Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.

Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial.

Importance: Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified.

Objective: To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type.

Design, Setting, And Participants: In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts.

Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma.

Context: Aggressive pituitary tumors that have progressed following temozolomide have limited treatment options. Peptide receptor radionuclide therapy and immunotherapy may have a complementary role in the management of these tumors.

Methods: We provide follow-up data on a previously reported patient with a hypermutated recurrent tumor.

Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.

Purpose: Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent mutations or specific gene fusions, most commonly involving . Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically.

Experimental Design: A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; = 136) or hotspot 8-oncogene genotyping ( = 64).

Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age: A Report of the Children's Oncology Group (ACNS1221).

Purpose: Nodular desmoplastic medulloblastoma (ND) and medulloblastoma with extensive nodularity (MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients.

Patients And Methods: ACNS1221 was a prospective single-arm trial of conventional chemotherapy for nonmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotrexate, aiming to achieve similar outcome (2-year progression-free survival [PFS] ≥ 90%) with reduced treatment-related neurotoxicity.

Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma.

Medulloblastoma, which is the most common malignant paediatric brain tumour, has a 70% survival rate, but standard treatments often lead to devastating life-long side effects and recurrence is fatal. One of the emerging strategies in the search for treatments is to determine the roles of tumour microenvironment cells in the growth and maintenance of tumours. The most attractive target is tumour-associated macrophages (TAMs), which are abundantly present in the Sonic Hedgehog (SHH) subgroup of medulloblastoma.

Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma.

Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation.

Author Correction: The landscape of genomic alterations across childhood cancers.

In this Article, author Benedikt Brors was erroneously associated with affiliation number '8' (Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA); the author's two other affiliations (affiliations '3' and '7', both at the German Cancer Research Center (DKFZ)) were correct. This has been corrected online.

Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial.

Background: Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure.

The landscape of genomic alterations across childhood cancers.

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers.

The whole-genome landscape of medulloblastoma subtypes.

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets.

[Applicability of coexpression networks analysis to anticancer drug targets discovery].

Identification of proteins that can be therapeutically targeted is an important problem in molecular biology. Transcriptomics approaches such as coexpression network analysis have been previously proposed as tools facilitating drug targets discovery. To assess whether coexpression network analysis is applicable to prediction of novel anticancer drug targets, we compared known targets of 103 antineoplastic drugs with those of 776 drugs irrelevant to cancer in terms of their position in the coexpression network of glioblastoma--one of the most malignant human cancer types.

[Hemostasis system disturbances and their correction in patients with pyonecrotic forms of diabetic foot].

Severe hypercoagulation syndrome was diagnosed in patients with various forms of diabetic foot. Pathology at coagulogram parameters reflects systemic metabolic and inflammatory disturbances. Anticoagulant therapy should be combined with correction of glycemia, treatment of infection and critical ischemia.

[Experience in the use of vessel due F (sulodexide) in patients with suppurative-necrotic forms of diabetic foot without critical ischemia].

Aim: To evaluate effectiveness of sulodexide in patients with pyonecrotic complications of diabetic foot.

Material And Method: Sulodexide was given to 15 patients which were examined for blood fibrinogen, foot tissues saturation with oxygen, microbic contamination of the wound tissue. In addition, ultrasound dopplerography of foot arteries, laser doppler flowmetry were performed.

Platelet monoamine oxidase activity during surgical intervention under condition of hypothermic perfusion.

Platelet and plasma monoamine oxidase activity was determined at early stages of hypothermic perfusion and circulatory arrest. Monoamine oxidase activity decreased more drastically and restored more slowly against the background of deep (14 degrees C) compared to moderate hypothermia (26-29 degrees C). The decrease in platelet monoamine oxidase activity was accompanied by its increase in the plasma, which attests to mechanical (in tubes) and toxic damage to platelets.

[The effect of the perfusion parameters on the functional characteristics of the thrombocytes].

Platelet and plasma monoamine oxidase (MAO) activity was evaluated in two groups of patients at different stages of surgery (before perfusion, at the depth of cooling, height of warming, and 1 h and 24 h after perfusion). Group 1 consisted of 26 patients with acquired heart diseases operated on under artificial circulation and hypothermia (26-29 degrees C), group 2 consisted of 13 patients subjected to reconstructive operations on the aorta under artificial circulation with deep hypothermia (14 degrees C) and circulatory arrest for 50 min. The activity of platelet MAO was decreased in group 1 (by more than 50% during cooling and by 68% during warming and 1 h after perfusion); 24 h after surgery MAO activity increased, but did not reach the initial value.

[Study of pathogenetic mechanisms of intoxication in patients with anaerobic non-clostridial infection].

Pyoinflammatory diseases continue to be one of the most topical problem of modern medicine. Anaerobic non-clostridial infection is essential in the etiological pattern of pyoinflammatory diseases. Its specific feature is early developed severe intoxication.

Ultrastructural localization of HIV-1 RNA and core proteins. Simultaneous visualization using double immunogold labelling after in situ hybridization and immunocytochemistry.

The analysis of human immunodeficiency virus type 1 (HIV-1) RNA sequences in CEM and Jurkat lymphoid cells infected with the virus has been performed at the subcellular level. Using a biotinylated DNA probe specific for HIV-1, virus RNA sequences were detected on Lowicryl thin sections after immunogold cytochemistry. The labelling observed on the cytoplasm was localized near the plasma membrane connected with extracellular cluster of virions.

[Characteristics of vascular changes and hemostatic reaction of the body in nonspecific aorto-arteritis].

Laboratory criteria to differentiate diagnostically nonspecific aorto-arteritis with other forms of obliterating arterial diseases have been established by hemostatic, morphological and cytological investigations. Factors of plasmic hemostasis and platelet functional activity are able to indicate etiological cause of aortal lesion in noninvasive clinical examination. Identification of platelet--forming reaction type shows that nonspecific aorto--arteritis is characterized by "red" platelet formation and fibrinization of the body.

[Thrombocytic diseases in generalized myasthenia gravis and their correction by using plasmapheresis and administration of anti- immunoglobulin antisera].

Platelet adhesion and aggregation studies were performed in different test systems in 25 patients with plasmapheresis-treated myasthenia patients. In vivo studies with plasmapheresis and in vitro investigation with anti-immunoglobulin antisera revealed the normalization of the impaired platelet functions.

[Inhibition of platelet aggregation by dinitrosyl iron complexes with low molecular weight ligands].

The dinitrosyl iron complexes (DNIC) with thiosulphate, cysteine or phosphate were shown to inhibit in vitro (in citrate plasma) the human platelet aggregation induced by ADP, collagen or adrenaline. This effect cannot be explained by the toxic action of DNIC on the platelet membrane, since DNIC-pretreated platelets are capable of aggregating under the action of 10(-8) M/ml of phorbol ester, which is known to cause direct activation of protein kinase C. The antiaggregatory activity of DNIC exceeds that of Na-nitroprusside and seems to be due to nitric oxide capable to activate guanylate cyclase of platelets.

[State of tissue-vascular permeability in diabetic patients with parodontosis].

The state of the parodontium was studied clinically and morphologically in 70 patients suffering from diabetes mellitus. Blood histamine and serotonin level was determined fluorometrically. Gingivitis was revealed in diabetic patients; the severity of inflammatory changes in the gingiva proved to depend on the duration and the severity of diabetes mellitus.