Potential Involvement of NSD1, KRT24 and ACACA in the Genetic Predisposition to Colorectal Cancer.

The ALFRED (Allelic Loss Featuring Rare Damaging) in silico method was developed to identify cancer predisposition genes through the identification of somatic second hits. By applying ALFRED to ~10,000 tumor exomes, 49 candidate genes were identified. We aimed to assess the causal association of the identified genes with colorectal cancer (CRC) predisposition. Of the 49 genes, NSD1, HDAC10, KRT24, ACACA and TP63 were selected based on specific criteria relevant for hereditary CRC genes. Gene sequencing was performed in 736 patients with familial/early onset CRC or polyposis without germline pathogenic variants in known genes. Twelve (predicted) damaging variants in 18 patients were identified. A gene-based burden test in 1596 familial/early-onset CRC patients, 271 polyposis patients, 543 TCGA CRC patients and >134,000 controls (gnomAD, non-cancer), revealed no clear association with CRC for any of the studied genes. Nevertheless, (non-significant) over-representation of disruptive variants in NSD1, KRT24 and ACACA in CRC patients compared to controls was observed. A somatic second hit was identified in one of 20 tumors tested, corresponding to an NSD1 carrier. In conclusion, most genes identified through the ALFRED in silico method were not relevant for CRC predisposition, although a possible association was detected for NSD1, KRT24 and ACACA.

The Inherited and Familial Component of Early-Onset Colorectal Cancer.

Early-onset colorectal cancer (EOCRC), defined as that diagnosed before the age of 50, accounts for 10-12% of all new colorectal cancer (CRC) diagnoses. Epidemiological data indicate that EOCRC incidence is increasing, despite the observed heterogeneity among countries. Although the cause for such increase remains obscure, ≈13% (range: 9-26%) of EOCRC patients carry pathogenic germline variants in known cancer predisposition genes, including 2.5% of patients with germline pathogenic variants in hereditary cancer genes traditionally not associated with CRC predisposition. Approximately 28% of EOCRC patients have family history of the disease. This article recapitulates current evidence on the inherited syndromes that predispose to EOCRC and its familial component. The evidence gathered support that all patients diagnosed with an EOCRC should be referred to a specialized genetic counseling service and offered somatic and germline pancancer multigene panel testing. The identification of a germline pathogenic variant in a known hereditary cancer gene has relevant implications for the clinical management of the patient and his/her relatives, and it may guide surgical and therapeutic decisions. The relative high prevalence of hereditary cancer syndromes and familial component among EOCRC patients supports further research that helps understand the genetic background, either monogenic or polygenic, behind this increasingly common disease.

TP53, a gene for colorectal cancer predisposition in the absence of Li-Fraumeni-associated phenotypes.

OBJECTIVE: Germline TP53 pathogenic (P) variants cause Li-Fraumeni syndrome (LFS), an aggressive multitumor-predisposing condition. Due to the implementation of multigene panel testing, TP53 variants have been detected in individuals without LFS suspicion, for example, patients with colorectal cancer (CRC). We aimed to decipher whether these findings are the result of detecting the background population prevalence or the aetiological basis of CRC. DESIGN: We analysed TP53 in 473 familial/early-onset CRC cases and evaluated the results together with five additional studies performed in patients with CRC (total n=6200). Control population and LFS data were obtained from Genome Aggregation Database (gnomAD V.2.1.1) and the International Agency for Research on Cancer (IARC) TP53 database, respectively. All variants were reclassified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), following the ClinGen TP53 Expert Panel specifications. RESULTS: P or likely pathogenic (LP) variants were identified in 0.05% of controls (n=27/59 095) and 0.26% of patients with CRC (n=16/6200) (p<0.0001) (OR=5.7, 95% CI 2.8 to 10.9), none of whom fulfilled the clinical criteria established for TP53 testing. This association was still detected when patients with CRC diagnosed at more advanced ages (>50 and>60 years) were excluded from the analysis to minimise the inclusion of variants caused by clonal haematopoiesis. Loss-of-function and missense variants were strongly associated with CRC as compared with controls (OR=25.44, 95% CI 6.10 to 149.03, for loss of function and splice-site alleles, and OR=3.58, 95% CI 1.46 to 7.98, for missense P or LP variants). CONCLUSION: TP53 P variants should not be unequivocally associated with LFS. Prospective follow-up of carriers of germline TP53 P variants in the absence of LFS phenotypes will define how surveillance and clinical management of these individuals should be performed.

Bacteriemia con afectación inflamatoria pélvica y miositis secundaria a histeroscopia diagnóstica. Reporte de un caso / Bacteremia with pelvic inflamatory involvement and secondary myositis due to diagnostic hysteroscopy. A case report

Resumen ANTECEDENTES: Las complicaciones infecciosas secundarias a la histeroscopia diagnóstica ambulatoria son bajas (0.6%). CASO CLÍNICO: Paciente de 46 años que a los 6 días posthisteroscopia diagnóstica ambulatoria por pólipos endometriales ingresó al servicio de Ginecología debido a un cuadro de piomiositis del músculo piriforme izquierdo, secundario a bacteriemia por Streptococcus pyogenes luego de un procedimiento ginecológico. Se trató con una dosis subcutánea de 40 mg de enoxaparina al día, y 2 g de ceftriaxona intravenosa cada 24 h, 240 mg de gentamicina intravenosa una vez al día. En las siguientes 48 horas se retiró la gentamicina y se prescribió 1 g de amoxicilina cada 8 h, por vía oral más 300 mg de clindamicina cada 8 h, también por vía oral que la paciente continuó durante 7 días más. En la resonancia magnética de control tomada a los 10 días quedó de manifiesto la tromboflebitis séptica en la vena iliaca interna izquierda y la persistencia del cuadro de piomiositis, con colección pélvica intra y extramuscular. Se decidió reingresarla para tratarla con el siguiente esquema: 1 g de amoxicilina por vía intravenosa cada 8 horas y 900 mg de clindamicina con igual pauta; se suspendió a las 24 h enseguida de la valoración por el infectólogo. Se indicó nuevo tratamiento antitrombótico con 0.5 mL de fraxiparina forte cada 24 horas, por vía subcutánea. El eco-Doppler descartó la trombosis venosa profunda; los hemocultivos que resultaron negativos. La paciente fue dada de alta con prescripción de fraxiparina Forte a dosis de 0.5 mL cada 24 horas durante 6 semanas; la evolución clínica fue favorable. La resonancia magnética de control a los 30 días reportó la desaparición completa del proceso inflamatorio. Luego de un año, la paciente permanece asintomática y continúa en seguimiento médico anual. CONCLUSIONES: La histeroscopia diagnóstica ambulatoria es una técnica eficaz y segura aunque excepcionalmente pueden sobrevenir complicaciones infecciosas derivadas de la técnica. Esto se previene con profilaxis antibiótica. La valoración previa a la histeroscopia es indispensable para advertir factores de riesgo que puedan controlarse o contraindiquen la realización del procedimiento.

Abstract BACKGROUND: Infectious complications due to diagnostic hysteroscopy are uncommon, being only 0.6% of all complications. CLINICAL CASE: A 46-year-old patient who, 6 days after performing an outpatient diagnostic hysteroscopy due to endometrial polyps, was admitted to the Gynecology Department, due to pyomyositis of the left piriformis muscle secondary to Streptococcus pyogenes bacteremia after gynecological procedure. Antithrombotic treatment was initiated with Enoxaparin 40 mg, 1/24h subcutaneously and antibiotic therapy with Ceftriaxone 2g/24h intravenously (iv) and Gentamicin 240 mg/24h iv, which 48 hours later were changed to Amoxicillin 1g/8h orally (VO) and Clindamycin 300 mg/8 hours orally for another 7 days. In the 10-day control magnetic resonance imaging (MRI), septic thrombophlebitis was seen in the left internal iliac vein as well as persistence of the pyomyositis condition, with intra and extramuscular pelvic collections. Therefore, a new admission was decided to start antibiotic therapy again with Amoxicillin 1g/8h IV and Clindamycin 900 mg/8h IV, which was suspended 24 hours after assessment by the Infectious Diseases Unit; and new antithrombotic treatment with Fraxiparin Forte 0.5 mL/24h subcutaneous, by consensus with the Vascular Surgery Service. ECO-DOPPLER was performed, which ruled out Deep Venous Thrombosis (DVT); and negative blood cultures. The patient was discharged with Fraxiparina Forte 0.5 mL/24h for 6 weeks presenting good clinical evolution. A new MRI control was scheduled for the following month, finding a complete resolution of the inflammatory process. Currently, one year later, the patient is asymptomatic and continues in annual follow-up in our consultations. CONCLUSIONS: Outpatient diagnostic hysteroscopy is an effective and safe technique. Infectious complications derived from the technique are infrequent, which is why it is not necessary to perform an antibiotic prophylaxis in patients who are going to undergo this test

NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas.

The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas.

Resultados de la implantación de un protocolo para reconstrucción vulvar inmediata tras vulvectomía / Outcomes of the implementation of a protocol for immediate vulvar reconstruction after vulvectomy

Introducción y objetivo. La cirugía de vulvectomía se asocia a una gran incidencia de complicaciones de la herida quirúrgica que pueden evitarse mediante la reconstrucción inmediata de la vulva. En este trabajo buscamos presentar los resultados obtenidos en nuestro centro hospitalario mediante la introducción de un protocolo de reconstrucción inmediata tras vulvectomía. Material y método. En enero de 2017 se implantó en nuestro hospital un protocolo de reconstrucción inmediata tras vulvectomía con el fin de establecer una serie de criterios que permitan al ginecólogo detectar aquellas pacientes con alto riesgo de dehiscencia de la herida tras vulvectomía y contactar con el Servicio de Cirugía Plástica para coordinar la reconstrucción inmediata de la vulva. Durante un periodo de 18 meses registramos los datos de las pacientes sometidas a dicha intervención: edad, tipo de neoplasia, criterio reconstructivo, técnica reconstructiva, uni o bilateralidad, estancia hospitalaria y complicaciones en los 30 primeros días de postoperatorio. Resultados. Registramos un total de 9 pacientes sometidas a reconstrucción inmediata: 8 mediante colgajo en flor de loto y 1 mediante colgajo miocutáneo de gracilis. La estancia media hospitalaria fue de 31.4 días y 3 pacientes presentaron complicaciones postoperatorias en forma de dehiscencia de la herida quirúrgica. Conclusiones. Consideramos que nuestro protocolo es una herramienta adecuada para desarrollar una colaboración interdepartamental entre Ginecología y Cirugía Plástica y para implantar la reconstrucción vulvar inmediata

Background and objective. Vulvectomy surgery is associated with a high incidence of surgical wound complications that may be avoided with immediate vulvar reconstruction. In this paper we present the results obtained in our hospital with the implementation of an immediate vulvar reconstruction protocol. Methods. In January 2017 we established an immediate vulvar reconstruction protocol in our center with a list of criteria that would allow the gynecologist to detect those patients with a high risk of wound dehiscence after vulvectomy in order to coordinate the immediate reconstruction of the vulva with our Plastic Surgery Service. For the next 18 months, we recorded the information of those patients intervened: age, pathology, reconstructive criteria, reconstructive technique, laterality, hospital stay and complications during the first 30 postoperative days. Results. We performed immediate vulvar reconstruction in 9 patients: 8 with a lotus flap and 1 with a gracilis myocutaneous flap. Mean stay was 31.4 days and 3 patients developed complications in the form of surgical wound dehiscence. Conclusions. We consider that our protocol is a useful tool for the implantation of immediate vulvar reconstruction and to establish a collaboration between gynecologists and plastic surgeons

Adenocarcinoma mucinoso bien diferenciado de tipo gástrico (adenoma maligno): un reto diagnóstico / Gastric-type mucinous well differentiated adenocarcinoma (adenoma malignum): a diagnostic challenge

Resumen ANTECEDENTES: El adenocarcinoma mucinoso bien diferenciado de tipo gástrico (adenoma maligno) es una variante histológica poco frecuente de adenocarcinoma mucinoso cervical. La hidrorrea, el sangrado vaginal persistente y las formaciones quísticas cervicales son manifestaciones sugerentes de la enfermedad. CASO CLÍNICO: Paciente de 52 años, que acudió a consulta por hidrorrea y sangrado genital persistente. Después de la exploración física se tomaron muestras de: exudado vaginal, citología cervical, biopsia endometrial e identificación de virus del papiloma humano. También se practicaron estudios de: colposcopia, legrado endocervical, ecografía transvaginal, histeroscopia y resonancia magnética. Se visualizaron múltiples quistes de Naboth, menores de 2 cm; líquido en la cavidad uterina y el canal endocervical, sin hallazgos patológicos adicionales. Por la persistencia de los síntomas se decidió efectuar la histerectomía total simple con doble anexectomía, por laparotomía. El reporte anatomopatológico fue: adenocarcinoma mucinoso bien diferenciado de tipo gástrico, estadio IB2 (FIGO). Se prescribieron: tratamiento coadyuvante, radioterapia externa y braquiterapia. Después de 12 esquemas de tratamiento no se identificaron signos de recidiva. CONCLUSIONES: Establecer el diagnóstico anatomopatológico preoperatorio es decisivo para disminuir la morbilidad y mortalidad por adenocarcinoma mucinoso. Es importante establecer el diagnóstico diferencial exhaustivo con lesiones benignas cervicales.

Abstract BACKGROUND: Gastric-type mucinous well differentiated adenocarcinoma (adenoma malignum) is an infrequent cervical mucinous adenocarcinoma. It must be suspected if persistent hydrorrhea or vaginal bleeding are present, as well as multiple cervical cysts. CLINICAL CASE: A case of a 52-year-old woman with persistent hydrorrhea and vaginal bleeding. The study was completed with vaginal culture, cervical cytology and HPV (Human Papiloma Virus), colposcopy, endocervical curettage, transvaginal ultrasound, endometrial biopsy, hysteroscopy and magnetic resonance imaging. Multiple Nabothian cysts <2 cm and fluid in the uterine cavity and the endocervical canal were observed, with no other pathological findings. Due to the symptom persistence and severity, surgical treatment was decided, revealing the diagnosis of gastric-type mucinous well differentiated adenocarcinoma, stage IB2 (FIGO). Adjuvant treatment consisted in external radiotherapy and brachytherapy. After one year of follow-up, the patient did not show any sign of relapse. CONCLUSIONS: Reaching a pathological diagnosis prior to surgery has a crucial importance to decrease morbi-mortality. A thorough differential diagnosis including benign cervical lesions is essential.

Molecular diagnosis of bloodstream infections with a new dual-priming oligonucleotide-based multiplex PCR assay.

Mortality from bloodstream infections (BSIs) correlates with diagnostic delay and the use of inappropriate empirical treatment. Early PCR-based diagnosis could decrease inappropriate treatment, improving patient outcome. The aim of the present study was to assess the clinical utility of this molecular technology to diagnose BSIs. We assessed a new dual-priming oligonucleotide-based multiplex PCR assay, the Magicplex Sepsis Test (MST) (Seegene), along with blood culture (BC). A total of 267 patients from the intensive care unit and haematology and emergency departments were enrolled. Clinical data were also used by physicians to determine the likelihood of infection. Ninety-eight (37 %) specimens were positive: 29 (11 %) by both the MST and BC, 29 (11 %) by the MST only, and 40 (15 %) by BC only. The proportion of agreement between the two methods was 73 % (Cohen's κ: 0.45; 0.28-0.6; indicating fair to moderate agreement). According to clinical assessment, 63 (64 %) positive specimens were considered BSIs: 23 (36 %) were positive by both the MST and BC, 22 (35 %) were positive only by BC, and 18 (29 %) were positive only by the MST. Thirty-eight (14 %) positive specimens by the MST and/or BC were considered as contaminants. Of 101 specimens collected from patients receiving antibiotics, 20 (20 %) were positive by the MST and 32 (32 %) by BC. Sensitivity and specificity were 65 % and 92 %, respectively, for the MST and 71 % and 88 %, respectively for BC. We concluded that the MST shows a high specificity but changes in design are needed to increase bacteraemia detection. For viability in clinical laboratories, technical improvements are also required to further automate the process.

Limnology of cuban reservoirs III: Zaza / Limnología de los embalses cubanos III: Zaza

Studies of physical, chemical and biological variables of the pelagic community were performed during 1989 in Zaza, the largest freshwater reservoir in Cuba. The reservoir is warm-monomictic. The circulation period lasted from October to March and the water column stability was low, due to a large surface area and to a wind exposed location. Dissolved oxygen was usually below the saturation point, owing to a high load of organic matter. The low oxygen concentrations appear to have responsible for a low efficiency in the decomposition of organic matter and in denitrification. The inorganic fraction of nitrogen was always detectable in the upper circulating layer (0-12 m), whereas inorganic phosphorus was only detectable after June. Standing stock of phytoplankton was relatively low. Phytoplankton production was probably limited by light and phosphorus. Diatoms dominated during the mixing period and Cyanophyceae and Crytophyceae during stratification. For most part of the year biomass of Copepoda was higher than biomass of Cladocera and Rotatoria