Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I.

BACKGROUND: Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. RESULTS: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. CONCLUSIONS: In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.

Opportunities in immunotherapy of ovarian cancer.

Ovarian cancer (OC) is the most important cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease. Although surgery and chemotherapy can improve survival, the 5-year survival rates remain ominously low at 45%. Novel therapies are urgently needed. The presence of T cells in the OC tumor microenvironment is correlated with improved progression-free and overall survival, while the presence of regulatory T cells and expression of T-cell inhibitory molecules is correlated with a poor prognosis. These data indicate that immunotherapy could hold promise in improving the treatment of OC. In this review, we will discuss the rational of immunotherapy, highlight current results with cancer vaccines, adoptive T-cell therapy and immunomodulatory agents and summarize the immune effects of selected chemotherapeutic and radiotherapeutic agents.

MLH1 and MSH2 mutation screening in HNPCC families of Hungary - Two new MMR gene mutations.

INTRODUCTION: Hereditary Non-Polyposis Colorectal Cancer is an inherited disease with deleterious germline mutations in the DNA mismatch repair genes causing the development of colon cancer and other malignancies. This is the first study in Hungary screening the population of our colorectal cancer patients in order to identify the prevalence of the disease. METHODS: In families who met the Modified Amsterdam and Bethesda Criteria the removed tumor tissue was first examined by immunohistochemistry and microsatellite instability analysis. Those cases which showed high microsatellite instability underwent DNA sequencing and multiple ligation dependent probe amplification. RESULTS: Of the 1576 patients with colorectal cancer underwent screening for the modified Amsterdam and Bethesda criteria, 69 (4.4%) and 166 (10.5%) fulfilled the criteria respectively. 15 patients (31%) of the Amsterdam positive group and 19 patients from the Bethesda positive (18.1%) were MSI-H. There were 8 pathogenic mutations identified in 9 families (60%) in the Amsterdam positive group. 5 mutations were found in 5 families (26%) in the Bethesda positive group. 12 pathogenic mutations were identified, two of these are newly identified, and being published first in this work. These two new mutations were located on MLH1 (g.31276_35231del) and MSH2 (c.969_970delTC) genes. CONCLUSION: The prevalence of the mutations in the MLH1 and MSH2 genes was almost equal in our Hungarian colorectal cancer patients. One mutation in the MLH1 gene (c.143A > C; p.Q48P) was identified in three different families. Whether this mutation is the most frequent in the Hungarian population is still unidentified and warrant further investigation.

Dynamic conformal arc cranial stereotactic radiosurgery: implications of multileaf collimator margin on dose-volume metrics.

OBJECTIVE: The effect of multileaf collimator (MLC) margin on target and normal tissue dose-volume metrics for intracranial stereotactic radiosurgery (SRS) was assessed. METHODS: 118 intracranial lesions of 83 SRS patients formed the basis of this study. For each planning target volume (PTV), five separate treatment plans were generated with MLC margins of -1, 0, 1, 2 and 3 mm, respectively. Identical treatment planning parameters were employed with a median of five dynamic conformal arcs using the Varian/BrainLab high-definition MLC for beam shaping. Prescription dose (PD) was such that 22 Gy covered at least 95% of the PTV. Dose-volume and dose-response comparative metrics included conformity index, heterogeneity index, dose gradient, tumour control probability (TCP) and normal tissue complication probability (NTCP). RESULTS: Target dose heterogeneity decreased with increasing MLC margin (p<0.001); mean heterogeneity index decreased from 70.4 ± 12.7 to 10.4 ± 2.2%. TCP decreased with increasing MLC margin (p<0.001); mean TCP decreased from 81.0 ± 2.3 to 62.2 ± 1.8%. Normal tissue dose fall-off increased with MLC margin (p<0.001); mean gradient increased from 3.1 ± 0.9 mm to 5.3 ± 0.7 mm. NTCP was optimal at 1 mm MLC margin. No unambiguous correlation was observed between NTCP and PTV volume. Plan delivery efficiency generally improved with larger margins (p<0.001); mean monitor unit per centigray of the PD decreased from 3.60 ± 1.30 to 1.56 ± 0.13. Conclusion Use of 1 mm MLC margins for dynamic conformal arc-based cranial radiosurgery resulted in optimal tumour control and normal tissue sparing. Clinical significance of these comparative findings warrants further investigation.

Papillary thyroid cancer arising in struma ovarii.

Malignant struma ovarii is a rare clinical entity that poses a therapeutic challenge, as there is no 'gold standard' of care. We aimed to develop evaluation and treatment guidelines by reviewing presentation and outcomes of the available literature. We present a 60-year-old female with papillary thyroid carcinoma arising in a mature teratoma, and our multidisciplinary approach to care and follow-up. We examined 59 cases for characteristics, including rates of metastasis and recurrence, and response to surgical and adjuvant treatment. We found higher rates of metastasis and recurrence than traditionally reported, and found no recurrence in patients treated with oophorectomy, thyroidectomy, and I-131 radioablation. A multimodal approach to the treatment of malignant struma ovarii may improve survival and decrease risk of recurrence.

SU-E-J-27: Effects of Metal Artifacts of KV and MV CT Images on Structure Delineation and Tissue Electron/Mass Density Calculation.

PURPOSE: To quantitatively evaluate effects of image artifacts of hip prostheses on the accuracy of structure delineation and tissue density calculation on kV and MV CT images. METHODS: Five hip prostheses made of stainless steel, titanium and cobalt chrome alloys were positioned inside a water tank and scanned respectively on a Philips CT and a Tomotherapy Hi-Art unit. Prostheses were positioned to mimic single and bilateral implantations. Rods of tissue materials of lung, water and bone were placed at locations next and distal to metal implants near femoral head, neck and stem of prostheses. kV and MV CT scans were repeated for each placement. On CT images, cross-sectional outlines of metal implants and tissue rods were delineated. Densities of rod materials were determined and compared to the true values. RESULTS: Metal artifacts were severe on kV CTs and minimal on MV CTs. Cross-sectional outlines of metal implants and tissue rods on kV CTs were severely distorted by artifacts while those on MV CTs remained clearly identifiable. For kV CTs, deviations of measured tissue density from true value were up to 51.3%, 30.6% and 40.9% respectively for lung, bone and solid water. The magnitude of deviation was generally larger at locations closer to metal implants and greater with bilateral implants than single implant. For MV CTs, deviations of measured density from true value were less than 6% for all three tissue materials either with single or bilateral implants. Magnitude of deviation appeared to be uniform and independent of locations relative to metal implants. CONCLUSIONS: High Z metal artifacts on kV CTs can have severe impact on the accuracy of structure delineation and tissue density calculation, while on MV CTs, the impact is substantially less and insignificant. MV CTs should be considered for treatment planning on patients with high Z metal implants.

Impact of the high-definition multileaf collimator on linear accelerator-based intracranial stereotactic radiosurgery.

OBJECTIVES: The impact of two multileaf collimator (MLC) systems for linear accelerator-based intracranial stereotactic radiosurgery (SRS) was assessed. METHODS: 68 lesions formed the basis of this study. 2.5 mm leaf width plans served as reference. Comparative plans, with identical planning parameters, were based on a 5 mm leaf width MLC system. Two collimation strategies, with collimation fixed at 0° or 90° and optimised per arc or beam, were also assessed. Dose computation was based on the pencil beam algorithm with allowance for tissue heterogeneity. Plan normalisation was such that 100% of the prescription dose covered 95% of the planning target volume. Plan evaluation was based on target coverage and normal tissue avoidance criteria. RESULTS: The median conformity index difference between the MLC systems ranged between 0.8% and 14.2%; the 2.5 mm MLC exhibited better dose conformation. The median reduction of normal tissue exposed to ≥100%, ≥50% and ≥25% of the prescription dose ranged from 13.4% to 29.7%, favouring the 2.5 mm MLC system. Dose fall-off was steeper for the 2.5 mm MLC system with an overall median absolute difference ranging from 0.4 to 1.2 mm. The use of collimation optimisation resulted in a decrease in differences between the MLC systems. The results demonstrated the dosimetric merit of the 2.5 mm leaf width MLC system over the 5 mm leaf width system, albeit small, for the investigated range of intracranial SRS targets. CONCLUSION: The clinical significance of these results warrants further investigation to determine whether the observed dosimetric advantages translate into outcome improvements.

A new mutation in Muir-Torre syndrome associated with familiar transmission of different gastrointestinal adenocarcinomas.

Hereditary Nonpolyposis Colorectal Carcinoma (HNPCC) is the most frequent inherited disease which can lead to the development of tumors in the colon and other locations. Its genetic basis is related to the germline mutation of the Mismatch Repair (MMR) genes. Muir-Torre syndrome is considered one of the subtypes of this disease, in which the HNPCC tumor spectrum is frequently associated with sebaceous carcinoma of the skin or keratoacanthoma. A 57 years old male patient is presented with a mucinous carcinoma of the caecum and an adenocarcinoma of the pancreas head. A malignant sebaceous carcinoma was removed from his left neck area. His family history was significant for two cases of colon carcinoma, two cases of stomach cancer and a case of metacron endometrial and skin tumor as well. Both the colon carcinoma and the skin tumor proved to be microsatellite unstable. An Arg>Pro switch missense mutation was found in codon 265 of the hMLH1 gene. This error was found in 4 other members of his family. The detected genetic alteration was considered pathogenic and was not published yet in English literature. The significance of this particular case is the rare tumor association in a patient with Muir-Torre syndrome (MTS). In cases of sebaceous skin lesions, evaluation of family history is of utmost importance in the early detection of HNPCC and in the follow up care of family members with the particular mutation.

Difficulties in recognizing families with Hereditary Non-polyposis Colorectal Carcinoma. Presentation of 4 families with proven mutation.

INTRODUCTION: Hereditary Non-polyposis Colorectal Carcinoma is the most frequent genetic disease leading to colon and other malignancies. Recognizing the condition requires extensive family history going back several generations focusing particularly on the types of tumors occurring in the family at different age groups. METHODS: In families who met the Amsterdam and Bethesda Criteria, the removed tumor tissue was first examined by immunohistochemistry and microsatellite instability analysis. Subsequently DNA sequencing was performed to detect an underlying Mismatch Repair Gene mutation and multiple ligation dependent probe amplification was applied for recognizing large deletions in Mismatch Repair Genes. RESULTS: In the investigated families 3 pathogen mutations, 1 large deletion and 2 cases of polymorphism were found. There is considerable difference between the families in terms of the types of malignancies and the age in which those appeared. CONCLUSION: Recognizing families with Hereditary Non-polyposis Colorectal Carcinoma presents great difficulties because of the variety of phenotypes in presentation. Special attention should be paid to small families and those who present with cancer of other than colon origin. Practicing physicians should be made aware of the fact that this disease may have atypical presentations. Follow up of families who have already been screened may be difficult for social, economical or religious reasons.

Torovirus detection in faecal specimens of calves and pigs in Hungary: short communication.

Bovine torovirus is an established aetiological agent of disease in cattle, while porcine torovirus has only been isolated from healthy animals. Evidence for the presence of torovirus has been described in several European countries and also in the United States. A survey was performed to detect toroviruses in Hungary by means of sampling ten swine and nine bovine herds. Rectal swabs and faecal specimens were collected from diarrhoeic calves and from weaned piglets. The samples were tested by the reverse transcription-polymerase chain reaction (RT-PCR) using torovirus-specific primers and the positive samples were further examined by electron microscopy (EM). Torovirus was detected in 4 diarrhoeic calves (out of 111) and in 10 healthy weaned pigs (out of 200 tested), representing two of the 9 calf herds and two of the 10 pig herds tested. This is the first report of exact diagnosis of torovirus in Hungary.

[The role of MIBI scintigraphy in the early detection of breast cancer]. / A MIBI szcintigráfia szerepe az emlórákok korai diagnosztikájában.

The authors investigate the role of MIBI scintigraphy in the early diagnosis of breast cancer. The importance of early diagnosis is emphasized by the fact that breast cancer has the highest morbidity and mortality preceding cervical carcinoma amongst women. Retrospective examinations were made in case of 42 patients operated before because of breast cancer in order to examine accuracy of both mammography and scintigraphy in comparison with the results of histological diagnosis. In these cases sensitivity of scintigraphy turned out to be 69%, while its specificity 42%. In cases of mammographical investigations the sensitivity proved to be 74% and specificity was 61%. Besides mammography, scintigraphy has a very important additional role in the diagnosis of breast cancer. Because of its results and costs scintigraphy is not able to take over the mammography's dominant position (as a popular diagnostic method) but in selected patients' groups it can help to realise tumors as well as to avoid unnecessary operations or needle biopsis. Based on our results this method can give significant additional information in T1b and especially in T1c states of tumors. Therefore this method can be offered as an additional investigation in cases of physically realised or mammographically screened, but not-palpable, larger than 1 cm size lumps when there is little or moderate risk of malignancy.

[Atypical process of acute disturbance of liver function with severe thrombocytopenia in the third trimester]. / Atypischer Verlauf einer akuten Leberfunktionsstörung mit schwerer Thrombozytopenie im dritten Trimester.

The authors diagnosed disturbance of liver-function associated with severe thrombopenia in a pregnant woman in the third trimester. Principally, acute fatty liver of pregnancy can be characterized by existing symptoms, e.g. nausea, vomiting, epigastric pain, jaundice, hyperbilirubinemia, moderately elevated SGOT and SGPT levels, thrombopenia, leukocytosis, low fibrinogen level and disseminated intravascular coagulopathy, but hepatomegaly, purpura and petechia on lower and upper extremities, and high ALP and GGT levels during postpartum period do not confirm suspicion of this diagnosis. The present report draws attention to the difficulties of differential diagnosis of pregnancy-induced elevated liver enzymes diseases associated with low platelets, as there are several identical pathophysiological processes. Although causes and exact pathophysiology of disorders are unknown, similar symptoms during the process of diseases leave the question open whether they are different diseases or whether they are different manifestations of the same disease, and what kind of relationship exists between these diseases and preeclampsia. This case suggests careful evaluation of the whole clinical picture, moreover it is emphasized that prompt, aggressive treatment of hemostatic disturbance and the expeditious delivery can save maternal life.

[Mutation analysis of the beta-catenin gene in epithelial carcinomas of the ovaries]. / A beta-catenin génmutáció analízise epithelialis ovarium-carcinomákban.

beta-catenin is a continuously expressed cytoplasmic protein that has an important role is both E-cadherin-mediated cell-cell adhesion and in activation of Wnt/Wingless transcriptional pathway. The accumulation of stabilized beta-catenin caused by the mutation of the exon 3 of beta-catenin gene can stimulate the T-cell factor/Lymphoid enhancing factor-mediated transcriptional activation. The activation of transcriptional pathway may through oncogenes is an important step of the oncogenesis in solid tumors. In this study we analyzed mutations in exon 3 of the beta-catenin gene in 18 sporadic epithelial ovarian tumors. Three mutations were found from these 18 ovarian tumor samples which contained 8 serous, 3 mucinous, 5 endometrioid, one malignant Brenner-type tumor and one transitional cell carcinoma. Two mutations occurred in endometrioid-type (in 47 and 55 codons) and one in serous-type (in 47 codon) ovarian carcinomas, and both mutations were missense and somatic. The patients with mutated beta-catenin gene appeared from the younger patients under the age of 50. Our results suggest that the stabilization of beta-catenin protein by the mutation of CTNNB1 gene can contribute to the multistep process of the oncogenesis of epithelial ovarian tumors. Furthermore these mutations mostly occurs in the endometrioid-type of EOT, but can appear in other types such as serous-type ovarian tumor.

Preliminary studies on feline coronavirus distribution in naturally and experimentally infected cats.

The shedding, tissue distribution and quasispecies composition of feline coronaviruses were studied in naturally and experimentally infected cats. The infection remained subclinical, but the majority of the animals shed the virus via faeces throughout the experiment. Sequences corresponding to the viral nucleocapsid region were amplified by reverse-transcription polymerase chain reaction from the cortex, dura mater, pancreas, lungs, third eyelid, and the heart muscle in four cases. Interestingly, the ORF7b viral region - a supposed virulence factor - was detected in fewer organs, raising the possibility that this region can be affected by deletions during virus replication in vivo. It is demonstrated that the composition of the viral quasispecies differs between organs, and that genomic regions with different functions undergo distinct processes of selection, which should be considered during the evolution of feline coronaviruses.

Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of factor V Leiden mutation and 5,10 methylenetetrahydrofolate reductase.

OBJECTIVE: To investigate the potential perinatal effects of Factor V Leiden mutation and 5,10 methylenetetrahydrofolate reductase C677T polymorphism in preeclamptic women. STUDY DESIGN: One hundred twenty preeclamptic women (N = 120) and 101 healthy pregnant controls (N = 101) were recruited and evaluated for frequency of Leiden and 5,10 methylenetetrahydrofolate reductase (MTHFR) mutations using polymerase chain reaction (PCR). Perinatal outcomes were then recorded and analyzed for all study participants and their neonates. RESULTS: Laboratory analysis yielded 22 (18.33%) heterozygous carriers of Factor V Leiden mutation among preeclamptic women and 3 (2.97%) heterozygous carriers among the healthy controls; differences between the two groups were found to be statistically significant [p < 0.001, the relative risk (RR) = 6.17, 95% confidence interval (95% CI) = 1.90-20.02]. Homozygous MTHFR mutations were found in 8 of 120 (6.67%) preeclamptic women and in 6 of the 101 (5.94%) healthy controls evaluated. Among preeclamptic women, episodes of hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome were reported in 7 of 22 (31.81%) of those with Factor V Leiden mutation and in 11 of 98 (11.22%) of those who were negative for the mutation. Group differences were determined to be statistically significant (p < 0.015, RR = 2.83, 95% CI = 1.24-6. 48). Perinatal indicators collected from the two groups included frequency of intrauterine growth retardation, birth weight, and gestational age. No statistically different perinatal outcomes were found between Factor V Leiden positive and negative preeclamptic women. In addition, MTHFR gene polymorphism did not appear to be correlated with the development of preeclampsia. CONCLUSION: Although the frequency of Factor V Leiden mutation appears to be significantly higher among preeclamptic women, the mechanism of pathogenesis and potential influence on perinatal outcomes is not yet well understood. Relatively high rates of HELLP syndrome among those with Factor V Leiden mutation suggest that this thrombogene mutation may play a significant role in hemostatic system activation. Our results suggest that the role of MTHFR polymorphism and other factors such as folic acid supplementation will require more extensive analysis in controlling worldwide morbidity and mortality associated with this important maternal condition.

Prevalence and genetic pattern of feline coronaviruses in urban cat populations.

The prevalence and phylogeny of feline coronaviruses were studied in urban cat populations by sampling of 113 clinically healthy cats. Rectal swab samples were subjected to a nested reverse-transcription polymerase chain reaction, specific for the conservative nucleocapsid region of the virus genome. More than 30% of the sampled animals proved positive for the presence of feline coronaviruses. The nucleotide sequences of amplified 440 bp products were determined, aligned and the phylogenetic analysis revealed noticeable genetic clusters among the prevalent feline coronaviruses in the surveyed geographic area. These findings will hopefully contribute to the elucidation of the epidemiology of feline infectious peritonitis.

New pig disease in Hungary: postweaning multisystemic wasting syndrome caused by circovirus (short communication).

Postweaning multisystemic wasting syndrome (PMWS), a new disease in Hungary, was recognized in a swine herd located in Southeast Hungary, during the early winter of 1999. The first clinical signs of paleness, anaemia, and leanness appeared immediately after weaning, at the age of 40-50 days. Pustules were frequently observed on the skin of the trunk, and signs of necrotic dermatitis were also visible. A syndrome of poor growth and wasting was characteristic of the affected pigs. A porcine circovirus (PCV), the suspected causative agent, was detected by polymerase chain reaction (PCR). Sequencing data and restriction endonuclease (RE) analysis of the PCR products suggested that the virus belonged to the PCV-II group where all the causative agents of PMWS are also grouped.

Natural deoxynivalenol (DON) contamination of wheat samples grown in 1998 as determined by high-performance liquid chromatography.

A high-performance liquid chromatography--diode array detection (HPLC-DAD) method was developed for determining the deoxynivalenol (DON) content of wheat and other cereals. The samples were extracted with a mixture of acetonitrile and water (84 + 16). Part of the extract was evaporated and purified on Florisil and activated charcoal columns. HPLC separation was performed on a C18 column, using acetonitrile-water (8 + 92) as eluent. Diode array detection (DAD) was performed at 218 and 236 nm, by determination of the UV spectrum. Quantitative analysis was carried out by the external standard method, using the UV spectrum obtained by DAD for confirmation. The recovery rate of DON was 75 +/- 3.1% and the detection limit was 0.05 mg/kg DON. Using this method, the DON content of 99 feeding wheat samples grown in the northeastern part of Hungary in 1998 was determined. Eighty-eight percent of the samples originating from three counties contained 0.94 mg/kg DON on the average. The highest individual value was 4.3 mg/kg. DON contamination of wheat was of higher prevalence (100%) and severity (0.27-4.3 mg/kg) in the southeastern county of Békés than in Szabolcs county located in the northeastern part of Hungary (ratio of positive samples: 82%; DON concentration: 0.05-1.3 mg/kg). The higher than usual DON contamination of feeding wheat can be explained by the rainy summer weather. DON contamination of feeding wheat poses a major risk to the production and animal health status of pig herds.

Trisomy 12 in juvenile granulosa cell tumor of the ovary during pregnancy. A report of two cases.

BACKGROUND: Granulosa cell tumors constitute only 5% of ovarian neoplasms, and their coexistence with pregnancy is extremely rare. Juvenile granulosa cell tumor has a good prognosis if it is confined to the ovary, but this type behaves more aggressively than the adult type at advanced stages. CASES: We report on successful completion of two singleton pregnancies and deliveries of normal infants in two young women with juvenile granulosa cell tumor diagnosed and treated during pregnancy. This tumor has rarely been described in association with pregnancy. The presence of trisomy 12 as a single chromosomal abnormality was detected in these two tumors. Both tumors were localized strictly to the ovary, so conservative surgery was applied and proved sufficient to remove all tumor tissue. Follow-up showed no signs of recurrence 18 and 53 months after the interventions. CONCLUSION: These cases support the contention that trisomy 12 is a nonrandom chromosome abnormality in juvenile granulosa cell tumors and that pregnancy may affect nuclear stability in this tumor.