Late Campanian-Early Maastrichtian Vertebrates From The James Ross Basin, West Antarctica: Updated Synthesis, Biostratigraphy, And Paleobiogeography.

The Snow Hill Island Formation (SHIF; late Campanian - early Maastrichtian) crops out in the northeast of the Antarctic Peninsula and constitutes the basal part of the late Campanian-early Maastrichtian sedimentary succession of the James Ross Basin (NG Sequence). Its major exposures occur at the James Ross and Vega islands. Several fossil-bearing localities have been identified in the SHIF providing a valuable fauna of invertebrates and vertebrates, and flora. Our study focuses on the vertebrate fauna recovered at Gamma and Cape Lamb members of the SHIF. The marine vertebrate assemblages include chondrichthyans, actinopterygians, and marine reptiles (elasmosaurid plesiosaurs and mosasaurs). A diverse terrestrial vertebrate assemblage has been reported being characterized by dinosaurs (sauropod, elasmarian ornithopods, nodosaurid ankylosaur, and a paravian theropod), pterosaurs and birds. Most SHIF dinosaurs share close affinities with penecontemporaneous taxa from southern South America, indicating that at least some continental vertebrates could disperse between southern South America and Antarctica during the Late Cretaceous. The Snow Hill Island Formation provides the most diverse Late Cretaceous marine and continental faunas from Antarctica. The present study summarizes previous and new vertebrate findings with the best actualized stratigraphical framework, providing a more complete fauna association and analyzing further perspectives.

Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer.

BACKGROUND: Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non-small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG. MATERIALS AND METHODS: Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. RESULTS: One hundred twenty-nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression-free survival (PFS) in the unselected intent-to-treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37-1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16-0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97-4.76; p = .059, HRG-by-treatment interaction, p value = .0016). CONCLUSION: The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). IMPLICATIONS FOR PRACTICE: The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.

Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial.

PURPOSE: To evaluate the efficacy of adding lapatinib to capecitabine and oxaliplatin (CapeOx) in patients with previously untreated human epidermal growth factor receptor 2 (HER2) -amplified advanced gastroesophageal adenocarcinoma. PATIENTS AND METHODS: Patients with HER2-positive advanced gastroesophageal adenocarcinoma were randomly assigned at a one-to-one ratio to CapeOx plus lapatinib 1,250 mg or placebo daily. Primary end point was overall survival (OS) in patients with centrally confirmed HER2 amplification in the primary efficacy population. RESULTS: A total of 545 patients were randomly assigned, and 487 patients comprised the primary efficacy population. Median OS in the lapatinib and placebo arms was 12.2 (95% CI, 10.6 to 14.2) and 10.5 months (95% CI, 9.0 to 11.3), respectively, which was not significantly different (hazard ratio, 0.91; 95% CI, 0.73 to 1.12). Median progression-free survival in the lapatinib and placebo arms was 6.0 (95% CI, 5.6 to 7.0) and 5.4 months (95% CI, 4.4 to 5.7), respectively (hazard ratio, 0.82; 95% CI, 0.68 to 1.00; P = .0381). Response rate was significantly higher in the lapatinib arm: 53% (95% CI, 46.4 to 58.8) compared with 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031). Preplanned exploratory subgroup analyses showed OS in the lapatinib arm was prolonged in Asian and younger patients. No correlation was observed between HER2 immunohistochemistry status and survival. There were increased toxicities in the lapatinib arm, particularly diarrhea. CONCLUSION: Addition of lapatinib to CapeOx did not increase OS in patients with HER2-amplified gastroesophageal adenocarcinoma. There were clear differences in the effect of lapatinib depending on region and age. Future studies could examine this correlation.

Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study.

PURPOSE: This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. RESULTS: Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. CONCLUSION: Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.

Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31.

PURPOSE: The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (BC) is unknown. PATIENTS AND METHODS: The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. RESULTS: From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). CONCLUSION: As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.

CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

PURPOSE: CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. PATIENTS AND METHODS: Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m(2) per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m(2) per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, -1.6%; 95% CI, -2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. CONCLUSION: CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.

Weddellian marine/coastal vertebrates diversity from a basal horizon (Ypresian, Eocene) of the Cucullaea I Allomember, La Meseta formation, Seymour (Marambio) Island, Antarctica

The La Meseta Formation crops out in Seymour/Marambio Island, Weddell Sea, northeast of the Antarctic Peninsula and contains one of the world's most diverse assemblages of Weddellian marine/coastal vertebrates of Early Eocene (Ypresian) age. The La Meseta Formation is composed of poorly consolidated, marine sandstones and siltstones which were deposited in a coastal, deltaic and/or estuarine environment. It includes marine invertebrates and vertebrates as well as terrestrial vertebrates and plants. The highly fossiliferous basal horizon (Cucullaea shell bed, Telm 4 of Sadler 1988) of the Cucullaea I Allomember is a laterally extensive shell bed with sandy matrix. The fish remains, including 35 species from 26 families, of the Ypresian Cucullaea bed represent one of the most abundant and diverse fossil vertebrate faunas yet recorded in southern latitudes. Stratigraphic distribution and phylogenetic relationships of the Weddellian sphenisciforms are consistent with a first radiation of this group in the Early Eocene. The first inquestionable archaeocete from Antarctica is recorded in this unit and is referred to a new taxon

La Formación La Meseta aflora en la Isla Seymour/Marambio, Mar de Weddell, noreste de la Península Antártica y contiene una de las asociaciones de vertebrados costeros/marinos de edad Eoceno temprano (Ypresiano) más diversa que se conoce a nivel mundial. Esta unidad está compuesta por areniscas marinas pobremente consolidadas las cuales fueron depositadas en ambientes costeros, deltaicos y/o estuarinos. Esta incluye invertebrados y vertebrados marinos así como plantas y vertebrados terrestres. El horizonte basal (el banco de Cucullaea, Telm 4) del Alomiembro Cucullaea I es lateralmente extensor y altamente fosilífero. Los restos de peces del banco de Cucullaea (Ypresiano) incluyen 35 especies con 26 familias y representa una de las más abundantes y diversas fauna de vertebrados fósiles registradas en latitudes altas. La distribución estratigráfica y las relaciones filogenéticas de los pingüinos fósiles (Sphenisciformes) son consistentes con la primera radiación de este grupo en el Eoceno temprano. El primer incuestionable Archaeoceti de Antártida es registrado en esta unidad y es referido un nuevo taxón

Clinical outcomes of HER2-positive metastatic breast cancer patients with brain metastasis treated with lapatinib and capecitabine: an open-label expanded access study in Korea.

BACKGROUND: To evaluate efficacy in patients with brain metastasis (BM) on entry into the lapatinib expanded access program (LEAP). METHODS: LEAP is a worldwide, single-arm, open-label study. HER2-positive, locally-advanced or metastatic breast cancer patients with progression after an anthracycline, taxane, and trastuzumab were eligible. Patients received capecitabine 2000 mg/m(2) daily in two divided doses, days 1-14, every 21 days and lapatinib 1250 mg once daily. RESULTS: Among 186 patients enrolled in 6 Korean centers, 58 had BM. Progression-free survival (PFS) was 18.7 weeks in patients with BM and 19.4 weeks without BM (P = 0.88). In patients with BM, brain response was synchronized with systemic responses (P = 0.0001). Overall survival (OS) was 48.9 weeks in patients with BM and 64.6 weeks without BM (P = 0.23). Multivariable analysis found hormone receptor positivity (P = 0.003) and clinical benefit rate (CBR) of combined systemic and brain disease (P < 0.0001) significantly associated with prolonged brain PFS, and CBR of combined systemic and brain disease (P = 0.03) and longer trastuzumab use (P = 0.047) associated with prolonged OS in patients with BM; prior capecitabine did not affect PFS or OS in patients with BM. CONCLUSION: Lapatinib plus capecitabine is equally effective in patients with or without BM. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00338247).

A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression.

PURPOSE: This phase II trial of pemetrexed explored potential correlations between treatment outcome (antitumor activity) and molecular target expression. EXPERIMENTAL DESIGN: Chemonaïve patients with advanced breast cancer received up to three cycles of pemetrexed 500 mg/m2 (10-minute i.v. infusion) on day 1 of a 21-day cycle, with folic acid and vitamin B12 supplementation. Tumors were surgically removed after the last cycle of pemetrexed as clinically indicated. Biopsies were taken at baseline, 24 hours after infusion in cycle 1, and after cycle 3. RESULTS: Sixty-one women (median age, 46 years; range, 32-72 years) were treated and were evaluable for response. Objective response rate was 31%. Simple logistic regression suggested a potential relationship between mRNA expression of thymidylate synthase (TS) and pemetrexed response (P = 0.103). Based on threshold analysis, patients with "low" baseline TS (< or = 71) were more likely to respond to pemetrexed than patients with "high" baseline TS (>71). Expression of baseline dihydrofolate reductase and glycinamide ribonucleotide formyl transferase tended to be higher in responders but this association was not significant (P > 0.311). TS expression increased significantly between baseline and biopsy 2 (P = 0.004) and dropped to near baseline levels at biopsy 3. Conversely, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase decreased after pemetrexed chemotherapy. CONCLUSIONS: Our results suggest a potential association between "low" pretreatment TS expression levels and response to pemetrexed chemotherapy. Future trials examining expression levels of other genes important to the folate pathway and/or breast cancer may identify a more robust multigene profile that can better predict response to this novel antifolate.

Concurrent cisplatin/gemcitabine chemotherapy along with radiotherapy in locally advanced cervical carcinoma: a phase II trial.

OBJECTIVE: To evaluate the efficacy and safety of a concurrent regimen of gemcitabine/cisplatin and radiotherapy in women with locally advanced cervical carcinoma (LACC). METHODS: From April 2001 to June 2002, we enrolled women diagnosed with histologically proven LACC (FIGO stages IIA through IIIB), for treatment with concurrent regimen of chemo-radiotherapy. The treatment consisted of: cisplatin 40 mg/m(2), followed by gemcitabine 125 mg/m(2), once weekly, given about 1 to 2 h before radiotherapy. External beam radiation was delivered 5 days/week to entire pelvic radiation field for a total of 50 Gy in 25 fractions over 5 weeks. After completion of external radiation, patients received brachytherapy with cesium-137 via standard Fletcher-suit applicators delivering 30 Gy to point A. RESULTS: Of the 23 enrolled patients (mean age 47 years), 20 completed the treatment and were evaluable for response and safety. The complete response rate was 90% (18/20), and partial response rate was 10% (2 patients with persistent disease after therapy). Toxicity was moderate: 2 patients required blood transfusions; 5% patients had grade 2 leukopenia or thrombocytopenia; 40% had grade 1-2 nausea-vomiting, and 50% had grade 1 diarrhea. At a median follow-up of 12 months, all patients are alive, and 16/20 (80%) are disease-free. CONCLUSIONS: The gemcitabine/cisplatin combination administered concurrently with radiotherapy is highly active in locally advanced cervical carcinoma. The tolerable toxicity and synergistic activity of this concurrent chemoradiation regimen are consistent with prior reports. Definitive results are awaited from an on-going large, randomized trial comparing this regimen with standard treatment.

Acute promyelocytic leukaemia in patients originating in Latin America is associated with an increased frequency of the bcr1 subtype of the PML/RARalpha fusion gene.

The PML/RARalpha fusion gene in acute promyelocytic leukaemia (APL) has three subtypes based on the breakpoint site of the PML gene: long (bcr1), short (bcr3) and variable (bcr2) subtypes. The PML/RARalpha fusion protein is involved in the pathogenesis of APL and the breakpoint site of the PML gene might be associated with aetiological factor(s). Because APL is over-represented in patients that originate in Latin America (Latinos), we evaluated whether the distribution of the PML/RARalpha fusion mRNA in this population is different to that reported in non-Latinos. Among 52 APL patients (28 from Mexico and Central America diagnosed in Los Angeles and 24 from Peru, South America), bcr1, bcr2 and bcr3 expression was 75%, 10% and 15% respectively. However, bcr1 breakpoints were significantly higher compared with non-Latino patients (340/654, 52%) reported in four studies. Often bcr1 and bcr2 are reported together; 862 (60%) of 1429 non-Latino APL patients reported in nine studies were either bcr1 or bcr2, compared with 44 (85%) in our 52 Latino patients. This difference was also statistically significant when our patients were compared to each of the individual studies from USA and Europe, but not for a small series from China and Japan. These results suggest that the overrepresentation of APL among Latin American patients can be accounted for by an increase of a single subtype--bcr1, and the breakage sites in the PML gene may not be random but possibly influenced by genetic and/or environmental factor(s).

Linfomas del tracto gastrointestinal: una enfermedad neoplásica del subdesarrollo / Gastrointestinal lymphomas: malignant disease of under development

Cuatrocientos cincuentaiocho de los 3,495 casos de linfoma maligno registrados entre los años 1965 y 1992 en el Instituto de Enfemedades Neoplásicas, correspondieron a Linfomas del Tracto Gastrointestinal. Esta es una de las series de linfoma del TGI más grande entre las reportadas por hospitales de cáncer, y sugiere que esta rara patología es relativamente frecuente en nuestro medio. El análisis de esta casuística muestra una mayor frecuencia relativa de la localización en el intestino delgado de esta serie comparte algunas características con el linfoma de la enfermedad inmunoproliferativa del intestino delgado descrita en las poblaciones jóvenes y pobres del Mediterraneo. La enfermedad confinada a la viscera (estadíos I y II) es curable por cirugía en 0 por ciento de casos. La enfermedad avanzada incompletamente resecada puede beneficiarse con quimioterapia complementaria. La enfermedad irresecable quirurgicamente puede ser tratada con quimioterapia complementaria de inducción sin que el riesgo de perforación o hemorragia sea prohibitivo el 50 por ciento de los casos inoperables tratados con quimioterapia alcanzaron sobrevidas a 5 y 10 años libres de recidiva de la enfermedad

Enfermedad del injerto contra el huesped asociado a transfusión (T-GVHD) en la enfermedad de Hodgkin / Transfusion Associated Graft versus Host Disease (T-GVHD) in Hodgkin disease

El empleo de regímenes de tratamiento antineoplásico más intensos provoca la frecuente utilización de soporte hematológico en Oncología. Una complicación distintiva de la terapia trasfusional es el desarrollo de la Enfermedad del injerto contra el huésped, asociada a transfusión (T-GVHD). Esta entidad, cada vez más frecuentemente descrita entre pacientes oncol gicos, se caracteriza por lesiones dérmicas, gastrointestinales, hepáticas y característicamente pancitopenia, por aplasia medular, cursando con una mortalidad de 90 por ciento. El cuadro se desarrolla en inmunodeficiencias primarias, pacientes portadores de neoplasias malignas especialmente hematológicas e incluso en pacientes inmunocompetentes, siendo la incidencia real desconocida. No existe tratamiento efectivo y la única forma de prevención es el uso de productos sanguíneos irradiados en la población en riesgo. Reportamos los dos primeros casos de T-GVHD diagnosticados en el Instituto Nacional de Enfermedades Neoplásicas del Perú. Discutimos los aspectos epidemiológicos, fisiopatológicos y clínicos de esta entidad así como revisamos las medidas preventivas a tomarse entre los pacientes oncológicos