Intermittent BRAF inhibition in advanced BRAF mutated melanoma results of a phase II randomized trial.

Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. Previous preclinical studies suggested that an intermittent dosing of these drugs could delay the emergence of resistance. Contrary to expectations, the first published phase 2 randomized study comparing continuous versus intermittent schedule of dabrafenib (BRAFi) plus trametinib (MEKi) demonstrated a detrimental effect of the "on-off" schedule. Here we report confirmatory data from the Phase II randomized open-label clinical trial comparing the antitumoral activity of the standard schedule versus an intermittent combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF mutant melanoma patients (NCT02583516). The trial did not meet its primary endpoint of progression free survival (PFS) improvement. Our results show that the antitumor activity of the experimental intermittent schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule. Detection of BRAF mutation in cell free tumor DNA has prognostic value for survival and its dynamics has an excellent correlation with clinical response, but not with progression. NGS analysis demonstrated de novo mutations in resistant cases.

Clinical impact of obesity on respiratory diseases: A real-life study.

BACKGROUND: Obesity has become an epidemic that affects Mexico; significantly interferes with respiratory physiology by decreasing lung volumes, therefore, might be considered as a relevant risk factor associated with the development of respiratory diseases. OBJECTIVE: Our primary outcome was to analyze the frequency and risk factors between obesity and respiratory disease in the Mexican population. MATERIALS AND METHODS: An observational, single-center, descriptive study, which included the totality of patients who were referred for medical attention at the Respiratory and Thorax Surgery Unit at the Hospital Regional de Alta Especialidad de la Península de Yucatán during the period from January 2015 to December 2018. The cases were grouped based on the existence or not of respiratory disease and the presence or absence of obesity (body mass index [BMI] >30 kg/m2). RESULTS: A total of 1167 patients were included; about 39% of the population had average BMI 36.5 kg/m2. The primary respiratory diseases in obese patients were Obstructive Sleep Apnea Syndrome (OSAS, 19%) and asthma (15%). The logistic regression analysis showed a direct association between the presence of obesity with respiratory disease (odds ratio 1.58, 95% confidence interval 1.22-2.03, P < 0.001), the strength of this association was related with asthma and OSAS. CONCLUSION: The presence of obesity is an independent risk factor for respiratory disease, primarily for OSAS and asthma.

International Delphi Expert Consensus on Safe Return to Surgical and Endoscopic Practice: From the Coronavirus Global Surgical Collaborative.

OBJECTIVE: The aim of this work is to formulate recommendations based on global expert consensus to guide the surgical community on the safe resumption of surgical and endoscopic activities. BACKGROUND: The COVID-19 pandemic has caused marked disruptions in the delivery of surgical care worldwide. A thoughtful, structured approach to resuming surgical services is necessary as the impact of COVID-19 becomes better controlled. The Coronavirus Global Surgical Collaborative sought to formulate, through rigorous scientific methodology, consensus-based recommendations in collaboration with a multidisciplinary group of international experts and policymakers. METHODS: Recommendations were developed following a Delphi process. Domain topics were formulated and subsequently subdivided into questions pertinent to different aspects of surgical care in the COVID-19 crisis. Forty-four experts from 15 countries across 4 continents drafted statements based on the specific questions. Anonymous Delphi voting on the statements was performed in 2 rounds, as well as in a telepresence meeting. RESULTS: One hundred statements were formulated across 10 domains. The statements addressed terminology, impact on procedural services, patient/staff safety, managing a backlog of surgeries, methods to restart and sustain surgical services, education, and research. Eighty-three of the statements were approved during the first round of Delphi voting, and 11 during the second round. A final telepresence meeting and discussion yielded acceptance of 5 other statements. CONCLUSIONS: The Delphi process resulted in 99 recommendations. These consensus statements provide expert guidance, based on scientific methodology, for the safe resumption of surgical activities during the COVID-19 pandemic.

[Pancreatoblastoma in a pediatric patient: a case report]. / Pancreatoblastoma en paciente pediátrico: reporte de caso.

Pancreoblastoma is a very rare tumor that originates from the exocrine epithelial cells of the pancreas. However, it is the most frequent pancreatic tumor in children. It usually appears in the first decade of life with an average of 5 years old. The clinical manifestations are usually unspecific, being the abdominal pain and the abdominal mass the most frequent. The radiological signs are not very well described in medical literature. The definite diagnosis should always be established with biopsia and histological examination. Here it is presented a clinical case of pancreoblastoma with unusual involvement of a major duodenal papilla in a pediatric patient.

Impact of treatment in long-term survival patients with follicular lymphoma: A Spanish Lymphoma Oncology Group registry.

BACKGROUND: Follicular lymphoma is the second most common non-Hodgkin lymphoma in the United States and Europe. However, most of the prospective randomized studies have very little follow-up compared to the long natural history of the disease. The primary aim of this study was to investigate the long-term survival of our series of patients with follicular lymphoma. PATIENTS AND METHODS: A total of 1074 patients with newly diagnosed FL were enrolled. Patients diagnosed were prospectively enrolled from 1980 to 2013. RESULTS: Median follow-up was 54.9 months and median overall survival is over 20 years in our series. We analyzed the patients who are still alive beyond 10 years from diagnosis in order to fully assess the prognostic factors that condition this group. Out of 166 patients who are still alive after more than 10 years of follow-up, 118 of them (73%) are free of evident clinical disease. Variables significantly associated with survival at 10 years were stage < II (p <0.03), age < 60 years (p <0.0001), low FLIPI (p <0.002), normal ß2 microglobulin (p <0.005), no B symptoms upon diagnosis (p <0.02), Performance Status 0-1 (p <0.03) and treatment with anthracyclines and rituximab (p <0.001), or rituximab (p <0.0001). CONCLUSIONS: A longer follow-up and a large series demonstrated a substantial population of patients with follicular lymphoma free of disease for more than 10 years.

Sam68 Mediates the Activation of Insulin and Leptin Signalling in Breast Cancer Cells.

Obesity is a well-known risk factor for breast cancer development in postmenopausal women. High insulin and leptin levels seem to have a role modulating the growth of these tumours. Sam68 is an RNA-binding protein with signalling functions that has been found to be overexpressed in breast cancer. Moreover, Sam68 may be recruited to insulin and leptin signalling pathways, mediating its effects on survival, growth and proliferation in different cellular types. We aimed to study the expression of Sam68 and its phosphorylation level upon insulin and leptin stimulation, and the role of Sam68 in the proliferative effect and signalling pathways that are activated by insulin or leptin in human breast adenocarcinoma cells. In the human breast adenocarcinoma cell lines MCF7, MDA-MB-231 and BT-474, Sam68 protein quantity and gene expression were increased upon leptin or insulin stimulation, as it was checked by qPCR and immunoblot. Moreover, both insulin and leptin stimulation promoted an increase in Sam68 tyrosine phosphorylation and negatively regulated its RNA binding capacity. siRNA was used to downregulate Sam68 expression, which resulted in lower proliferative effects of both insulin and leptin, as well as a lower activation of MAPK and PI3K pathways promoted by both hormones. These effects may be partly explained by the decrease in IRS-1 expression by down-regulation of Sam68. These results suggest the participation of Sam68 in both leptin and insulin receptor signaling in human breast cancer cells, mediating the trophic effects of these hormones in proliferation and cellular growth.

Effectiveness of chemotherapy in advanced differentiated thyroid cancer: a systematic review.

In differentiated thyroid carcinoma refractory to radioactive iodine (CDT-RTI), chemotherapy has been considered for decades to be the only systemic therapy with palliative purpose. Phase II studies assessing the efficacy of different chemotherapy outlines have been published. Nevertheless, phase III studies in these tumours have not been performed. Our objective is to evaluate the effectiveness of chemotherapy in patients with CDT-RTI by a systematic review of published studies. Systematic research of the literature in Medline and Embase databases (among others) was carried out. The full texts of selected references were analysed by two independent reviewers and then assessed for risk of bias in each study. We also extracted data using specifically designed questionnaires. Later, a qualitative synthesis of results was performed and pooled data were calculated. We found that 16 studies with 473 patients published in the last 40 years were included out of 509 identified references in databases. Thirteen studies (176 patients) included data on response to treatment and histology. Four studies included 70 patients only with well-differentiated non-medullary tumours. Response rate (RR) was 22.1% (0-57%) for 13 studies, 25% for the 176 patients and 27.1% for the 70 patients, with 2.5, 3.4 and 2.8% complete responses respectively. Survival times could not be assessed or pooled due to the lack of data and heterogeneity of the studies, and was determined to have a high risk of bias. Although it has not been possible to find solid evidence about the efficacy of chemotherapy, the results shown indicate that it may have some effectiveness, although this should be proven with well-designed studies using modern drugs.

Altered expression of CKs 14/20 is an early event in a rat model of multistep bladder carcinogenesis.

Cytokeratins (CKs) 14 and 20 are promising markers for diagnosing urothelial lesions and for studying their prognosis and histogenesis. This work aimed to study the immunohistochemical staining patterns of CK14/20 during multistep carcinogenesis leading to papillary bladder cancer in a rat model. Thirty female Fischer 344 rats were divided into three groups: group 1 (control); group 2, which received N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 20 weeks plus 1 week without treatment; and group 3, which received BBN for 20 weeks plus 8 weeks without treatment. Bladder lesions were classified histologically. CK14 and CK20 immunostaining was assessed according to its distribution and intensity. In control animals, 0-25% of basal cells and umbrella cells stained positive for CK14 and CK20 respectively. On groups 2 and 3, nodular hyperplastic lesions showed normal CK20 and moderately increased CK14 staining (26-50% of cells). Dysplasia, squamous metaplasia, papilloma, papillary tumours of low malignant potential and low- and high-grade papillary carcinomas showed increased CK14 and CK20 immunostaining in all epithelial layers. Altered CK14 and CK20 expression is an early event in urothelial carcinogenesis and is present in a wide spectrum of urothelial superficial neoplastic and preneoplastic lesions.

Consolidation treatment with Yttrium-90 ibritumomab tiuxetan after new induction regimen in patients with intermediate- and high-risk follicular lymphoma according to the follicular lymphoma international prognostic index: a multicenter, prospective phase II trial of the Spanish Lymphoma Oncology Group.

Relapse is the main cause of therapeutic failure in follicular lymphoma (FL). We set out to evaluate the role of consolidation with Yttrium-90 ibritumomab tiuxetan in patients with intermediate- and high-risk FL after four cycles of CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab) and two cycles of CHOP. Thirty patients were included. The overall response rate after consolidation therapy was 93%. Of the 18 patients who presented with a partial response after induction treatment, 11 had a complete response after consolidation treatment. The complete clinical response rate was 76.6%. The most important grade 3-4 toxicity was hematological, with 46% thrombopenia and 56% neutropenia. With a median follow-up of 26 months, the means for progression-free survival and overall survival were not reached. Our data support consolidation with Yttrium-90 ibritumomab tiuxetan as an effective treatment, which provides long progression-free and overall survival, in first line after a response to induction treatment in patients with intermediate- and high-risk FL.

Are there any significant variations in the clinical or histological presentation of lymphoid pathologies over the course of time in Spain?

INTRODUCTION: Little data is available concerning variations in the clinical characteristics of lymphoid neoplasms at presentation. We decided to investigate whether any variations in these characteristics had occurred in Spain during the last few years. MATERIALS AND METHODS: The GOTEL group database is an archive of all new lymphoma cases, regardless of their histological subtype, diagnosed in the hospitals within the group. An analysis was made of all the records between 1 January 1999 and 1 January 2009. Though the number of hospitals submitting data has changed over the course of time, data were provided by 26 hospitals from 16 Spanish provinces. RESULTS: A total of 3651 cases of lymphoma were recorded during this period. Grouped by clinical features, 42.8% (1561 patients) had low-grade lymphoma, 30.4% (1110 patients) intermediate-grade lymphoma and 15.2% (556 patients) Hodgkin's lymphoma; 208 patients had T lymphoma (5.7%), 111 patients high-grade lymphoma (3%) and 105 patients (2.9%) suffered lymphomas that were difficult to classify. A total of 6.3% of the diagnoses (231 patients) were made prior to 1999, 29.5% between 2000 and 2001, 25.7% between 2002 and 2003, 19.7% between 2004 and 2005, 11.2% between 2006 and 2007, and there were 200 entries from 2008 to the close of the study period, corresponding to 1.5% of the complete database. The median age at diagnosis was 60 (range 7-105 years), by percentiles: 25 corresponded to 44 years old, 50 to 60 years old and 75 to 71. Distribution by gender was 53.1% male and 46.9% female. An analysis was made of all the clinical variables collected, comparing their behaviour during the different diagnostic periods. The periods, gender, ECOG, stage, LDH, ß2 microglobulin, Hodgkin's or non- Hodgkin's type neoplasm, B lymphoma vs. Hodgkin's, NK or T, nodal or extra-nodal origin, median age at diagnosis and histological type by region of origin did not show any statistically significant differences in their distribution over the course of time. CONCLUSION: In our experience, there are no significant variations in clinical presentation or histological type in lymphomas diagnosed over the course of time in Spain.

The effects of sirolimus on urothelial lesions chemically induced in ICR mice by BBN.

BACKGROUND: Sirolimus was originally used as an immunosuppressant drug but recent reports have indicated that it may have other potential biological effects as an anticancer drug. The chemopreventive efficacy of sirolimus was evaluated in an experimental model of invasive urinary bladder cancer. MATERIALS AND METHODS: ICR mice received N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in drinking water for a period of twelve weeks. Sirolimus was administered 5 days a week. Animals were sacrificed either one or four weeks after their final treatment. Ki-67 was immunohistochemically analysed in paraffin-embedded tissue. RESULTS: No evidence of host toxicity was found. The incidence of BBN-induced invasive urothelial carcinoma was significantly reduced in mice treated with sirolimus. Preneoplastic and neoplastic lesions exhibited a significant decrease in cellular proliferation. CONCLUSION: Histopathological and immunohistochemical studies showed that sirolimus reduced tumour incidence and proliferation. Sirolimus should be considered for further in vitro and in vivo studies in order to provide evidence of effectiveness.

Correction of nasojugal groove with tunnelled fat graft.

BACKGROUND: Pronounced nasojugal sulcus (tear trough deformity) is a frequent and distressing symptom in aesthetic palpebral surgery. The sliding fat technique using the transcutaneous or transconjunctival approach has proven to be considerably useful in patients with clinically evident fat bags. In the absence of fat bags, commonly used techniques can lead to unpredictable (and frequently less than optimal) results. OBJECTIVE: The authors report their experience with correcting the nasojugal groove in the absence of palpebral fat bags by use of a one-piece, free fat graft as an alternative to autologous fat injections or the placement of alloplastic materials. METHODS: The authors conducted a retrospective study of a consecutive series of 34 patients (33 women and one man) between 42 and 57 years of age. In all cases, small, free fat grafts harvested from the medial fat compartment of the upper eyelid were placed precisely under the depression through two stab incisions in the suborbicularis plane, filling in the groove. RESULTS: Results were considered excellent in 24 out of the 34 patients. Results in the remaining 10 patients were rated as good, in most cases because of mild undercorrection. All patients expressed a high degree of satisfaction. Recovery time was very short and no eye or eyelid complications were observed. CONCLUSIONS: Correction of the nasojugal groove with a tunnelled fat graft causes minimal tissue trauma and allows exact placement of the graft. The upper palpebral fat has unique characteristics that render it an ideal graft material for correction of the nasojugal groove in patients with no concomitant lower fat bags. This procedure offers more predictable results and a lower incidence of adverse effects than more commonly used techniques.

DNA content analysis, expression of Ki-67 and p53 in rat urothelial lesions induced by N-butyl-N-(4-hydroxybutyl) nitrosamine and treated with mitomycin C and bacillus Calmette-Guérin.

N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced urothelial carcinogenesis is a useful model for studying urothelial carcinogenesis. Here, the DNA content and the expression of Ki-67 and p53 in urothelial lesions induced by BBN and treated with mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) were investigated. Female Fisher 344 rats were distributed into five groups treated with 0.05% BBN in their drinking water for 20 weeks. Ten animals were used as negative control. Intravesical instillations were performed with MMC, BCG and physiological saline solution (PSS), once per week, for 6 weeks. The animals were sacrificed 1 week after the last intravesical instillation. DNA ploidy analysis was carried out by static cytometry. Ki-67 and p53 were analysed immunohistochemically in paraffin-embedded tissue. The incidence of lesions developed in rats with PSS was greater than in rats instilled with MMC and BCG. The incidence of aneuploidy was lower in tumours treated with MMC and BCG. Low- and high-grade papillary carcinoma treated with MMC and BCG showed a decrease in labelling index and an increase of apoptotic index. The proliferative index was correlated with the apoptotic index (r=0.438, p<0.01). Significant correlations were also found between the proliferative index and lesion, and the apoptotic index and lesion (r=0.425, p<0.01 and r=0.275, p<0.01), respectively. A significant correlation was found between ploidy and the apoptotic index (r=0.245, p<0.05). Our results provide information on the biological behaviour of chemically-induced bladder tumours treated with MMC and BCG.

Mastopexy utilizing a dermoglandular hammock flap.

BACKGROUND: Many procedures have been described in the search for the ideal mastopexy technique, ranging from simple cutaneous reduction, with or without glandular remodelling, to the use of dermal flaps fixed to the pectoral fascia, or even the use of silicone mesh or sheets. OBJECTIVE: We describe a technique that uses a dermoglandular hammock flap to achieve optimal position and shape of the breast; well located, good quality scars that are as short as possible; and satisfactory early- and long-term results. METHODS: A superior pedicle dermoglandular flap was raised from the lower pole of the breast and transposed to the upper pole. The flap is fixed like a hammock to the pectoral fascia and the wedge-shaped donor defect is closed by approximation and fixation of the medial and lateral pillars with absorbable sutures, thus releasing the tension in the skin suture line. RESULTS: Twenty-eight patients aged 19 to 58 years underwent the procedure. Adequate shape and projection were achieved in all cases. Partial dehiscence of the suture line developed in 1 patient. The scar quality was excellent, except in 2 cases in which some degree of temporary hypertrophy occurred. CONCLUSIONS: In our experience with this technique, we obtained satisfactory position and shape; good quality, well-placed scars; long-lasting results; and preservation of the patient's ability to breast feed. The technique is simple to perform and is indicated in cases of moderate ptosis.

Evaluacion anatomoangiografica del complejo de la arteria comunicante anterior en casos de aneurismas de dicho sector / anatomo-angyographic evaluation of anterior artery complex in aneurysm cases in that area

Objetivos: Analizar variantes anatomicas observadas en pacientes con aneurismas del complejo comunicante anterior evaluando la importancia de la dominancia de flujo en su formacion y ruptura. Materiales y metodos: analizamos las angiografaias digitales de 58 pacientes tratados por via endovascular y sus controles angiograficos. Para definir la direccion del aneurisma tomamos como punto cardinal la Arteria Comunicante Anterior (ACoA). Consideramos hipoplasico el segmento A1 -comunicante en 30 por ciento. La proyeccion de los aneurismas coincidio con la direccion A1 dominante. Conclusiones: los aneurismas del complejo comunicante anterior se originaron en el eje A1 dominante o isodominante. Los aneurismas de ACoA propiamente dicha se formaron cuando existia isodominancia. La hipoplasia es la unica variante anatomica correlacionable con aneurismas. El punto de ruptura fue coincidente con la direccion del flujo

Iatrogenia e interacción de drogas / Drugs interaction and iatrogeny

Se estudia el grave problema de la patología iatrogénica. EL MEDICO COMO FUENTE DE ENFERMEDAD que en la actualidad esta cobrando importancia creciente en todo el extenso campo de la medicina y de sus especialidades. Se propone un esquema de clasificación de la iatrogenia en general y se estudia en forma específica la iatrogenia medicamentosa, haciendo hincapié en los mecanismos y las causas determinantes. Se revisa la iatrogenia producida por interacción de drogas y se enumeran sus mecanismos. Por último, se formulan algunas sugerencias cuya adopción en opinión de los autores, podría contribuir a reducir el número y la gravedad de los accidentes de iatrogenia medicamentosa