In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.     

Living unrelated donor kidney transplantation between spouses

From November 3, 1975 to November 3, 1990, 874 kidney transplants were performed at our centers. Of these, 675 (77.2%) were from living donors and 199 (22.8%) were from cadaver donors. Five hundred eighty (66.4%) of the living donors were first degree related while 99 (11.3%) were unrelated or second degree related donors, 29 of which were spouses. All donor recipient pairs were ABO-compatible, with the exception of one pair. Donor recipient relations were wife to husband in 25 cases and husband to wife in 4 cases. All were first grafts and started functioning during surgery. In this series, the follow-up for the recipients was 4 to 64 months (mean 33.5 ± 4.5 months). One-year patient survival and graft survival rates were 92.4% and 81.9%, respectively. Two-year patient survival and graft survival rates were 92.4% and 78.2%, respectively. The single ABO-incompatible case is also doing well, 21 months postoperatively. This study demonstrates that the interspouse kidney transplantation may be used when cadaver organ shortage is a problem. While providing the couple with a better quality of life, interspouse kidney transplantation also enables the couple to share the joy of giving and receiving the gift of life from one another.

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Resumen En nuestro centro se efectuaron 874 trasplantes renales entre noviembre 3 de 1975 y noviembre 3 de 1990; 675 (77.2%) fueron de donantes vivos y 199 (22.8%) de donantes cadavéricos; 580 (66.4%) de los donantes vivos fueron familiares de primer grado y 99 (11.3%) fueron donantes no relacionados familiarmente o familiares de segundo grado, de los cuales 29 eran cónyuges. Todas las parejas donante-recipiente exhibieron compatibilidad ABO, con excepción de una. La relación donante-recipiente fue esposa a esposo en 25 casos y esposo a esposa en 4 casos. Todos los injertos eran de primera vez y todos comenzaron a funcionar en la mesa de cirugía. El seguimiento osciló entre 4 y 64 meses (33.5 ± 4.5). Las tasas de sobrevida a un año del paciente y del injerto fueron 92.4% y 81.9% respectivamente; las tasas a dos años fueron 92.4% y 78.2% respectivamente. El único caso ABO no compatible también se encuentra bien, a 21 meses en la actualidad. El presente estudio demuestra que el trasplante renal entre esposos puede ser utilizado cuando haya escases de órganos cadavéricos. Al tiempo que permite una mejor calidad de vida, el procedimiento da a la pareja la oportunidad de gozar el hecho de otorgar y de recibir el regalo de la vida entre uno y otro.

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Résumé Nous avons effectué 874 transplantations rénales dans nos centres de transplantation entre le 3 Nov, 1975 et le 3 Nov, 1990. Parmi celles-ci, 675 (77.2%) provenaient de donneurs vivants et 199 (22.8%) des reins provenaient de cadavres. Cinq cent quatre vingt des donneurs vivants (66.4%) étaient parents au premier degré alors que 99 (11.3%) étaient parents au 2è degré ou n'étaient pas parents, parmi lesquels 29 étaient des époux. Tous les couples donneur/receveur, sauf un, étaient compatibles dans le système ABO. Le couple donneur/receveur était femme à mari dans 25 cas et mari à femme dans quatre. Il s'agissait dans tous les cas d'une première greffe et qui a commencé à bien fonctionner sur la table d'opération. Dans cette série, le suivi des receveurs allait de 4 à 64 (33.5 ± 4.5) mois. Les taux de survie des malades et des greffes à un an étaient respectivement de 92.4% et 81.9%. Les taux de survie des malades et des greffes à deux ans étaient respectivement de 92.4% et 78.2%. Le seul cas avec incompatabilité ABO va très bien avec un recul de 21 mois. Cette étude montre que la transplantation entre époux est une solution valable en cas de manque de reins. En plus d'améliorer la qualité de survie du receveur et par là même du couple, cette variété de transplantation donne également au couple la possibilité d'avoir la joie de donner et de recevoir un cadeau de vie de leur époux.

     

Quercetin sensitizes cells in a tumour-like low pH environment to hyperthermia.

Quercetin has been shown to act as a hyperthermia sensitizer by inhibiting the synthesis of heat shock protein 70 (HSP70) in a variety of tumour cell lines. It is most effective under conditions of low pH. This study was designed to test the hypothesis that quercetin suppresses thermotolerance development in cells adapted to growth at low pH and renders them as responsive as acutely acidified cells to hyperthermia-induced cytotoxicity. Chinese hamster ovarian carcinoma cells (OvCa) were exposed to 42 degrees C hyperthermia and/or quercetin (50-200 mm) at their growth pH of either 7.3 or 6.7 or after acute acidification from 7.3 to 6.7. Thermotolerance development was measured by colony survival. HSP70 synthesis and total protein synthesis were measured by radioactive precursor pulse labelling techniques. Quercetin, in a concentration-dependent manner, reduced the rate of total protein synthesis and increased cytotoxicity equally after acute acidification to pH 6.7 or growth at pH 6.7 at 37 degrees C, and to a greater extent than it did in cells at pH 7.3. At 42 degrees C, 100 mm quercetin inhibited total protein synthesis, HSP70 synthesis and thermotolerance development to a similar extent in cells grown at pH 6.7 or acutely acidified to pH 6.7. In contrast, quercetin reduced but did not completely inhibit HSP70 synthesis and thermotolerance development in cells grown and heated at pH 7.3. These results support the hypothesis that quercetin can specifically reduce thermotolerance development in tumour cells adapted to growth at pHe 6.7 so that they respond similarly to acutely acidified cells. Since many tumours are adapted to growth at low pH and may resist a wide variety of therapeutic modalities, inhibition of thermotolerance expression by quercetin may not only enhance the response to hyperthermia but the response to commonly used therapies such as chemotherapy and radiation.     

The effect of age on peripheral stem cell mobilization in healthy donors,single center experience

Purpose : Peripheral stem cell transplantation is used as a life‐saving therapeutic option in hematological malignancies. As previously established, most hematological malignancies are seen in the elderly population. Therefore, possible HLA‐identical sibling donors of elderly patients are generally of an advanced age. In this study, we aimed to evaluate the effect of old age on stem cell mobilization and quality in older adult healthy sibling donors. Materials and Methods : Between 2006 and 2014, we evaluated 38 healthy donors aged ≥55 years. The granulocyte‐colony stimulating factor (G‐CSF) analogs were used at a dose of 5 µg/kg/day and administered subcutaneously twice a day for five days. CD34+ cells were estimated in the peripheral blood before collection of the apheresis product. The National Marrow Donor Program selects healthy unrelated donors if they are younger than 60 years. Therefore, we compared the product quality in donors over the age of 60 to that in donors aged 60 years or less. Results : We collected sufficient products from all the donors with one to three apheresis procedures. No serious complication was detected in all donors. Reaching the target CD34+ cell count in one day were detected in 83% of younger and 79% of older donors (P = NS). Collected CD34+ cells x10e6/recipient body weight (kg) was same and 5.1 in the groups (P = NS). There were no correlation between the donor age and these parameters. Conclusion : Healthy donor apheresis in older adults can be performed effectively and possible donors should be evaluated regardless of their age. J. Clin. Apheresis 32:16–20, 2017. © 2016 Wiley Periodicals, Inc.     

Blastic Plasmacytoid Dendritic Cell Neoplasm: Single Center Experience on a Rare Hematological Malignancy

PurposeBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and poor prognostic hematological malignancy. There is still no standard treatment established for BPDCN patients. We aim to summarize the main clinical, biological features and treatment of 9 BPDCN patients.MethodsNine patients with BPDCN who had been diagnosed between July 2008 and December 2018 in Ankara University School of Medicine, were retrospectively evaluated.ResultsAll patients (n = 9) were male, median age was 64 (21–80). Five patients (55.6%) had bone marrow infiltration, 5 patients (55.6%) cutaneous lesions, 6 patients (66.7%) lymph node involvement, 2 patients (22.2%) central nervous system involvement and 2 patients (22.2%) spleen involvement at time of diagnosis. Complex karyotype was observed in 2 patients. CHOP was given to 5 patients (55.6%), hyper-CVAD to 2 patients (22.2%), fludarabine, cyclophosphamide and mitoxantrone to 1 patient (11.1%) and cyclophosphamide, etoposide, methylprednisolone to 1 patient (11.1%) as first line chemotherapy. Four patients (44.4%) underwent allogeneic hematopoietic stem cell transplantation (AHSCT) in complete remission (CR) 1. Venetoclax was given to a transplant ineligible patient who had skin and lymph node involvement, with the off-label use. The median follow-up time was 15.9 months (3–48.6 months). Estimated median overall survival was 15.9 + 1.6 (95% CI 12.7–19.1) months.ConclusionIntensive induction therapies followed by AHSCT in CR seems to be best approaches for patients with BPDCN. Thus, more effective treatment strategies particularly targeted therapies should be warranted to improve the survival of patients with this rare disease.     

Association of the angiotensinogen M235T and angiotensin-converting enzyme insertion/deletion gene polymorphisms in Turkish type 2 diabetic patients with and without nephropathy

OBJECTIVE: Recent studies have suggested an association between a deletion variant of the angiotensin-converting enzyme (ACE) gene and diabetic nephropathy. However, this finding has not been confirmed by all investigators. Furthermore, an M235T variant of the angiotensinogen (AGT) gene has been associated with hypertension, an important risk factor for the development and progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS: We investigated the relationship of the ACE insertion/deletion (I/D) and AGT M235T gene polymorphisms in Turkish patients with type 2 diabetes mellitus (DM) with and without diabetic nephropathy. A total of 102 individuals were screened for the presence of the ACE I/D and AGT M235T polymorphism: 46 individuals who had type 2 DM with diabetic nephropathy and, as controls, 56 individuals who had type 2 DM without diabetic nephropathy. Gene polymorphisms were determined by the specific melting temperature (T(m)) values of the resulting amplicons after real-time online polymerase chain reaction and melting curve analysis. RESULTS: The frequencies of the ACE DD, ID, and II genotypes were 34.8%, 37.0%, and 28.3%, respectively, among type 2 diabetic patients with nephropathy, and 33.9%, 42.9%, 23.2%, respectively (P=.788), in the control subjects without diabetic nephropathy. On the other hand, the frequencies of the AGT MM, MT, and TT genotypes among the same groups were 26.1%, 52.2%, 21.7% and 26.8%, 57.1%, 16.1%, respectively (P=.758). CONCLUSIONS: There were no differences in the frequencies of the AGT M235T and ACE I/D genotypes between Turkish patients with type 2 DM with and without nephropathy.