Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer.

OBJECTIVE: The AGO-OVAR16 study was designed to test the efficacy, safety, and tolerability of pazopanib maintenance after first-line chemotherapy in patients with newly diagnosed advanced ovarian cancer (AOC). METHODS: Nine hundred and forty patients with histologically confirmed AOC, International Federation of Gynecology and Obstetrics (FIGO) stage II-IV, were randomized in a 1:1 ratio to receive either 800 mg pazopanib once daily or placebo for up to 24 months, unless there was disease progression, toxicity, withdrawal of consent, or death. The primary endpoint (investigator-assessed progression-free survival [PFS]) was met and previously reported. The results of final analyses of overall survival (OS) are reported here. RESULTS: A third OS interim analysis showed futility and led to study closure and a final OS analysis after last patient last visit. At the time of the final OS analysis, 494 (89.7% of the planned 551) events had occurred. No difference was observed in OS between pazopanib and placebo. The hazard ratio (HR) was 0.960 (95% confidence interval [CI]: 0.805-1.145), and the median OS from randomization was 59.1 months in pazopanib and 64.0 months in placebo arms. For the East Asian patients, similar to the first three interim OS analyses, a numerical negative trend was observed favoring placebo (HR, 1.332; 95% CI: 0.863-2.054). Exploratory analyses showed a trend for a longer time to first subsequent anti-cancer therapy or death with pazopanib over placebo (HR, 0.829; 95% CI: 0.713-0.965), with a median estimate of 19.0 and 14.5 months, respectively. No new safety signals were observed. CONCLUSION: Although pazopanib prolonged PFS, this was not associated with improvement in median OS. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov: NCT00866697.

Magnetoencephalographic Source Localization of the Eye Area of the Motor Homunculus.

A patient with intractable epilepsy, previous right frontal resection, and active vagus nerve stimulation (VNS) developed new onset quasi-continuous twitching around the left eye. Electroencephalography showed no correlate to the orbicularis oculi twitches apart from myographic potentials at the left supraorbital and anterior frontal electrodes. Magnetoencephalography was performed using spatiotemporal signal space separation to suppress magnetic artifacts associated with the VNS apparatus. Magnetoencephalographic source imaging performed on the data back-averaged from the left supraorbital myographic potentials revealed an intrasulcal cortical generator situated in the posterior wall of the right precentral gyrus representing the eye area of the motor homunculus.

Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer.

BACKGROUND: PM01183 is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. PM01183 showed strong antitumor activity in preclinical models of cisplatin-resistant epithelial ovarian cancer. PATIENTS AND METHODS: Patients with platinum-resistant/refractory ovarian cancer were included in a two-stage, controlled, randomized (in a second stage), multicenter, phase II study. Primary endpoint was overall response rate (ORR) by RECIST and/or GCIG criteria. The exploratory first stage (n = 22) confirmed the activity of PM01183 as a single agent at 7.0 mg flat dose every 3 weeks (q3wk). The second stage (n = 59) was randomized and controlled with topotecan on days 1-5 q3wk or weekly (every 4 weeks, q4wk). RESULTS: ORR was 23% (95% CI, 13%-37%) for 52 PM01183-treated patients. Median duration of response was 4.6 months (95% CI, 2.5-6.9 months), and 23% (95% CI, 0%-51%) of responses lasted 6 months or more. Ten of the 12 confirmed responses were reported for 33 patients with platinum-resistant disease [ORR = 30% (95% CI, 16%-49%)]; for the 29 patients treated with topotecan in the second stage, no responses were found. Median PFS for all PM01183-treated patients was 4.0 months (95% CI, 2.7-5.6 months), and 5.0 months (95% CI, 2.7-6.9 months) for patients with platinum-resistant disease. Grade 3/4 neutropenia in 85% of patients; febrile neutropenia in 21% and fatigue (grade 3 in 35%) were the principal safety findings for PM01183. CONCLUSION: PM01183 is an active drug in platinum-resistant/refractory ovarian cancer and warrants further development. The highest activity was observed in platinum-resistant disease. Its safety profile indicates the dose should be adjusted to body surface area (mg/m2). TRIAL CODE: EudraCT 2011-002172-16.

Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer.

BACKGROUND: In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1. PATIENTS AND METHODS: Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes. RESULTS: Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35). CONCLUSIONS: Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings. CLINICAL TRIAL REGISTRATION: NCT01345682.

Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.

BACKGROUND: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years. PATIENTS AND METHODS: Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed. RESULTS: Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. CONCLUSIONS: Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. CLINICAL TRIAL REGISTRATION: NCT01345682 (ClinicalTrials.gov).

Fine-mapping butyrophilin family genes revealed several polymorphisms influencing viral genotype selection in hepatitis C infection.

Host-viral genetic interaction has a key role in hepatitis C infection (HCV) and maybe in the viral selection. In a preliminary GWAS analysis, we identified BTN3A2 rs9104 to be associated with HCV genotype 1. Therefore, our aim was to determine the influence of BTN family on the selection of HCV genotype. We performed a fine-mapping analysis of BTN gene region in a cohort of chronic HCV infection (N=841), validating significant results in another independent chronic HCV infection cohort (N=637), according to selection of viral genotype. BTN3A2 rs9104, BTN3A2 rs733528, BTN2A1 rs6929846, BTN2A1 rs7763910 and BTN3A3 rs13220495 were associated with viral genotype selection. Interestingly, BTN3A2 rs9104 GG genotype was closely related to genotype 1 infection (80.7% (394/488) compared with genotype 3 infection (53.5% (23/43); P=0.0001) in patients harboring IL28B-CT/TT genotype, although this effect was not observed in IL28B-CC genotype. Similarly, BTN3A3 rs13220495 CC genotype was linked to genotype 3 infection (100% (32/32)) compared to genotype 1 (87.3% (137/157); P=0.028) in patients harboring IL28B-CC genotype, but did not in IL28B-CT/TT genotype. Genetic variants in the butyrophilin family genes may alter susceptibility to infection, selecting HCV genotype and influencing disease progression. BTN3A2 rs9104 was strongly associated with genotype 1 infection and the haplotype BTN3A3 rs13220495 CC+IL28B genotype CC was universal in patients with hepatitis C genotype 3a.

A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck.

BACKGROUND: Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy. PATIENTS AND METHODS: An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m(2)/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR). RESULTS: A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab. CONCLUSION: Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.

Hepatitis C virus infection alters lipid metabolism depending on IL28B polymorphism and viral genotype and modulates gene expression in vivo and in vitro.

Hepatitis C virus (HCV) interacts with lipid receptors to enter the cell, circulates as lipoviroparticle and is secreted as VLDL. We aimed to investigate the role of the rs12979860 polymorphism in the IL28B gene in 143 with chronic hepatitis C genotype 1, 144 infected with genotype 3, 90 genotype 4 and 413 noninfected individuals on lipid profile and to test the impact of HCV infection in an in vitro model on VLDL biosynthesis-related gene expression rs12979860 polymorphism was analysed using real-time PCR coupled to Fluorescence Resonance Energy Transfer (FRET). Huh7.5 (rs12979860 CT) and Huh7 (genotype CC) cells were infected with JFH-1 particles and serum from patients infected with genotypes 1 and 3. Gene expression of apolipoprotein B (apoB), microsomal triglyceride transfer protein (MTP), acetyl CoA carboxylase (ACC), diacylglycerol acyltransferase 2 (DGAT2), diacylglycerol acyltransferase 1 (DGAT1) and low-density lipoprotein receptor (LDLr) genes were determined by semiquantitative RT-PCR in vivo and in vitro. Genotype CC rs12979860 polymorphism was associated with significantly higher serum LDL and total cholesterol levels in patients with hepatitis C genotype 1 but not in patients with hepatitis C genotype 3, genotype 4 and control (noninfected) population. Genotype CC was more often seen in genotype 3 and healthy people in comparison with genotype 1; P = 0.001. In vitro results showed that HCV infection promotes lipid metabolism gene expression induction depending on viral genotype, but to a lesser extent in cells with CT genotype. These results demonstrate that IL28B genotype influences lipid metabolism in patients with hepatitis C but not in noninfected and it seems to be viral genotype-mediated. HCV infection modifies lipid-related genes expression (DGAT1 and DGAT2) in cultured cells based on viral genotype and IL28 polymorphism.

Update in imaging tests used for the localization of parathyroid pathology.

Preoperative localization of parathyroid pathology, generally a parathyroid adenoma, can be difficult in some cases due to the anatomical variants that these glands present. The objective of this review is to analyse the different imaging techniques used for preoperative localization of parathyroid pathology (scintigraphy, ultrasound, CT, MRI and PET). There is great variability between the different tests for the preoperative localization of parathyroid pathology. The importance of knowing the different diagnostic options lies in the need to choose the most suitable test at each moment and for each patient for an adequate management of primary hyperparathyroidism (PHP) with surgical criteria.

Chalicogloea cavernicola gen. nov., sp. nov. (Chroococcales, Cyanobacteria), from low-light aerophytic environments: combined molecular, phenotypic and ecological criteria.

This work characterizes a unicellular cyanobacterium with nearly spherical cells and thin-outlined sheaths that divide irregularly, forming small packets immersed in a diffluent mucilaginous layer. It was isolated growing on calcite speleothems and walls in a show cave in Collbató (Barcelona, Spain). Spectral confocal laser and transmission electron microscopy were used to describe the morphology, fine structure and thylakoid arrangement. The pigments identified were phycoerythrin, phycocyanin, allophycocyanin and chlorophyll a. Three-dimensional reconstructions, generated from natural fluorescence z-stacks, revealed a large surface area of nearly flat, arm-like thylakoidal membranes connected to each other and forming a unified structure in a way that, to our knowledge, has never been described before. Phylogenetic analyses using the 16S rRNA gene sequence showed 95% similarity to strain Chroococcus sp. JJCM (GenBank accession no. AM710384). The diacritical phenotypic features do not correspond to any species currently described, and the genetic traits support the strain being classified as the first member of an independent genus in the order Chroococcales and the family Chroococcaceae. Hence, we propose the name Chalicogloea cavernicola gen. nov., sp. nov. under the provisions of the International Code of Nomenclature for Algae, Fungi and Plants. The type strain of Chalicogloea cavernicola is COLL 3(T) (=CCALA 975(T) =CCAP 1424/1(T)).

[Acute disseminated encephalomyelitis associated with SARS-CoV-2 infection without respiratory compromise]. / Encefalomielitis aguda diseminada asociada a infección por el SARS-CoV-2 sin afectación respiratoria.

INTRODUCTION: COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to grow all over the world since december of 2019. Although the main clinical manifestation is pulmonary disease, neurological manifestations are a prominent and increasingly recognized feature of the disease. The Acute Disseminated Encephalomyelitis (ADEM) is a rare autoimmune disorder, most commonly triggered by a viral infection. There are a few case reports of ADEM associated with COVID-19, almost all of them associated pulmonary disease. We report the case of a young patient with diagnosis of ADEM with SARS-CoV-2 infection without clinical respiratory symptoms. CASE REPORT: A 20-year-old woman with no relevant medical history was brought to the emergency department with a progressive confusional state lasted for 7 days. Family reported the development of smell and taste deficit since two weeks before the onset of neurological symptoms. There were no complaints of pulmonary symptoms. At admission, she was drowsy and disoriented. Left homonymous hemianopsia and an ipsilateral Babinski sign was identified. A brain magnetic resonance image was done showing multiple hyperintense bilateral, asymmetric patchy and poorly marginated lesions with gadolinium enhancement. She was SARS-CoV-2 PCR positive on nasopharyngeal swab. Intravenous high-dose glucocorticoids were administered with marked clinical improvement. CONCLUSION: ADEM is an extremely uncommon complication of SARS-CoV-2infection. Acute disseminated encephalomyelitis should be considered a potentially treatable cause of encephalopathy or multifocal neurological deficits in COVID-19 patients, even in the absence of respiratory symptoms.

TITLE: Encefalomielitis aguda diseminada asociada a infección por el SARS-CoV-2 sin afectación respiratoria.Introducción. COVID-19 (coronavirus disease-2019) es la enfermedad secundaria a la infección por el coronavirus de tipo 2 o SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2), que se ha constituido como pandemia desde diciembre de 2019. Si bien la afectación más frecuente y grave es la pulmonar, las complicaciones neurológicas secundarias a la COVID-19 son cada vez más reconocidas. La encefalomielitis aguda diseminada (EMAD) es una enfermedad autoinmune poco frecuente, clásicamente secundaria a una infección viral previa o concomitante. Existen informes de EMAD asociada a la COVID-19, casi todos con afectación respiratoria asociada. Presentamos el caso de una mujer joven diagnosticada con EMAD secundaria a la infección por el SARS-CoV-2 sin afectación respiratoria. Caso clínico. Mujer de 20 años que consultó por cuadro de desorientación y alteración conductual de una semana de evolución. Destaca en la historia la presencia de anosmia y sensación febril dos semanas antes del inicio de los síntomas neurológicos. En el examen físico destacó somnolencia, desorientación, hemianopsia homónima izquierda y síndrome piramidal ipsilateral. Se realizó una resonancia magnética encefálica que mostró múltiples lesiones inflamatorias desmielinizantes bihemisféricas de la sustancia blanca sugerentes de EMAD. La reacción en cadena de la polimerasa del SARS-CoV-2 en aspirado nasofaríngeo resultó positiva. Se descartaron otras causas de lesiones inflamatorias. Recibió esteroides con excelente respuesta. Conclusión. La EMAD es una complicación extremadamente rara en pacientes con COVID-19 que debe considerarse como una causa tratable de encefalopatía y/o déficits neurológicos multifocales en pacientes con infección activa o reciente por SARS-CoV-2 con o sin manifestaciones respiratorias.

Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2-6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity. RESULTS: Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received 4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib. CONCLUSION: Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.

Use of HOMA-IR in hepatitis C.

Chronic infection with hepatitis C virus (HCV) can induce insulin resistance (IR) in a genotype-dependent manner and contributes to steatosis, progression of fibrosis and resistance to interferon plus ribavirin therapy. Our understanding of HCV-induced IR has improved considerably over the years, but certain aspects concerning its evaluation still remain elusive to clinical researchers. One of the most important issues is elucidating the ideal method for assessment of IR in the setting of hepatitis C. The hyperinsulinaemic euglycaemic clamp is the gold standard method for determining insulin sensitivity, but is impractical as it is labour intensive and time-consuming. To date, all human studies except for four where IR was evaluated in the HCV setting, an estimation of IR has been used rather than direct measurements of insulin-mediated glucose uptake. The most commonly used estimation in the HCV population is the homeostasis model assessment of insulin resistance (HOMA-IR) which is calculated from a single measurement of fasting insulin and glucose. In this article, we review the use and reporting of HOMA in the literature and provide guidance on its appropriate as well as inappropriate use in the hepatitis setting.

Feasibility of a modified outpatient regimen of intravenous/intraperitoneal chemotherapy in optimally debulked stage III ovarian cancer patients: a GEICO study.

OBJECTIVES: The objective of the study was to assess the feasibility, toxicity, and reasons for early discontinuation of a modified outpatient intraperitoneal/intravenous (IP/IV) chemotherapy regimen for the treatment of patients with optimally debulked stage III ovarian cancer. METHODS: Between February 2006 and November 2008, 51 consecutive patients from Institutions of the Spanish Ovarian Cancer Group (GEICO) were treated with a modified outpatient IP chemotherapy regimen. Patients received IV paclitaxel 175 mg/m over 3 hours on day 1, followed by IP cisplatin 100 mg/m (or 75 mg/m according to the principal investigator's criteria) on day 2. On day 8, patients received IP paclitaxel 60 mg/m. To homogenize the IP administration and supportive measures, a GEICO guideline for IP chemotherapy was established. Patients were treated with the intention to receive 6 courses of chemotherapy every 21 days. RESULTS: The median age of the patients was 49 years (range, 36-75 years), and most of them had papillary serous ovarian cancer (78%), International Federation of Gynecology and Obstetrics stage IIIC (76%). Thirty-nine patients completed 4 or more IP cycles, and 28 (61%) completed all 6 IP cycles. Twenty-two patients discontinued the IP/IV treatment, mainly because of chemotherapy toxicity (10 patients) and catheter-related complications (5 patients). The most prevalent grade 3/4 toxicities were neutropenia (14 patients; 30%) and gastrointestinal events (12 patients; 26%). CONCLUSIONS: The GEICO outpatient modified regimen resulted in a lesser toxicity and a greater rate of treatment completion than previously reported. The accurate selection of patients and the administration following well-defined guidelines can increase the feasibility of IP chemotherapy administration.

Associations of physical activity with muscular fitness in adolescents.

The aim of this study was to examine the associations between objectively assessed physical activity (PA) and muscular fitness (MF) in adolescents, and to determine whether only resistance training exercise is associated with the increase of MF. A sample of 211 Spanish adolescents (105 girls) wore the ActiGraph monitor for 7 days. Participants also completed a fitness evaluation including three MF tests (handgrip strength, a 60-s abdominal test and a standing broad jump), a cardiorespiratory fitness assessment and anthropometric measures. A standardized MF score was computed using the three muscular tests. Adolescent participation in resistance training was self-reported. Linear regression showed that only vigorous PA was significantly (P=0.041) and positively (ß=0.133) associated with MF after adjustment by gender, age, pubertal status, BMI, and cardiorespiratory fitness. Significant differences in MF were found between youth in the lowest and upper tertiles of vigorous PA. Moreover, adolescents who were involved in resistance training had significantly higher MF scores compared with youth in low and medium tertiles of vigorous PA, but no significant differences were found when compared with non-lifters from the highest tertile of vigorous PA (P=0.356). These findings suggest that vigorous activity may be associated with indicators of MF in adolescents.

Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer.

BACKGROUND: This randomized, open-label, phase II clinical trial evaluated the optimal regimen of trabectedin administered every 3 weeks in patients with platinum-sensitive, relapsed, advanced ovarian cancer (AOC). PATIENTS AND METHODS: Patients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0. RESULTS: ORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B). CONCLUSIONS: Both every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.

Risk of recurrence during follow-up for optimally treated advanced epithelial ovarian cancer (EOC) with a low-level increase of serum CA-125 levels.

BACKGROUND: Our group evaluated the risk of recurrence for optimally treated advanced epithelial ovarian cancer (adEOC) in patients with a low-level rising serum CA-125 concentration within the normal range (0-35 kU/l). In addition, we tested the new proposed early CA-125 signal of progressive disease (EPD) criterion in the same study population. PATIENTS AND METHODS: Patients treated from 1998 to 2006 for adEOC were identified at our institution. Inclusion criteria were as follows: CA-125 at time of diagnosis (>35 kU/l); International Federation of Gynecology and Obstetrics stages III-IV treated with optimal primary treatment; and complete response (CR) to primary treatment with normalization of CA-125. RESULTS: Median progression-free survival and overall survival for the recurrence group (n = 60) were 17.7 and 38.2 months, respectively. The median follow-up time from CR to last contact was 40.2 months for patients in the nonrecurrence group (n = 36). An absolute increase in serum CA-125 levels of >or=5 kU/l compared with baseline CA-125 nadir values was significantly predictive of recurrence (odds ratio for recurrence = 402.98, P < 0.0001). The progression date was predated by the EPD criterion in 77% of patients with known progressive disease (median, 58 days early) with a sensitivity of 90%, a positive predictive value of 96.4%, and a false-positive rate of 5.6%. CONCLUSIONS: Among patients with optimally treated adEOC in complete remission, a low-level increase in serum CA-125 concentration within the normal range is a strong independent predictive factor for disease recurrence. In this patient population, future prospective randomized trials should consider the evaluation of the EPD criterion.

Nadir CA-125 concentration in the normal range as an independent prognostic factor for optimally treated advanced epithelial ovarian cancer.

BACKGROUND: The amount of residual disease after surgery is considered the most important factor influencing the survival of patients with advanced epithelial ovarian cancer (adEOC). In optimally treated patients with adEOC, there are no well-established prognostic factors [excluding International Federation of Gynecology and Obstetrics (FIGO) stage]. The aim of this retrospective study is to analyze the prognostic value of the CA-125 nadir after the completion of an optimal primary treatment. PATIENTS AND METHODS: Patients treated for adEOC were identified from January 1998 to December 2006. INCLUSION CRITERIA: elevated CA-125 at time of diagnosis (>35 kU/l); FIGO stage III-IV treated with optimal primary treatment (residual tumor <1 cm and carboplatin/taxane-based combination chemotherapy); and complete response to optimal primary treatment with normalization of CA-125. RESULTS: Patients, n = 96: 44 group A (< or =10 kU/l); 52 group B (11-35 kU/l). Median progression-free survival (PFS) was 42 and 20 months for groups A and B, respectively (P = 0.0087). Median overall survival (OS) was 84 and 43 months for groups A and B, respectively (P < 0.0001). The Cox model showed a highly significant impact on PFS and OS in relation to CA-125 nadir levels. CONCLUSIONS: The CA-125 nadir value is a strong independent prognostic factor for optimally treated adEOC after achieving a complete response.

Update in the management of ovarian and cervical carcinoma.

Ovarian and cervical cancers are significant health problems. This article provides an update in selected management topics. Paclitaxel and platinum derivatives are the first-line treatment for patients with advanced disease. In selected patients, intraperitoneal chemotherapy has been associated with improved survival but the broad applicability of this strategy is limited by issues of toxicity and feasibility. Management of patients with recurrent disease is based on a number of factors and includes surgery in selected cases, platinum-based chemotherapy for patients with platinum-sensitive disease and other agents such as topotecan and pegylated liposomal formulation of doxorubicin for patients with platinum-resistant disease. In cervical cancer, the most significant issue/event is the demonstration of superior survival with topotecan and cisplatin compared to cisplatin alone. Finally, new agents such as epidermal growth factor receptor inhibitors and antiangiogenic agents are being currently tested in these settings.

Feasibility of magnetoencephalographic source imaging in patients with thalamic deep brain stimulation for epilepsy.

Source localization of interictal spikes in patients with medically refractory epilepsy is the most common clinical application of magnetoencephalography (MEG). In recent decades, many patients with intractable epilepsy have been treated with various forms of neurostimulation, including thalamic deep brain stimulation (DBS). Patients with suboptimal seizure control after DBS might in some cases benefit from further investigations for resective epilepsy surgery, including MEG source imaging (MSI). We sought to determine the feasibility and accuracy of MSI in the setting of active thalamic DBS. Simultaneous EEG/MEG was obtained in a patient using an Elekta 306-channel MEG system, with high-frequency (100 Hz) DBS of the thalamic anterior nuclei cycling between on and off states. Magnetic artifacts associated with the DBS apparatus were successfully suppressed using the spatiotemporal signal space separation (tSSS) method. Electrical stimulation artifact was removed by standard digital low-pass filtering. Dipole source modeling results for spike foci in frontal and posterior temporal regions were comparable between stimulation on and stimulation off states, and the source solutions corresponded well to the localization of spikes documented by intracranial EEG. MSI is thus feasible and source solutions can be accurate when performed in patients with active thalamic DBS for epilepsy.