Real-world first-line treatment of patients with BRAFV600E-mutant metastatic colorectal cancer: the CAPSTAN CRC study.

BACKGROUND: BRAFV600E mutations occur in 8%-12% of metastatic colorectal cancer (mCRC) cases and are associated with poor survival. European guidelines recommend combination (doublet or triplet) chemotherapy plus bevacizumab in first line. However, an unmet need remains for more effective treatments for these patients. PATIENTS AND METHODS: CAPSTAN CRC is a European, retrospective, multicenter, observational study evaluating real-world treatment practices for patients with BRAFV600E-mutant mCRC treated between 1 January 2016 and 31 January 2020. The primary objective was to describe first-line treatment patterns. Secondary objectives included describing baseline demographics, mutational testing procedures, treatment effectiveness, and safety. RESULTS: In total, 255 patients (median age 66.0 years; 58.4% female) with BRAFV600E-mutant unresectable mCRC from seven countries were included. Most had right-sided tumors (52.5%) and presented with synchronous disease at diagnosis (66.4%). Chemotherapy plus targeted therapy (68.7%) was preferred at first line over chemotherapy alone (31.3%). The main first-line treatments were FOLFOX plus bevacizumab (27.1%) and FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan) with/without bevacizumab (27.1%/19.2%). Median duration of first-line treatment was 4.9 months. Overall, 52.5% received second-line treatment. Across all first-line regimens, progression-free survival (PFS) and overall survival were 6.0 [95% confidence interval (CI) 5.3-6.7] months and 12.9 (95% CI 11.6-14.1) months, respectively. Triplet plus targeted therapy was associated with more adverse events (75.0%) compared with triplet chemotherapy alone (50.0%) and doublet chemotherapy alone (36.1%). Multivariate analysis identified low body mass index and presence of three or more metastatic sites as significant prognostic factors for PFS. CONCLUSIONS: This study is, to date, the largest real-world analysis of patients with BRAFV600E-mutant mCRC, providing valuable insights into routine first-line treatment practices for these patients. The data highlight the intrinsic aggressiveness of this disease subgroup, confirming results from previous real-world studies and clinical trials, and stressing the urgent need for more effective treatment options in this setting.

[Alpha-blockers or phytotherapy as first-line treatment of LUTS/BPH in general medicine: The PERSAT non-interventional study]. / Alpha-bloquants ou phytothérapie en traitement de première intention des SBAU/HBP en médecine générale : l'étude non interventionnelle PERSAT.

PURPOSE: The objective of the PERSAT study was to evaluate first-line treatment of BPH-associated LUTS in real-life conditions. METHODS: This prospective observational study was conducted in France by general practitioners (GP) on patients with moderate to severe LUTS (IPSS ≥12). GPs freely decided to prescribe either an alpha-blocker (AB) or phytotherapeutic treatment (PT). The main criterion was the percentage of responding patients (decrease in total IPSS score ≥3) at 6 months. RESULTS: Of the 849 patients included, 759 were analysed (381 treated with AB and 378 with PT); 718 were followed up at 6 months, 90% of which had no treatment modification. Their inclusion characteristics were similar between the AB and PT groups (mean IPSS: 18.6±4.5 and 17.8±4.1, respectively). Treatment response rates at 6 months were 94.2% [91.2%; 96.4%] in AB and 92.5% [89.2%; 95.1%] in PT. The IPSS decreased by 10.0±5.6 points, with no difference between groups. The proportion of patients bothered by their LUTS (IPSS-QoL ≥4) evolved from 88.5% to 6.5% at 6 months. The improvement of LUTS was perceived by more than 94% of patients (PGI-I) and doctors (CGI-I), 93% of patients were satisfied with the treatment at 6 months, regardless of the treatment initiated. The most reported adverse reactions were ejaculation disorder (3.9% for AB and 0.9% for PT). CONCLUSION: PERSAT confirms in current practice the effectiveness of AB and PT treatments, recommended as first-line treatment in LUTS/BPH. LEVEL OF PROOF: 3.

Validation of the Patient-Oriented SCORing for Atopic Dermatitis tool for black skin.

BACKGROUND: SCORing for Atopic Dermatitis (SCORAD) is a tool developed by the European Task Force on Atopic Dermatitis (AD) which is used by physicians to assess AD severity during consultations with their patients. Patient-Oriented SCORAD (PO-SCORAD) is a self-assessment tool for use by patients which has been validated in a study performed in European countries. However, there is currently no adapted tool for evaluating AD severity in black skin. OBJECTIVE: To evaluate the performance of the version of the PO-SCORAD specifically adapted for black skin patients (children and adults) with AD. METHODS: In this multicenter, cross-sectional and non-interventional study, children and adults with AD were recruited during regular consultations. This international study was performed in seven sub-Saharan countries (Benin, Burkina Faso, Cameroon, Ivory Coast, Gabon, Mali and Senegal). During the consultation, AD severity was assessed by the physician using SCORAD score and by the patients or parents using PO-SCORAD. RESULTS: One hundred and thirteen patients were included, 72 children and 41 adults, mainly females (61.6%). SCORAD assessed by physicians and PO-SCORAD assessed by patients/parents were well correlated (r = 0.66, P < 0.0001). Correlation coefficients for SCORAD and PO-SCORAD subscale scores were also good, except for symptom intensity criteria. CONCLUSION: Altogether, these data indicate that PO-SCORAD for black skin correlates well with SCORAD and is therefore a valuable tool, which requires no specific level of education, for use by black skin patients with AD.

Partial trisomy 20q in a newborn with dextrocardia.

A female newborn is reported with dextrocardia and a partial trisomy 20q, derived from a t(2;20) paternal translocation. The most discriminating findings of the condition include brachycephaly, bulging forehead, deep set eyes, short nose, large ears, dimpled chin, short neck and a heart defect. Previously reported patients with this rare chromosomal anomaly are reviewed.

Unusual presentation of typhoid fever: cutaneous vasculitis, pancreatitis, and splenic abscess.

We report a case of typhoid fever with an unusual presentation: prolonged fever with cutaneous vasculitis, pancreatitis, and splenic abscess. This is the first case of cutaneous leukocytoclastic vasculitis associated with Salmonella typhi. The diagnosis was made upon isolation of S. typhi in blood cultures, and after ruling out other causes of leukocytoclastic vasculitis. The outcome was favourable with antibiotics alone without surgery.

Solution structure of the orphan nuclear receptor rev-erb beta response element by 1H, 31P NMR and molecular simulation*.

Rev-erb beta is an orphan receptor that binds as a homodimer or as a monomer to DNA. The solution structure of the non-palindromic 15 bp DNA duplex d(TAGAATGTAGGTCAG), the response element of Rev-erb beta for monomeric binding, was determined by 1H and 31P NMR, energy minimization with NMR-derived restraints for distances and NOE back-calculation methods. The refined final structures have the typical overall features of B-type DNA. However, titration of this 15 bp duplex with ReDBD, the DNA binding domain of Rev-erb beta, showed large shifts of imino protons and 31P signals, suggesting major conformational changes.

31P NMR analysis of the DNA conformation induced by protein binding SRY/DNA complexes.

Complexes of the HMG box protein SRY with two duplexes of 8 and 14 base pairs have been studied by 31P NMR and complete assignment of all phosphorus signals of the bound DNA duplexes are presented. While for the free DNA, all 31P signals display limited spectral dispersion (< 0.8 p.p.m.) for the bound duplexes, 31P resonances are spread over 2 p.p.m. Based on the previously published 3D structure of hSRY-HMG, with the 8 mer it is demonstrated that the upfield shifted resonances correspond to the site of partial intercalation of an isoleucine side chain into the DNA. Moreover, the observation of significant difference in linewidths between the two duplexes allows to estimate lifetime of the complexes from 31P-31P 2D exchange experiments.

Secondary structure of the C-terminal domain of the tyrosyl-transfer RNA synthetase from Bacillus stearothermophilus: a novel type of anticodon binding domain?

The tyrosyl-tRNA synthetase catalyzes the activation of tyrosine and its coupling to the cognate tRNA. The enzyme is made of two domains: an N-terminal catalytic domain and a C-terminal domain that is necessary for tRNA binding and for which it was not possible to determine the structure by X-ray crystallography. We determined the secondary structure of the C-terminal domain of the tyrosyl-tRNA synthetase from Bacillus stearothermophilus by nuclear magnetic resonance methods and found that it is of the alpha+beta type. Its arrangement differs from those of the other anticodon binding domains whose structure is known. We also found that the isolated C-terminal domain behaves as a folded globular protein, and we suggest the presence of a flexible linker between the two domains.

Effect of conditioned medium, nutritive elements and mitotic synchronization on the accuracy of the cytogenetic analysis in patients with chronic myeloid leukemia at diagnosis and during alpha-interferon therapy.

To improve the yield of the cytogenetic analysis in patients with CML at presentation and during alpha-interferon therapy, three culture conditions for bone marrow or peripheral blood cells were tested in parallel. The effects of 5637 conditioned medium (CM), nutritive elements (NE), and methotrexate (MTX) cell synchronization were investigated in 10 Ph-positive (Ph+) CML patients at diagnosis (group 1), and in 13 Ph+ CML patients receiving treatment with alpha-interferon (group 2). In the presence of 5637 CM and NE with or without MTX, the mitotic index values were significantly improved in both groups. In group 2, the morphological index was significantly increased when using 5637 NE, and percentages of abnormal cells did not differ in 5637 NE and 5637 NE MTX compared to the control condition. Although cessation of interferon administration before sampling may improve the yield of the technique, it does not seem necessary when using 5637 CM and NE. The variability of the response of leukemic cells to different culture conditions further supports the recommendation that, in addition to the control condition, supplementations with 5637 CM and NE with or without cell synchronization be used in parallel in all CML patients. Results suggest that, when the number of cells available is not sufficient for several cultures, 5637 NE with or without MTX should replace the control condition.

[Autoimmune cholangitis successfully treated with corticotherapy. One case]. / Cholangite auto-immune traitée avec succés par corticothérapie. Un cas.

Autoimmune cholangitis is a rare cause of chronic liver disease which has recently been described and associates the clinical, biological, and histological patterns of primary biliary cirrhosis without serum anti-mitochondrial antibodies. We report a case of this disease in a 67-year-old female. The patient presented with jaundice and marked biological cholestasis associated with pulmonary fibrosis and salivary and lacrymal sicca syndrome. Serum anti-smooth muscle antibodies were found without anti-mitochondrial antibodies. Corticotherapy resulted in rapid improvement of clinical and hepatic abnormalities, as well as of pulmonary lesions. The patient was still healthy 18 months later, with low dose corticotherapy. This report emphasizes the possible effectiveness of corticotherapy in autoimmune cholangitis.

Effect of conditioned media, nutritive elements, and mitotic synchronization on the accuracy of the cytogenetic analysis in acute nonlymphocytic leukemia patients presenting with inv(16)/t(16;16) or t(15;17).

To improve the yield of the cytogenetic analysis in patients with acute nonlymphocytic leukemia (ANLL), six culture conditions for bone marrow or peripheral blood cells were tested in parallel. Two conditioned media (CM), phytohemagglutinin leukocyte PHA-LCM and 5637 CM, nutritive elements (NE), and methotrexate (MTX) cell synchronization were investigated in 14 patients presenting with either inv(16)/ t(16;16) (group 1, n = 9 patients) or t(15;17) (group 2, n = 5). The criteria used to identify the most favorable culture conditions were the mitotic index (MI), the morphological index (MorI), and the percentage of abnormal metaphases. In the presence of PHA-LCM and 5637 CM, the MI were significantly increased in group 2, whereas in the MTX conditions, MI remained very low in both groups. The values of the MorI did not reveal any significant changes in chromosome resolution between the conditions in either group. The addition of NE did not have a positive effect in quantity or quality of metaphases. Because of the variability of the response of leukemic cells to different stimulations in vitro, several culture conditions in parallel are required to ensure a satisfactory yield of the chromosome analysis in ANLL.

[Prevalence of hypertension in a black African diabetic population]. / Prévalence de l'hypertension artérielle dans une population de diabétiques africains.

BACKGROUND: It has been established that hypertension prevalence rate was higher in American Blacks than Whites or Mexicans. And hypertension is more frequent in diabetics. The prevalence of hypertension among diabetic African Blacks is not well documented. METHODS: A total of 550 diabetic patients attending to Central Hospital of Yaounde (Cameroon) were followed between 1990 and 1994. The 1993 WHO criteria were used to define hypertension (systolic blood pressure (SBP) > or = 140 or diastolic blood pressure (DBP) > or = 90 mmHg. We also have considered as hypertensive patients being treated with an antihypertensive medication before inclusion. All quantitative data are given as means +/- SD. RESULTS: For the whole study population characteristics were: age (at inclusion): 54.2 +/- 12.8 yrs: sex distribution: 341 men for 209 women (sex ratio: 1.63:1); known duration of diabetes: 5.7 +/- 5.6 yrs; Body Mass Index (BMI): 24.4 +/- 4.8 kg/m2. They are dividing into 136 IDDM, 405 NIDDM and 9 other types. In normotensive patients, blood pressure levels were: SBP 117 +/- 11 and DBP 75 +/- 8 mmHg, while in hypertensive: SBP 156 +/- 23 and DBP 95 +/- 13 mmHg. The difference between normo and hypertensive diabetics was significant (p > or = 0.001). Characteristics of hypertensive group were: age: 57 +/- 11.2 yrs, sex repartition 229 men for 136 women (sex ratio: 1.68:1), BMI: 24.9 +/- 4.8 kg/m2, diabetes classification: 63 IDDM, 297 NIDDM and 5 other types. According to recent WHO criteria (140/90) 365 subjects/550 were found to have high blood pressure, giving an overall prevalence of hypertension of 66.4% in the study population. Using former WHO definition (160/95) the prevalence was 42.2%. There was no statistical difference for prevalence between male (67.2%) and female (65.1%). But the difference was strongly significant (p < 0.001) between IDDM (46.3%) and NIDDM (73.3%). DISCUSSION: Hypertension prevalence studies in Africa have shown varying results (2.5-30%), with higher rates in urban than rural population. In African studies hypertension prevalence rates in diabetes were reported in the range 13-44%. The result of the present study is very near the high limit of known data in Africa. CONCLUSION: Such a prevalence rate of 66.4% in this Cameroonian diabetic population appears to be high, particularly in patients with NIDDM. These considerations bring to light the question of sensitiveness of African Blacks to hypertension when exposed to high blood pressure risk factors such as inadequate food and diabetes.

A prevalence survey of diabetes in Mauritania.

OBJECTIVE: To perform an epidemiological study of the prevalence of diabetes in Mauritania, West Africa, with little data available on diabetes in West Africa. RESEARCH DESIGN AND METHODS: The study was performed with a representative sample of the Mauritanian population. A random selection of the study population (n = 744) was drawn by a cluster sampling method. Screening for diabetes was made by capillary blood glucose (CBG) measurement, using strips analyzed by reflectance meter. Criteria for the diagnosis of diabetes were those of the World Health Organization (WHO). RESULTS: The survey performed a screening of 744 subjects whose sex distribution was 307 men and 437 women. Their mean age was 34.6 +/- 15.2 years, and their mean BMI was 22.7 +/- 5.1 kg/m2, with a significant difference for BMI between men (20.0 +/- 2.9 kg/m2) and women (24.3 +/- 5.5 kg/m2). According to the study criteria, we found 14 diabetic patients (4 men, 10 women). The crude prevalence of diabetes was 1.88% (95% CI 0.90-2.86). The difference in prevalence by sex was 1.30% (95% CI 0.00-2.60) for men and 2.29% (95% CI 0.89-3.43) for women. For the truncated 30- to 64-year-old age-group, the crude prevalence was 2.84%; the age-adjusted prevalence for the same 30- to 64-year-old age-group, using the standardized age distribution of Segi (10), was 2.61%. CONCLUSIONS: With a crude prevalence of diabetes of 1.88% and an age-adjusted prevalence of 2.61%, Mauritania may be classified among the countries with a low prevalence of diabetes, a finding which is not surprising, considering the low level of development of this region of Africa.

Tetrasomy 8 in a patient with acute nonlymphocytic leukemia: a metaphase and interphase study with fluorescence in situ hybridization.

Tetrasomy 8 constitutes a relatively rare recurring chromosome defect in myeloid disorders. The patient reported here, a 71-year-old man, presented with tetrasomy 8 as the sole chromosome abnormality associated with an acute nonlymphocytic leukemia of the M2 type. He failed to respond to chemotherapy and died one year after diagnosis. Following conventional cytogenetics and fluorescence in situ hybridization (FISH) with a centromeric probe specific for chromosome 8, tetrasomy 8 was detected in 61% of the metaphases analyzed and trisomy 8 in 39%. FISH analysis of interphase nuclei confirmed the existence of tetrasomic (35%) and trisomic cells (56%) and revealed a number of cells with two chromosomes 8 (8%). This normal population may represent lymphocytes or myeloid cells that escaped conventional analysis due to their inability to divide or to the small number of metaphases available. The relatively higher proportion of tetrasomic cells in metaphase compared with interphase may be attributed to a proliferative advantage of tetrasomic cells in vitro or to the longer duration of their cell cycle. The simultaneous presence of trisomic and tetrasomic cells confirms the hypothesis of a clonal relationship between trisomy 8 and tetrasomy 8. Our case brings further evidence to the specificity of tetrasomy 8 to myeloid disorders and to the association of this chromosome abnormality with a relatively poor prognosis. However, new patients must be studied to further delineate this cytogenetic entity.