Little is known about the spectrum or frequency of comorbidities in patients with chronic lymphocytic leukemia (CLL). We investigated the prevalence and prognostic implications of comorbidities in patients with newly diagnosed CLL. Local/non-referred patients with CLL evaluated by a hematologist at Mayo Clinic within 1 year of diagnosis were eligible for this retrospective review. Of 1195 individuals evaluated for newly-diagnosed CLL between 1995 and 2006, 373 (31%) were local/non-referred. At diagnosis, 89% of these patients had one or more comorbidities, and 46% had at least one major comorbidity. Twenty-six percent of patients failed to meet NCI working group guidelines to participate in a clinical trial. On multi-factor analysis, Rai risk category (1.39 per each risk category increase; p < 0.0001) and age (1.056 per year increase; p < 0.0001) were the only factors associated with overall survival. We conclude that, although common, comorbid conditions are less important than age and stage in predicting prognosis in newly diagnosed patients with CLL. Clinical trials evaluating treatments that are designed to be tolerated by patients who do not meet traditional clinical trial eligibility criteria are needed.

These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.

PURPOSE To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma. METHODS After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy. RESULTS Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached. CONCLUSION Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.

This study examines the frequency and duration of pain in same-sex anal intercourse in a sample of 277 adult men who have engaged in, or attempted to engage in, anal intercourse during their lifetime. Whereas estimates of frequency of pain appeared blocked distributed across a 7-point Likert scale, severity of pain appeared positively skewed, with 12% rating it as too painful to continue. Participants rated inadequate lubrication, psychological factors such as not feeling relaxed, and lack of digitoproctic stimulation prior to penetration as the three most important psychophysiological factors predicting pain. Factors associated with a greater amount of pain experienced in anal intercourse were depth and rate of thrusting, lack of social comfort with gay men, being more "closeted," and less concern over becoming old or unattractive as a gay or bisexual man. Pain was also positively related to anxiety. The use of condoms was not rated highly as a factor in receptive anal pain. Based on these findings, the authors define anodyspareunia to denote painful receptive anal intercourse, and suggest clinical criteria similar to that used for other sexual pain disorders.

This large, single-institution, retrospective series with long-term follow-up suggests that IP chromic phosphate P 32 and 5-fluorouracil after maximal surgical resection of PMC of appendiceal origin is associated with improved OS and disease-free survival.

In the presence of BCS, elevated serum Epo levels do not exclude the diagnosis of PV.

No abstract

BACKGROUND: Acquired hemoglobin disorders including α thalassemia (hemoglobin H (HbH) disease) can complicate neoplastic myeloid disorders, especially myelodysplastic syndrome (MDS). Acquired α thalassemia in MDS has recently been linked to mutations in the trans-acting ATRX at Xq13, a gene previously associated with inherited ATR-X (α thalassemia-mental retardation-X linked) syndrome. In the 3 instances where acquired ATRX point mutations predicted to affect splicing have been encountered, mRNA has been unavailable for assessment or unexpressed; in the 3 cases where ATRX splicing changes were described in MDS, the responsible genomic DNA mutation could not be located. Here we report a novel genomic point mutation in an ATRX splice donor motif and define the mutation’s splicing and expression consequences. METHODS AND RESULTS: A 59 year old anemic Swiss man with chronic myelomonocytic leukemia (CMML) and multiple autoimmune complications including granulomatous uveitis, diabetes insipidus, and pleuropericarditis, developed anemia (Hb 10 g/dL) with MCH of 16.7 pg and MCV of 54 fL. We detected 50% HbH-containing cells by supravital staining and 7.5% HbH by weak cation chromatography, confirmed as HbH by isoelectric focusing. Peripheral blood granulocytes, mononuclear cells and bone marrow mononuclear cells were isolated using dual density Ficoll-Hypaque, and DNA and RNA extracted for mutation screening. ATRX coding region (35 exons) and splice site DNA from mononuclear cells was amplified and subjected to denaturing high performance liquid chromatography (DHPLC). A heteroduplex peak was encountered in the amplicon centered on exon 4. Sequencing demonstrated thymidine to cytidine point mutation with high proportional clonality in the canonical GT splice donor motif 3′ to ATRX exon 4 (IVS 4+2 T&gt;C), also detectable in patient granulocytes. Electrophoresis of raw PCR product from the 5′ end of ATRX cDNA demonstrated multiple abnormal bands. Subcloning and sequencing of cDNA demonstrated 2 splicing consequences of this mutation: exon 4 skipping (i.e., exon 3 was spliced directly to exon 5), and a second isoform with intact exons 3, 4, and 5 but retaining 43 base pairs of intron 4 (including the T&gt;C point mutation in the splice donor site), activating a previously unrecognized cryptic splice site. Since exon 4 is 53 base pairs in length, both aberrant splicing consequences result in a frameshift and generation of a premature stop codon in the 5′ end of exon 5. Exon 6 is normally alternatively spliced, and this variation was retained, so there were two subforms of each aberrant spliceoform. Expression of ATRX mRNA in the patient’s monocytes, measured by RT-PCR probing the 3′ helicase domain, was 11.1% of healthy controls; in the granulocytes, expression was 15.3% of normal. CONCLUSION: Pre-mRNA splicing abnormalities such as that described here are increasingly recognized in association with human disease and particularly neoplasia, and may represent a potential therapeutic target. Point mutations in general are sought in myeloid disorders as they can provide proof of clonality in ambiguous cases and allow tracking of clonality with therapy and disease evolution. Germline 5′ ATRX splicing abnormalities are only rarely associated with inherited ATR-X syndrome, presumably because of the devastating consequences on gene expression and fetal development, but may be more common in acquired thalassemia. In future analyses of acquired HbH disease, when seeking ATRX mutations, splicing abnormalities should be routinely considered.