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Evolving treatment strategies for myeloma.

In this article, we will discuss how treatment strategies for myeloma have evolved and outline the challenges now faced following the introduction of a number of novel active agents. In particular, we will focus on how achieving a maximum response and maintaining such responses is becoming a key therapeutic strategy and how novel agents can be used to achieve this in the context of current strategies such as autologous transplantation.

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… The study of multistep models of cancer progression has suggested that in addition to genetic changes such as translocation and loss of heterozygosity, heritable epigenetic effects such as methylation of CpG islands and modulation of chromatin structure via acetylation of histone tails can lead to loss …

Keyword Index for Volume 88

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Increased Indoleamine 2, 3-Dioxygenase expression modulates Th1/Th17/Th22 and Treg pathway in humans with Helicobacter Pylori-Infected gastric mucosa.

Introduction and purposeIndoleamine 2, 3- dioxygenase (IDO) plays an importantrole in immunosuppressive pathway, as inhibits responsesof T cells and promotes immune tolerance. Host responsetoHelicobacter pylori (H. pylori) is involved in the infection persistenceand it is also associatedwith different clinical outcomes. The aim of this study was to investigate the role of IDO in H. pylori-infected patients with gastritis diseases and peptic ulcer diseases (PUD) through the assessment of the relationship among IDO protein expression and the numbers of T helper (Th)-1, Th17, Th22, and T regulato

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… Here we present an interesting case involving loss of heterozygosity (LOH) at the HLA-A locus. … Analysis of the copy numbers present at the HLA-A locus revealed a copy number of 1.2 when normalized with the full sequencing run, consistent with allele drop out or loss of heterozygosity (LOH). …

High frequency and unique subtypes of meningioma in patients with BAP1 tumor predisposition syndrome.

PURPOSE: BAP1-tumor predisposition syndrome (BAP1-TPDS) is associated with four main cancers: uveal melanoma, cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma. However, additional cancers are found more rarely in BAP1-TPDS patients. The aim of this study was to investigate the association, clinical, and pathologic characteristics of meningioma in BAP1-TPDS. METHODS: We conducted a retrospective chart review of meningiomas in two independent cohorts of patients with germline BAP1 pathogenic or likely pathogenic (P/LP) variants at The Ohio State University Wexner Medical Cent

Cytogenetic Abnormalities in Myelodysplastic Syndromes: An Overview.

Karyotype is one of the main constituents of the International Prognostic Scoring System (IPSS) and revised-IPSS that are the cornerstones for the prognostication of patients with myelodysplastic syndromes (MDS). Del(5q), -7/del(7q), +8 and -Y are among the most extensively studied cytogenetic abnormalities in MDS. The same applies for normal karyotype. There are hundreds of other rare cytogenetic abnormalities that have been reported in MDS, included but not limited to -X, 3q abnormalities, +13/del(13q), i(17q), +21/-21. However, due to a very low number of patients, their impact on the progn

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… Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. …

The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets.

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs

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… IGF2R loss of heterozygosity coupled with intragenic loss-of-function mutations in the remaining allele is a common event in hepatocarcinogenesis [ 138 , 139 ]. …

Causes, clinical findings and therapeutic options in chylomicronemia syndrome, a special form of hypertriglyceridemia.

The prevalence of hypertriglyceridemia has been increasing worldwide. Attention is drawn to the fact that the frequency of a special hypertriglyceridemia entity, named chylomicronemia syndrome, is variable among its different forms. The monogenic form, termed familial chylomicronemia syndrome, is rare, occuring in 1 in every 1 million persons. On the other hand, the prevalence of the polygenic form of chylomicronemia syndrome is around 1:600. On the basis of the genetical alterations, other factors, such as obesity, alcohol consumption, uncontrolled diabetes mellitus and certain drugs may sign

Diagnostic sequencing identifies high-risk markers and mechanisms of resistance to guide immunotherapy selection.

AbstractHere, we present the case for next-generation sequencing of samples from patients with multiple myeloma (MM), not only identify high-risk markers but also mutations and deletions relating to immunomodulatory drugs (IMiD), and more importantly to guide the sequencing of immunotherapy regimens in response to intrinsic antigen escape as a means of treatment resistance and relapse. This is a single-center study of CD138+ selected (n = 134) bone marrow aspirate samples from patients with smoldering MM (n = 11) and MM (newly diagnosed, n = 38; relapsed, n = 79). Samples were sequenced using

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… Given the purity of the sample (estimated at 71%) and the same allelic imbalance in single nucleotide polymorphisms elsewhere on 16p, we assume copy number neutral loss of heterozygosity for the mutated copy of TNFRSF17 . …

Tales from the Jazz ASH: highlights from the 2013 American Society of Haematology meeting.

The 55th annual ASH meeting was held in pleasant New Orleans and was the largest in its history, with 22,495 participants coming from 113 nations. A 'bench-to-bedside and back' attitude characterises haematology probably more than any other discipline in medicine and, as usual, this was reflected in the extremely wide breadth of the topics covered, including the last results from clinical trials and cutting-edge advancements in basic science. This year, the balance was arguably skewed: few truly clinical practice-changing results were presented. On the other hand, a great number of basic and t

A Review of the Regulatory Challenges of Personalized Medicine.

Personalized medicine integrates genomics with clinical and familial histories, revolutionizing healthcare by tailoring treatments to individual patient characteristics. At its core, pharmacogenomics enables the customization of medication prescriptions based on genetic profiles, enhancing drug efficacy and safety. This precision medicine approach addresses disease diagnosis, prevention, and treatment, offering targeted therapies for conditions like autoimmune disorders, rheumatoid arthritis, and neoplastic conditions. Examples of pharmacogenomics and personalized medicine include treatment fo

PARP Inhibitors and Haematological Malignancies-Friend or Foe?

Since their introduction several years ago, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have become the standard of care for breast and gynaecological cancers with BRCA gene mutations. Given that PARPi act by exploiting defective DNA repair mechanisms within tumour cells, they should be ideally suited to combatting haematological malignancies where these pathways are notoriously defective, even though BRCA mutations are rare. To date, despite promising results in vitro, few clinical trials in humans for haematological malignancies have been performed, and additional investigation is

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… Additionally, global HRR defect loss of heterozygosity (HRD-LOH) is associated with impaired outcomes in MM patients. Genome-wide HRD-LOH increases as the disease progresses, and also with higher risk groups [ 141 ]. …

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities.

Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymera

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… For example, tumors with BRCA1/2 mutations were associated with loss of heterozygosity (LOH), large genomic deletions, large-scale transitions (LST), and telomeric allelic imbalance (TAI) [ 170 , 171 , 172 , 173 , 174 ], while microsatellite instability (MSI) is characteristic of MMR deficiency [ 175 … Loss of heterozygosity on chromosome 13q12-q14, BRCA-2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumors. Cancer. 2001;92:787–795. doi: 10.1002/1097-0142(20010815)92:4<787::AID-CNCR1384>3.0.CO;2-4. 56. Zhang L., Long X. …

Inhibition of Cxcr4 chemokine receptor signaling improves habituation learning in a zebrafish model of neurofibromatosis.

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder caused by loss-of-function mutations in the gene neurofibromin 1 (NF1). NF1 encodes neurofibromin, a multifunctional tumor-suppressing protein that regulates Ras, cAMP and dopamine signaling. NF1 predisposes patients to a wide range of symptoms, including peripheral nerve tumors, brain tumors and cognitive dysfunction. Despite considerable work using animal models to investigate the role of neurofibromin in behavior, translating research into treatment for NF1-associated cognitive dysfunction has not yet been successful. Here, we provid

Abstracts from the ISSAID 2021 Periodic Congress : Virtual. May - Dec 2021

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Not so Fast: Co-Requirements for Sonic Hedgehog Induced Brain Tumorigenesis.

The Sonic hedgehog (Shh) pathway plays an integral role in cellular proliferation during normal brain development and also drives growth in a variety of cancers including brain cancer. Clinical trials of Shh pathway inhibitors for brain tumors have yielded disappointing results, indicating a more nuanced role for Shh signaling. We postulate that Shh signaling does not work alone but requires co-activation of other signaling pathways for tumorigenesis and stem cell maintenance. This review will focus on the interplay between the Shh pathway and these pathways to promote tumor growth in brain tu

Gaucher disease: the hematologist's perspective of a multisystemic disorder.

Gaucher disease (GD) exemplifies how a single genetic mutation can give rise to a complex multisystem disorder with profound hematological implications. Central to its pathophysiology is the lysosomal accumulation of glucosylceramide due to deficient glucocerebrosidase activity, together with abnormal folding and trafficking of the enzyme that induce endoplasmic reticulum stress and cellular dysfunction. These processes disrupt reticuloendothelial homeostasis and interfere with hematopoiesis. As a consequence, macrophage activation and chronic inflammation contribute to the cytopenias, splenom

Bispecific T-cell engagers in childhood B-acute lymphoblastic leukemia.

Immunotherapy has revolutionized treatment for a wide variety of cancers yet its use has been relatively limited in childhood malignancies. With the introduction of bispecific T-cell engagers (BiTE®) and chimeric antigen T-cell receptor technologies, previously refractory patients have attained remission, including molecularly negative states of disease, thus providing the possibility of long-term cure. Blinatumomab is a widely available CD3-CD19 BiTE that has dramatically changed the landscape of therapy for some children with precursor-B acute lymphoblastic leukemias (B-ALL) and lymphoblasti

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… However, unlike observations in the setting of CAR-T-cell-mediated antigen loss, no samples had copy-neutral loss of heterozygosity at this locus. 30 In a retrospective analysis of blinatumomab-treated patients, patients with CD19-negative relapse maintained an identical cytogenetic profile to that at …

Litigations for HIV Related Complications

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Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy.

After several decades without maintained responses or long-term survival of patients with lung cancer, novel therapies have emerged as a hopeful milestone in this research field. The appearance of immunotherapy, especially immune checkpoint inhibitors, has improved both the overall survival and quality of life of patients, many of whom are diagnosed late when classical treatments are ineffective. Despite these unprecedented results, a high percentage of patients do not respond initially to treatment or relapse after a period of response. This is due to resistance mechanisms, which require unde

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… Specifically, it has been observed that clonal neoantigens may be subject to loss of copy number (through HLA-LOH (loss of heterozygosity)) or transcription downregulation (by hypermethylation of the promoter, which occurs in ~23% of neoantigens, or other additional mechanisms) [ 100 ]. … On the other hand, loss of heterozygosity at microsatellites surrounding and intragenic to the PTEN locus occurs in 19% [ 132 ]. …

Значительное сокращение числа пациентов с несколькими миломами с левой венерической венерической глобальной продольной траекторией: экспериментальный анализ случайной осведомленности.

Множественная миелома (ММ) - это злонамеренный вид, связанный с сердечно-сосудистыми осложнениями. Хотя эхокардиография играет ключевую роль в оценке сердечной функции, ее использование для последующей работы с пациентами, страдающими от болезней, носит ограниченный характер. Для этого описательного анализа мы приводим несколько рекомендуемых объективных показателей систолической функции левого желудочка (LV), пиковой глобальной продольной деформации (PGLS) и систолической функции правого желудочка (RV) 147 Пациенты MM на различных этапах лечения были направлены в нашу эхокардиографическую лаб