new standard in patients with metastatic nonesmall-cell lung cancer. Yet, relatively few modern chemotherapy trials were conducted in patients characterized by epidermal growth factor receptor wild type. We describe the results of a multicenter phase II trial, testing in parallel 2 novel combination therapies, predefined molecular markers, and tumor rebiopsy at progression. Objective: The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced nonesmall-cell lung cancer are promising for further investigation. Methods: We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) ≥ 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated. Results: A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16.

Pencil Beam Scanning Proton Therapy for Pediatric Parameningeal Rhabdomyosarcomas: Clinical Outcome of Patients Treated at the Paul Scherrer Institute

BACKGROUND Parameningeal rhabdomyosarcomas (PM-RMSs) represent approximately 25% of all rhabdomyosarcoma (RMS) cases. These tumors are associated with early recurrence and poor prognosis. This study assessed the clinical outcome and late toxicity of pencil beam scanning (PBS) proton therapy (PT) in the treatment of children with PM-RMS. PROCEDURES Thirty-nine children with PM-RMS received neoadjuvant chemotherapy followed by PBS-PT at the Paul Scherrer Institute, with concomitant chemotherapy. The median age was 5.8 years (range, 1.2-16.1). Due to young age, 25 patients (64%) required general anesthesia during PT. The median time from the start of chemotherapy to PT was 13 weeks (range, 3-23 weeks). Median prescription dose was 54 Gy (relative biologic effectiveness, RBE). RESULTS With a mean follow-up of 41 months (range, 9-106 months), 10 patients failed. The actuarial 5-year progression-free survival (PFS) was 72% (95% CI, 67-94%) and the 5-year overall survival was 73% (95% CI, 69-96%). On univariate analysis, a delay in the initiation of PT (>13 weeks) was a significant detrimental factor for PFS. Three (8%) patients presented with grade 3 radiation-induced toxicity. The estimated actuarial 5-year toxicity ≥grade 3 free survival was 95% (95% CI, 94-96%). CONCLUSIONS Our data contribute to the growing body of evidence demonstrating the safety and effectiveness of PT for pediatric patients with PM-RMS. These preliminary results are encouraging and in line with other combined proton-photon and photons series; observed toxicity was acceptable.

CD34+ selected versus unselected autologous stem cell transplantation in patients with advanced-stage mantle cell and diffuse large B-cell lymphoma

Novel strategies aiming to increase survival rates in patients with advanced-stage mantle cell lymphoma (MCL) and relapsing diffuse large B-cell lymphoma (DLBCL) are a clinical need. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has improved progression-free (PFS) and overall survival (OS) in MCL and relapsed DLBCL. However, the role of CD34+ cell selection before ASCT in MCL and DLBCL is unclear. We retrospectively analyzed the outcome of 62 consecutive patients with advanced-stage MCL or relapsed DLBCL undergoing ASCT with (n=31) or without (n=31) prior CD34+ selection. All patients had stage III or IV disease, with 47% having DLBCL and 53% MCL. The median duration for neutrophil and platelet recovery was 12 and 16 days in CD34+ selected patients, and 11 (P<.001) and 14 days (P=.012) in the group without selection, respectively. No differences in toxicities were observed. The 5-year PFS for CD34+ selected versus not selected patients was 67% and 39% (P=.016), and the 5-year OS was 86% and 54% (P=.007). Our data suggest that using CD34+ selected autografts for ASCT in advanced stage MCL and DLBCL is associated with longer PFS and OS without increased toxicity.

Surgical Treatment of Recurrent Endometrial Cancer: Time for a Paradigm Shift.

BACKGROUND Although surgery represents the cornerstone treatment of endometrial cancer at initial diagnosis, scarce data are available in recurrent setting. The purpose of this study was to review the outcome of surgery in these patients. METHODS Medical records of all patients undergoing surgery for recurrent endometrial cancer at NCI Milano between January 2003 and January 2014 were reviewed. Survival was determined from the time of surgery for recurrence to last follow-up. Survival was estimated using Kaplan-Meier methods. Differences in survival were analyzed using the log-rank test. The Fisher's exact test was used to compare optimal versus suboptimal cytoreduction against possible predictive factors. RESULTS Sixty-four patients were identified. Median age was 66 years. Recurrences were multiple in 38 % of the cases. Optimal cytoreduction was achieved in 65.6 %. Median OR time was 165 min, median postoperative hemoglobin drop was 2.4 g/dl, and median length hospital stay was 5.5 days. Eleven patients developed postoperative complications, but only four required surgical management. Estimated 5-year progression-free survival (PFS) was 42 and 19 % in optimally and suboptimally cytoreduced patients, respectively. At multivariate analysis, only residual disease was associated with PFS. Estimated 5-year overall survival (OS) was 60 and 30 % in optimally and suboptimally cytoreduced patients, respectively. At multivariate analysis, residual disease and histotype were associated with OS. At multivariate analysis, only performance status was associated with optimal cytoreduction. CONCLUSIONS Secondary cytoreduction in endometrial cancer is associated with long PFS and OS. The only factors associated with improved long-term outcome are the absence of residual disease at the end of surgical resection and histotype.

The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: study protocol for a randomised controlled trial.

BACKGROUND Atypical meningiomas are an intermediate grade brain tumour with a recurrence rate of 39-58 %. It is not known whether early adjuvant radiotherapy reduces the risk of tumour recurrence and whether the potential side-effects are justified. An alternative management strategy is to perform active monitoring with magnetic resonance imaging (MRI) and to treat at recurrence. There are no randomised controlled trials comparing these two approaches. METHODS/DESIGN A total of 190 patients will be recruited from neurosurgical/neuro-oncology centres across the United Kingdom, Ireland and mainland Europe. Adult patients undergoing gross total resection of intracranial atypical meningioma are eligible. Patients with multiple meningioma, optic nerve sheath meningioma, previous intracranial tumour, previous cranial radiotherapy and neurofibromatosis will be excluded. Informed consent will be obtained from patients. This is a two-stage trial (both stages will run in parallel): Stage 1 (qualitative study) is designed to maximise patient and clinician acceptability, thereby optimising recruitment and retention. Patients wishing to continue will proceed to randomisation. Stage 2 (randomisation) patients will be randomised to receive either early adjuvant radiotherapy for 6 weeks (60 Gy in 30 fractions) or active monitoring. The primary outcome measure is time to MRI evidence of tumour recurrence (progression-free survival (PFS)). Secondary outcome measures include assessing the toxicity of the radiotherapy, the quality of life, neurocognitive function, time to second line treatment, time to death (overall survival (OS)) and incremental cost per quality-adjusted life year (QALY) gained. DISCUSSION ROAM/EORTC-1308 is the first multi-centre randomised controlled trial designed to determine whether early adjuvant radiotherapy reduces the risk of tumour recurrence following complete surgical resection of atypical meningioma. The results of this study will be used to inform current neurosurgery and neuro-oncology practice worldwide. TRIAL REGISTRATION ISRCTN71502099 on 19 May 2014.

Response to chemotherapy, recurrence and survival in advanced-stage ovarian, fallopian tube and primary peritoneal cancer patients with non-Ashkenazi Jewish BRCA mutations, compared to those without

Objectives. Previous studies have shown a survival advantage in ovarian cancer patients with Ashkenazi-Jewish (AJ) BRCA founder mutations, compared to sporadic ovarian cancer patients. The purpose of this study was to determine if this association exists in ovarian cancer patients with non-Ashkenazi Jewish BRCA mutations. In addition, we sought to account for possible "survival bias" by minimizing any lead time that may exist between diagnosis and genetic testing. ^ Methods. Patients with stage III/IV ovarian, fallopian tube, or primary peritoneal cancer and a non-Ashkenazi Jewish BRCA1 or 2 mutation, seen for genetic testing January 1996-July 2007, were identified from genetics and institutional databases. Medical records were reviewed for clinical factors, including response to initial chemotherapy. Patients with sporadic (non-hereditary) ovarian, fallopian tube, or primary peritoneal cancer, without family history of breast or ovarian cancer, were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. When possible, 2 sporadic patients were matched to each BRCA patient. An additional group of unmatched, sporadic ovarian, fallopian tube and primary peritoneal cancer patients was included for a separate analysis. Progression-free (PFS) & overall survival (OS) were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Matched pairs were treated as clusters. Stratified log rank test was used to calculate survival data for matched pairs using paired event times. Fisher's exact test, chi-square, and univariate logistic regression were also used for analysis. ^ Results. Forty five advanced-stage ovarian, fallopian tube and primary peritoneal cancer patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations, 86 sporadic-matched and 414 sporadic-unmatched patients were analyzed. Compared to the sporadic-matched and sporadic-unmatched ovarian cancer patients, non-AJ BRCA mutation carriers had longer PFS (17.9 & 13.8 mos. vs. 32.0 mos., HR 1.76 [95% CI 1.13–2.75] & 2.61 [95% CI 1.70–4.00]). In relation to the sporadic- unmatched patients, non-AJ BRCA patients had greater odds of complete response to initial chemotherapy (OR 2.25 [95% CI 1.17–5.41]) and improved OS (37.6 mos. vs. 101.4 mos., HR 2.64 [95% CI 1.49–4.67]). ^ Conclusions. This study demonstrates a significant survival advantage in advanced-stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. Our efforts to account for "survival bias," by matching, will continue with collaborative studies. ^

Ultrastructural Analysis of Transcription and Splicing in the Cell Nucleus after Bromo-UTP Microinjection

In this study we demonstrate, at an ultrastructural level, the in situ distribution of heterogeneous nuclear RNA transcription sites after microinjection of 5-bromo-UTP (BrUTP) into the cytoplasm of living cells and subsequent postembedding immunoelectron microscopic visualization after different labeling periods. Moreover, immunocytochemical localization of several pre-mRNA transcription and processing factors has been carried out in the same cells. This high-resolution approach allowed us to reveal perichromatin regions as the most important sites of nucleoplasmic RNA transcription and the perichromatin fibrils (PFs) as in situ forms of nascent transcripts. Furthermore, we show that transcription takes place in a rather diffuse pattern, without notable local accumulation of transcription sites. RNA polymerase II, heterogeneous nuclear ribonucleoprotein (hnRNP) core proteins, general transcription factor TFIIH, poly(A) polymerase, splicing factor SC-35, and Sm complex of small nuclear ribonucleoproteins (snRNPs) are associated with PFs. This strongly supports the idea that PFs are also sites of major pre-mRNA processing events. The absence of nascent transcripts, RNA polymerase II, poly(A) polymerase, and hnRNPs within the clusters of interchromatin granules rules out the possibility that this domain plays a role in pre-mRNA transcription and polyadenylation; however, interchromatin granule-associated zones contain RNA polymerase II, TFIIH, and Sm complex of snRNPs and, after longer periods of BrUTP incubation, also Br-labeled RNA. Their role in nuclear functions still remains enigmatic. In the nucleolus, transcription sites occur in the dense fibrillar component. Our fine structural results show that PFs represent the major nucleoplasmic structural domain involved in active pre-mRNA transcriptional and processing events.