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Genomic mutations drive the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia. While morphological and clinical features have dominated the classical criteria for diagnosis and classification, incorporation of molecular data can illuminate functional pathobiology. Here we show that unsupervised machine learning can identify functional objective molecular clusters, irrespective of anamnestic clinico-morphological features, despite the complexity of the molecular alterations in myeloid neoplasia. Our approach reflects disease evolution, informed classification, prognostication, and molecular interactions. We apply machine learning methods on 3588 patients with myelodysplastic syndromes and secondary acute myeloid leukemia to identify 14 molecularly distinct clusters. Remarkably, our model shows clinical implications in terms of overall survival and response to treatment even after adjusting to the molecular international prognostic scoring system (IPSS-M). In addition, the model is validated on an external cohort of 412 patients. Our subclassification model is available via a web-based open-access resource ( https://drmz.shinyapps.io/mds_latent ). Myeloid neoplasias can show complex mutation patterns and molecular features. Here, the authors apply machine learning to classify risk groups of myeloid neoplasia which may correlate with differential response to treatment.

Multiple myeloma (MM) is a blood cancer characterized by the accumulation of malignant monoclonal plasma cells in the bone marrow. It develops through a series of premalignant plasma cell dyscrasia stages, most notable of which is the Monoclonal Gammopathy of Undetermined Significance (MGUS). Significant advances have been achieved in uncovering the genomic aberrancies underlying the pathogenesis of MGUS-MM. In this review, we discuss in-depth the genomic evolution of MM and focus on the prognostic implications of the accompanied molecular and cytogenetic aberrations. We also dive into the latest investigatory techniques used for the diagnoses and risk stratification of MM patients.

PHF6 mutations ( PHF6 MT ) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study. Firstly, we show a different pattern of genes correlating with PHF6 MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 are co-mutated with PHF6 . In contrast, female cases reveal co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6 MT . Next, proteomics analysis reveals a direct interaction between PHF6 and RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrate a negative prognostic role of PHF6 MT , especially in association with RUNX1 . The negative effects on survival are additive as PHF6 MT cases with RUNX1 mutations have worse outcomes when compared to cases carrying single mutation or wild-type. PHD finger protein 6 (PHF6) somatic mutations have been identified in blood malignancies. Here, the authors perform genetic analyses of PHF6-mutant myeloid neoplasms which show specific sex-associated genetic correlations and functional collaboration between PHF6 and RUNX1 associated with prognostic value.

The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p  < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p  < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p  = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n  = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n  = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p  = 0.3798) and OS (not reached [NR] vs 27.5 months, p  = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p  < 0.0001) and OS (12.2 vs 27.5, p  = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.

Background TP53 mutations ( TP53 MT ) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis. Methods We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model by identifying an optimal VAF cutoff using a statistically robust strategy of sampling-based regression on survival data to accurately classify the TP53 allelic configuration and assess prognosis more precisely. Results Overall, TP53 MT were found in 1010 patients. Following the traditional criteria, 36% of the cases were classified as single hits, while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53 MT . Interestingly, our method was able to upstage 192 out of 352 (54.5%) traditionally single hit lesions into a probable biallelic category. Such classification was further substantiated by a survival-based model built after re-categorization. Among cases traditionally considered monoallelic, the overall survival of those with probable monoallelic mutations was similar to the one of wild-type patients and was better than that of patients with a biallelic configuration. As a result, patients with certain biallelic hits, regardless of the disease subtype (AML or MDS), had a similar prognosis. Similar results were observed when the model was applied to an external cohort. In addition, single-cell DNA studies unveiled the biallelic nature of previously considered monoallelic cases. Conclusion Our novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation. Key Points Patients with single TP53 mutations and variant allele frequency more than 23% act biologically like biallelic TP53 cases. Traditionally defined single hits might contain subclones with biallelic inactivation, which negatively influences prognosis.

Background Neuroendocrine carcinomas are extremely rare in the esophagus as they represent less than 0.04% of all neuroendocrine tumors. To date, only 14 cases of poorly differentiated, high-grade esophageal NEC have been described in the literature. The majority of these patients presented with typical dysphagia symptoms. Due to its rarity, no standardized guidelines have been proposed to treat esophageal neuroendocrine carcinoma, although general recommendations suggest surgery with adjuvant chemoradiotherapy as the treatment of choice. Case presentation A 67-year-old previously healthy White male presented with a year-long intermittent nonspecific retrosternal discomfort, with the absence of any other symptoms. Esophagogastroduodenoscopy revealed an ulcerative mass in his lower esophagus, with concern of malignancy. Endoscopic ultrasound-guided biopsy revealed poorly differentiated neuroendocrine carcinoma of the esophagus with metastasis to a diaphragmatic lymph node. He was treated with neoadjuvant chemoradiation followed by surgery, and he has been in remission for over 5 years. Conclusion Here, we review the literature and report a unique case of a patient with a vague presentation of esophageal neuroendocrine carcinoma as he enters his sixth year of survival following neoadjuvant chemoradiotherapy.

Most Middle East and North Africa (MENA) countries record pancreatic cancer incidence rates that are above the world's average. Reducing this burden requires evidence-based policies. This bibliometric review aims to examine the status of pancreatic cancer research in the MENA world, while systematically categorising publications across cancer care pathways. We searched Scopus, Medline and PubMed for peer-reviewed publications related to both pancreatic cancer and MENA countries by using controlled vocabulary and keywords. The results were screened for duplicates and later included in the analysis based on preset eligibility criteria. A structured data extraction form was used to collect data related to each article, its methodology, its cancer care pathway, funding status and authorship. A total of 5,848 publications resulted from our search, from which 1,098 articles remained after applying the eligibility criteria. Trends show a steady increase in pancreatic cancer research by MENA. Case reports are the most common, whereas a lack in high-evidence clinical studies as well as public health and epidemiological research was evident. Most studies were not funded and had no female contributions. Funding, if present, came mostly from foreign states. There exists a much greater focus in research on diagnosis and treatment among other cancer care pathways. Most MENA-based studies did not involve collaborations with other countries. Country gross domestic product and population are both correlated to the research output. This bibliometric analysis identified significant gaps and limitations in pancreatic cancer research in MENA countries. Vital domains requiring research investment have also been highlighted as a first step towards evidence-based health policies.

AimThis study aimed to explore the knowledge, attitude, and practice that community pharmacists of Lebanon hold with regard to checking for drug interactions.Subjects and methodsThis cross-sectional study involved data collected from 89 anonymous and self-administered survey questionnaires by community pharmacists from community pharmacies dispersed amongst the six governorates of Lebanon. It also entailed individual interviews with a self-selected few. Knowledge, attitude, and practice with regard to drug interactions were collected.ResultsThere is a large gap in the knowledge of the community pharmacists about drug interactions with other drugs, food, and herbs. When searching for interactions, pharmacists were found to refer mostly to the internet, drug applications, or colleagues. Their attitudes were positive and coherent with understanding their role in clarifying interactions when prescribing drugs; nevertheless, their practices were suboptimal.ConclusionCommunity pharmacists around Lebanon are aware of their role and responsibility concerning drug interactions though only a few do so in their daily work. Suggested interventions include further training and workshops to refresh the memories of these pharmacists on different interactions, and implementing software programs in pharmacies to detect these interactions on the spot.

Background Coronavirus disease 2019 has been a public health threat and a worldwide emergency for more than a year. Unfortunately, many questions concerning the pathophysiology, management, and long-term side effects remain unanswered, and novel aspects of the disease keep on emerging. Of concern to healthcare providers are the recent reported cases of reinfection. Serum coronavirus disease 2019 antibodies have been detected within a few days after onset of the disease. However, it remains unclear whether this immune response is universal, or whether it can lead to latent immunity. Case presentation A previously healthy 27-year-old white man presented with fever, chills, back pain, and other constitutional symptoms, 2 days after being exposed to coronavirus disease 2019 positive patients. His severe acute respiratory syndrome coronavirus 2 polymerase chain reaction was positive, and his symptoms resolved over the next 2 weeks. One month after a confirmatory negative severe acute respiratory syndrome coronavirus 2 polymerase chain reaction, he was found to be ineligible for plasma donation as his anti-severe acute respiratory syndrome coronavirus 2 serology was negative. The patient redeveloped symptoms similar to his first infection 3 weeks after the negative serology test. He and his wife both tested positive via polymerase chain reaction. Their symptoms resolved over the next few days, and they had a negative polymerase chain reaction test 10 days after the positive polymerase chain reaction. Conclusion While studies showed that anti-severe acute respiratory syndrome coronavirus 2 immunoglobulins start to develop early after infection, our healthy young patient’s immune system failed to mount latent immunity against the virus. This left him, especially amid widespread social and medical misconceptions, vulnerable to reinfection by severe acute respiratory syndrome coronavirus 2. Our case disputes the timelines for immune response that were set and supported by research studies. Our case also raises questions regarding prioritizing vaccinating other individuals over those with prior infection.