Cranial and postcranial anatomy of a juvenile baurusuchid (Notosuchia, Crocodylomorpha) and the taxonomical implications of ontogeny.

Baurusuchidae comprises a clade of top-tier terrestrial predators and are among the most abundant crocodyliforms found in the Adamantina Formation, Bauru Basin, Brazil (Campanian-Maastrichtian). Here, we provide a detailed description of the cranial and postcranial osteology and myology of the most complete juvenile baurusuchid found to date. Although the preservation of juvenile individuals is somewhat rare, previously reported occurrences of baurusuchid egg clutches, a yearling individual, and larger, but skeletally immature specimens, comprise a unique opportunity to track anatomical changes throughout their ontogenetic series. Its cranial anatomy was resolved with the aid of a three-dimensional model generated by the acquisition of computed tomography data, and its inferred adductor mandibular musculature was compared to that of mature specimens in order to assess possible ontogenetic shifts. A subsequent phylogenetic analysis included the scoring of Gondwanasuchus scabrosus, the smallest baurusuchid species known to date, to evaluate its phylogenetic relations relative to a known juvenile. We find considerable differences between juveniles and adults concerning skull ornamentation and muscle development, which might indicate ontogenetic niche partitioning, and also anatomical and phylogenetic evidence that G. scabrosus corresponds to a young semaphoront lacking mature cranial features.

Lower access to risk stratification tests and drugs, and worse survival of chronic lymphocytic leukaemia patients treated in public as compared to private hospitals in Brazil: A retrospective analysis of the Brazilian registry of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) has a highly variable clinical course. In addition to biological factors, socioeconomic factors and health system characteristics may influence CLL outcome. Data from the Brazilian Registry of CLL were analyzed to compare clinical and treatment-related characteristics in patients with CLL, from public or private institutions. A total of 3326 patients from 43 centres met the eligibility criteria, of whom 81% were followed up at public hospitals and 19% at private hospitals. The majority were male (57%), with a median age of 65 years. Comparing public and private hospitals, patients in public hospitals were older, had more advanced disease at diagnosis, and more frequently had elevated creatinine levels. All investigated prognostic markers were evaluated more often in private hospitals. First-line treatment was predominantly based on chlorambucil in 41% of the cases and fludarabine in 38%. Anti-CD20 monoclonal antibody was used in only 36% of cases. In public hospitals, significantly fewer patients received fludarabine-based regimens and anti-CD20 monoclonal antibodies. Patients from public hospitals had significantly worse overall survival (71% vs. 90% for private hospitals, p < 0.0001) and treatment-free survival (32% vs. 40%, for private hospitals, p < 0.0001) at seven years. Our data indicate striking differences between patients followed in public and private hospitals in Brazil. A worse clinical condition and lack of accessibility to basic laboratory tests and adequate therapies may explain the worse outcomes of patients treated in public institutions.

Paleoneurology of Baurusuchus (Crocodyliformes: Baurusuchidae), ontogenetic variation, brain size, and sensorial implications.

Knowledge on crocodyliform paleoneurology has significantly improved with development of computed tomography. However, studies so far have been able to reconstruct brain endocasts based only on single specimens for each taxon. Here for the first time, we reconstructed brain endocasts for multiple fossil specimens of the same crocodyliform taxon (Baurusuchus), consisting of complete skulls of two medium sized specimens, one large adult, and a late juvenile. In addition, we were able to reconstruct the inner ear anatomy of a fragmentary skull using microtomography. We present estimates of brain size using simple models, based on modern Crocodylia, able to adapt brain to endocranial cavity ratios to expected ontogenetic variation instead of using fixed ratios. We also analyzed relative brain sizes, olfactory ratios, facial sensation, alert head posture, best hearing frequencies, and hearing range. The calculated endocranial volumes showed that they can be greatly altered by taphonomic processes, altering both total and partial endocranial volumes. Reconstructed endocasts are compatible with different degrees of occupation along the endocranial cavity and some of their characteristics might be useful as phylogenetic characters. The relative brain size of Baurusuchus seems to be small in comparison to modern crocodilians. Sensorial abilities were somewhat similar to modern crocodilians and hearing ranges and best mean frequencies remarkably similar to modern taxa, whereas olfactory ratio values are a little higher. Differing from its modern relatives, Baurusuchus hypothesized alert head posture is compatible with a terrestrial habit.

Superiority of the triple combination of bortezomib, cyclophosphamide and dexamethasone versus cyclophosphamide, thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma, eligible for transplantation

ABSTRACT Background: The treatment of multiple myeloma (MM) has evolved significantly in the past decade, and new drug combinations have improved the response rates and prolonged survival. Studies comparing different induction chemotherapy regimens have shown that triple combinations have better results than double combinations. However, comparisons among different triple combinations are rare in the literature. Methods: We retrospectively compared two triple combinations comprising bortezomib, cyclophosphamide and dexamethasone (VCD) versus thalidomide, cyclophosphamide and dexamethasone (CTD), and aimed at identifying which of the two combinations would yield better response rates following four induction cycles prior to hematopoietic cell transplantation in patients with untreated multiple myeloma. Results: We retrospectively reviewed the medical records of 311 patients from 24 different centers.The VCD regimen was used as induction therapy by 117 (37.6%) patients, whereas 194 (62.4%) patients received the CTD regimen. After four cycles of induction on an intention-to-treat basis, 54% of the patients in the VCD group achieved at least very good partial response versus 42.8% in the CTD group (p = 0.05). We observed no difference in neuropathy or thrombotic events rates among the two regimens. Conclusion: Our results corroborate the superiority of the triple combination regimes containing bortezomib over the triple combination with thalidomide as pre ASCT induction therapy in MM.

Superiority of the triple combination of bortezomib, cyclophosphamide and dexamethasone versus cyclophosphamide, thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma, eligible for transplantation.

BACKGROUND: The treatment of multiple myeloma (MM) has evolved significantly in the past decade, and new drug combinations have improved the response rates and prolonged survival. Studies comparing different induction chemotherapy regimens have shown that triple combinations have better results than double combinations. However, comparisons among different triple combinations are rare in the literature. METHODS: We retrospectively compared two triple combinations comprising bortezomib, cyclophosphamide and dexamethasone (VCD) versus thalidomide, cyclophosphamide and dexamethasone (CTD), and aimed at identifying which of the two combinations would yield better response rates following four induction cycles prior to hematopoietic cell transplantation in patients with untreated multiple myeloma. RESULTS: We retrospectively reviewed the medical records of 311 patients from 24 different centers.The VCD regimen was used as induction therapy by 117 (37.6%) patients, whereas 194 (62.4%) patients received the CTD regimen. After four cycles of induction on an intention-to-treat basis, 54% of the patients in the VCD group achieved at least very good partial response versus 42.8% in the CTD group (p=0.05). We observed no difference in neuropathy or thrombotic events rates among the two regimens. CONCLUSION: Our results corroborate the superiority of the triple combination regimes containing bortezomib over the triple combination with thalidomide as pre ASCT induction therapy in MM.

Epidemiology of Hematologic Malignancies in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study.

PURPOSE: Limited information is available on multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) management in Latin America. The primary objective of the Hemato-Oncology Latin America (HOLA) study was to describe patient characteristics and treatment patterns of Latin American patients with MM, CLL, and NHL. METHODS: This study was a multicenter, retrospective, medical chart review of patients with MM, CLL, and NHL in Latin America identified between January 1, 2006, and December 31, 2015. Included were adults with at least 1 year of follow-up (except in cases of death within 1 year of diagnosis) treated at 30 oncology hospitals (Argentina, 5; Brazil, 9; Chile, 1; Colombia, 5; Mexico, 6; Panama/Guatemala, 4). RESULTS: Of 5,140 patients, 2,967 (57.7%) had NHL, 1,518 (29.5%) MM, and 655 (12.7%) CLL. Median follow-up was 2.2 years for MM, 3.0 years for CLL, and 2.2 years for NHL, and approximately 26% died during the study observation period. Most patients had at least one comorbidity at diagnosis. The most frequent induction regimen was thalidomide-based chemotherapy for MM and chlorambucil with or without prednisone for CLL. Most patients with NHL had diffuse large B-cell lymphoma (DLBCL; 49.1%) or follicular lymphoma (FL; 19.5%). The majority of patients with DLBCL or FL received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. CONCLUSION: The HOLA study generated an unprecedented level of high-quality, real-world evidence on characteristics and treatment patterns of patients with hematologic malignancies. Regional disparities in patient characteristics may reflect differences in ethnoracial identity and level of access to care. These data provide needed real-world evidence to understand the disease landscape in Latin America and may be used to inform clinical and health policy decision making.

Atypical chronic myeloid leukemia with t(9;22)(p24,11.2), a BCR-JAK2 fusion gene.

We report here on a rare case of BCR-ABL1-negative atypical chronic myeloid leukemia with a t(9;22)(p24;q11.2)translocation and a BCR-JAK2 fusion gene, with resistance to the tyrosine kinase inhibitors imatinib and dasatinib.At two years of follow-up, the patient showed no hematologic response and was submitted to an allogeneic bonemarrow transplantation. Fifty-three days after the procedure, he died due to acute graft-versus-host disease. This BCR-JAK2 fusion gene has so far been found in only five patients in the whole world, with three clinical presentations: myeloproliferative neoplasm, acute lymphoblastic leukemia and acute myeloid leukemia.

Atypical chronic myeloid leukemia with t(9; 22)(p24,11. 2), a BCR-JAK2 fusion gene

We report here on a rare case of BCR-ABL1-negative atypical chronic myeloid leukemia with a t(9;22)(p24;q11.2)translocation and a BCR-JAK2 fusion gene, with resistance to the tyrosine kinase inhibitors imatinib and dasatinib.At two years of follow-up, the patient showed no hematologic response and was submitted to an allogeneic bonemarrow transplantation. Fifty-three days after the procedure, he died due to acute graft-versus-host disease. This BCR-JAK2 fusion gene has so far been found in only five patients in the whole world, with three clinical presentations: myeloproliferative neoplasm, acute lymphoblastic leukemia and acute myeloid leukemia.

O transplante de células-tronco hematopoéticas na leucemia linfoide crônica, uma proposta do I encontro de diretrizes do transplante de medula óssea da sociedade brasileira de transplante de medula óssea, Rio de Janeiro 2009 / Hematopoietic stem cell transplantation in chronic lymphoid leukemia: a proposal by the Brazilian consensus on bone marrow transplantation of the Brazilian society of bone marrow transplantation, Rio de Janeiro 2009

Portadores de leucemia linfoide crônica (LLC) apresentam curso clínico indolente e prolongado que devem ser diferenciados daqueles que têm doença de evolução agressiva e fatal. Pacientes mais jovens e com critérios de alto risco podem se beneficiar com tratamento mais agressivo como o transplante de células-tronco hemopoéticas (TCTH). O transplante autólogo apresenta casos com remissão citogenética e molecular, baixa taxa de mortalidade, mas não demonstram platô nas curvas de sobrevivência e alta taxa de recaídas. Os transplantes alogênicos com regime mieloablativos têm altos índices de toxicidade e mortalidade, mas evidenciam o efeito enxerto versus leucemia, que aumenta a possibilidade de cura destes indivíduos. Assim, a opção dos transplantes alogênicos está dirigida para os transplantes com regime de condicionamento não mieloablativo, que pode ser aplicado inclusive a pacientes mais idosos ou portadores de comorbidades, e manter o potencial efeito GVL. A identificação dos pacientes que podem ser beneficiados por esses procedimentos, caracterizar e apontar os novos marcadores prognósticos permanece objeto de muitos estudos clínicos e foi o objetivo do grupo responsável em discutir as diretrizes do TCTH no consenso da Sociedade Brasileira de Transplante de Medula Óssea - SBTMO. Assim, consideramos que o TCTH para a leucemia linfoide crônica (LLC) deve seguir, para sua indicação, os critérios do European Group for Blood and Marrow Transplantation (EBMT) e, quando houver disponibilidade de um doador aparentado, a opção deve ser do TCTH alogênico com regime não mieloablativo. O TCTH alogênico não aparentado e o autólogo devem ser considerados como opção secundária de indisponibilidade de doador, situações especiais e ensaios clínicos.

Patients with chronic lymphocytic leukemia usually have an indolent and prolonged clinical course and need to be differentiated from those who have an aggressive and fatal disease. Younger patients with high-risk criteria may benefit with a more aggressive treatment that includes hematopoietic stem cell transplantation (HSCT). Autologous transplantation, despite of the encouraging results with cases of molecular and/or cytogenetic remission and low mortality rates, does not present a plateau in survival curves and has a high relapse rate. Allogeneic transplantations using myeloablative regimens, have high toxicity and mortality rates, but also demonstrate the graft-versus-leukemia effect that increases the possibility of cure of these individuals. So the option of allogeneic transplants for patients with CLL is directed to conditioning using non-myeloablative regimens, which can also be applied to older patients or those with comorbidities, and maintain a potential graft-versus-leukemia effect. The identification of patients who may benefit from these procedures and the characterization of new prognostic markers remain the subjects of many clinical studies and were the objective of the group responsible for discussing guidelines for CLL of the consensus on HSCT SBTMO. Thus we believe that HSCT for CLL should follow the criteria of the EBMT. When a sibling donor is available the best option is allogeneic HSCT with a myeloablative regimen. The strategy of unrelated allogeneic or autologous HSCT must be considered as a second option when no donor is available, for special situations and clinical trials.

Farnesyltransferase inhibitors and their role in the treatment of multiple myeloma.

BACKGROUND: Ras mutations are among the most common oncogene mutations found in multiple myeloma (MM). Patients with mutated Ras are less likely to respond to chemotherapy and have a shortened median survival. Therefore, targeting Ras farnesylation may be a valuable approach to treatment of MM. R115777 (tipifarnib) is a potent farnesyltransferase inhibitor (FTI) presently undergoing phase II/III clinical trials. METHODS: We reviewed the preclinical and clinical experience of FTIs as antineoplastic agents and describe their potential role in the treatment of MM. RESULTS: FTIs are a novel group of agents that selectively inhibit farnesyltransferase, an enzyme responsible for the posttranslational modification of several proteins including Ras. Since Ras is among the most commonly mutated oncogenes associated with cancer, this class of drugs has been evaluated in clinical trials in a diversity of tumors. R115777 has been evaluated in a phase II clinical trial in patients with advanced myeloma and found to be well tolerated. It induced disease stabilization in more than 60% of patients with advanced myeloma. CONCLUSIONS: The drug selectively targets farnesyltransferase, but this effect did not correlate with disease stabilization, suggesting that these drugs may be targeting a survival pathway independent of Ras processing. Further studies will evaluate the use of FTI in maintenance therapy as well as in combination with other agents in advanced myeloma.