Rectal Visceral Sensitivity in Women with Irritable Bowel Syndrome without Psychiatric Comorbidity Compared with Healthy Volunteers

Background. Psychiatric comorbidity and visceral hypersensitivity are common in patients with irritable bowel syndrome (IBS), but little is known about visceral sensitivity in IBS patients without psychiatric disorders. Aim. We wanted to examine rectal visceral sensitivity in IBS patients without comorbid psychiatric disorders, IBS patients with phobic anxiety and healthy volunteers. Methods. A total of thirty-eight female, non-constipated IBS patients without psychiatric disorders and eleven female IBS patients with phobic anxiety were compared to nine healthy women using a barostat double random staircase method. The non-psychiatric patients were divided into those with diarrhoea predominant symptoms and those with alternating stool habits. Results. The IBS patients without psychiatric disorders had normal visceral pressure thresholds. However, in the diarrhoea predominant subgroup, the volume discomfort threshold was reduced while it was unchanged in those with alternating stool habits. The phobic IBS patients had similar thresholds to the healthy volunteers. The rectal tone was increased in the non-psychiatric IBS patients with diarrhoea predominant symptoms and in the IBS patients with phobic anxiety. Conclusions. Non-constipated IBS patients without psychiatric disorders had increased visceral sensitivity regarding volume thresholds but normal pressure thresholds. Our study suggests that the lowered volume threshold was due to increased rectal tone

Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis

Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P=.002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates.Peer reviewe

A Nationwide Study of GATA2 Deficiency in Norway-the Majority of Patients Have Undergone Allo-HSCT

PurposeGATA2 deficiency is a rare primary immunodeficiency that has become increasingly recognized due to improved molecular diagnostics and clinical awareness. The only cure for GATA2 deficiency is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The inconsistency of genotype-phenotype correlations makes the decision regarding "who and when" to transplant challenging. Despite considerable morbidity and mortality, the reported proportion of patients with GATA2 deficiency that has undergone allo-HSCT is low (~ 35%). The purpose of this study was to explore if detailed clinical, genetic, and bone marrow characteristics could predict end-point outcome, i.e., death and allo-HSCT.MethodsAll medical genetics departments in Norway were contacted to identify GATA2 deficient individuals. Clinical information, genetic variants, treatment, and outcome were subsequently retrieved from the patients' medical records.ResultsBetween 2013 and 2020, we identified 10 index cases or probands, four additional symptomatic patients, and no asymptomatic patients with germline GATA2 variants. These patients had a diverse clinical phenotype dominated by cytopenia (13/14), myeloid neoplasia (10/14), warts (8/14), and hearing loss (7/14). No valid genotype-phenotype correlations were found in our data set, and the phenotypes varied also within families. We found that 11/14 patients (79%), with known GATA2 deficiency, had already undergone allo-HSCT. In addition, one patient is awaiting allo-HSCT. The indications to perform allo-HSCT were myeloid neoplasia, disseminated viral infection, severe obliterating bronchiolitis, and/or HPV-associated in situ carcinoma. Two patients died, 8 months and 7 years after allo-HSCT, respectively.ConclusionOur main conclusion is that the majority of patients with symptomatic GATA2 deficiency will need allo-HSCT, and a close surveillance of these patients is important to find the "optimal window" for allo-HSCT. We advocate a more offensive approach to allo-HSCT than previously described

Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis

Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P=.002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates

Rectal visceral sensitivity and autonomic function in female patients with irritable bowel syndrome (IBS)

Irritable bowel syndrome (IBS) is a common functional disorder characterised by chronic recurring abdominal pain. Female patients with IBS were recruited from newspaper advertisements and from general practitioners and compared to healthy women. Fifty-two IBS patients and 25 healthy controls constituted a pool of participants, and they were the basis for the clinical studies performed in this thesis in gastroenterology. The exact pathophysiology of IBS is still unknown. Probably it is caused from an interaction of both biological and psychosocial factors, and it is assumed that different pathogenetic factors may be involved in different subgroups of IBS. This study was conducted to see if altered function in the brain-gut axis characterized a population of IBS patients mainly without psychiatric comorbid disorders. The main focus was on rectal visceral sensitivity examined with a barostat, but autonomic and cerebral functions were also explored. Parasympathetic controlled respiratory sinus arrhythmia (RSA) and sympathetic controlled skin conductance were used as indexes of autonomic functions. Cerebral function was measured with event-related potentials (ERP). Our results demonstrated that the reproducibility of visceral sensitivity testing in the rectum using the barostat method may be applicable when comparing groups of subjects. The IBS patients had normal visceral sensitivity with regard to pressure thresholds, but the volume at the discomfort threshold was lowered compared to healthy controls. Our study suggested that the lowered volume threshold was due to increased rectal tone. Further, our findings support the increasing evidence of autonomic dysfunction in IBS patients. A subgroup of the IBS patients with phobic anxiety had decreased rectal gas sensitivity in addition to altered brain processing compared to IBS patients without psychiatric comorbidity, suggesting that comorbid phobic anxiety interferes with the cerebral processing of visceral information

Rare MLL-ELL fusion transcripts in childhood acute myeloid leukemia—association with young age and myeloid sarcomas?

Background The chromosomal translocation t(11;19)(q23;p13) with a breakpoint within subband 19p13.1 is found mainly in acute myeloid leukemia (AML) and results in the MLL-ELL fusion gene. Variations in the structure of MLL-ELL seem to influence the leukemogenic potency of the fusion in vivo and may lie behind differences in clinical features. The number of cases reported so far is very limited and the addition of more information about MLL-ELL variants is essential if the possible clinical significance of rare fusions is to be determined. Case presentation Cytogenetic and molecular genetic analyses were done on the bone marrow cells of a 20-month-old boy with an unusual form of myelomonocytic AML with multiple myeloid sarcomas infiltrating bone and soft tissues. The G-banding analysis together with FISH yielded the karyotype 47,XY, +6,t(8;19;11)(q24;p13;q23). FISH analysis also demonstrated that MLL was split. RNA-sequencing showed that the translocation had generated an MLL-ELL chimera in which exon 9 of MLL (nt 4241 in sequence with accession number NM_005933.3) was fused to exon 6 of ELL (nt 817 in sequence with accession number NM_006532.3). RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcript. Conclusions Based on our findings and information on a few previously reported patients, we speculate that young age, myelomonoblastic AML, and the presence of extramedullary disease may be typical of children with rare MLL-ELL fusion transcripts

Molecular Genetic Characterization of Acute Myeloid Leukemia With Trisomy 4 as the Sole Chromosome Abnormality

Background/Aim: The aim of the study was to determine the genetic and molecular consequences of trisomy 4, a recurrent but rare chromosomal abnormality in acute myeloid leukemia (AML). Materials and Methods: Interphase fluorescence in situ hybridization, reverse transcriptase-quantitative polymerase chain reaction for 28 chromosomal gene translocations/fusion genes, and targeted sequencing analyses were performed on five AMLs with trisomy 4 as the sole chromosomal anomaly. Results: An NPM1 frameshift mutation was found in all leukemic bone marrows, DNMT3A, FLT3, and IDH1 mutations were found in three, KIT and NRAS mutations in two, whereas IDH2 (R140Q), RUNX1, and WT1 mutations were found in only one patient each. The three patients with a DNMT3A (R882H) mutation have died. In contrast, the two patients whose leukemic cells were without this mutation, are alive 55 and 31 months after diagnosis, respectively. Conclusion: The results suggest a possible association between trisomy 4 and additional mutations that may influence prognosis

Neutropenia caused by hairy cell leukemia in a patient with myelofibrosis secondary to polycythemia vera: a case report

Background Polycythemia vera is a myeloproliferative disease that sometimes evolves to myelofibrosis, causing splenomegaly and neutropenia. In this case report, we describe a patient with polycythemia vera and unexplained neutropenia who later turned out to also have hairy cell leukemia. Case presentation A middle-aged Caucasian man with polycythemia vera presented to our hospital with chronic mouth ulcers. Later he developed leukopenia and pancytopenia. Bone marrow biopsies showed fibrosis. Further morphological analyses of bone marrow and blood smears revealed probable transformation into acute myeloid leukemia. However, there were also cells indicating hairy cell leukemia. Morphological and immunohistochemical analyses later confirmed the presence of hairy cell leukemia in biopsies that had been present for 3 years. Treatment with cladribine temporarily reversed the patient’s neutropenia. Conclusions Hairy cell leukemia may mimic development to myelofibrosis in patients with polycythemia vera