Citations

Abstract Figure Figure Background: An isolated 13q deletion in patients with chronic lymphocytic leukemia (CLL) is the single most common cytogenetic abnormality and is a favorable prognostic parameter (Dohner et al., NEJM3432:1910, 2000). Although 13q- can occur as either a heterozygous (13q-x1) or homozygous (13q-x2) deletion, it is unknown whether these two genetic types differ in their impact on clinical outcome. We previously postulated that 13q-x2 may be a more aggressive anomaly than 13q-x1 (Dewald et al., BJH121:287, 2003) and have undertaken a long-term clinical follow-up of patients with an isolated FISH detectable 13q- to test this hypothesis. Methods: We identified patients diagnosed with CLL between October 1992 to May 2008 and who had 13q deletion as their sole FISH abnormality. FISH was performed within 2 years of diagnosis and prior to treatment in all patients. Patients were sorted into three groups: 13q-x1 only, 13q-x2 only, or mosaic with both 13q-x1 and 13q-x2 cells. We assessed differences in percentage of abnormal cells, demographic characteristics, and clinical outcome among the three groups. Results: We identified 259 patients with isolated 13q deletion. Age ranged from 38 to 90 years (median=61) and included 99 women and 160 men. With respect to Rai stage, 142 patients (60%) had low risk [Rai 0], 81 (34%) intermediate risk [Rai I-II], and 13 (6%) high risk [Rai III-IV] disease. After a median follow-up of 1.9 years, 40 patients (15%) have been treated and 17 (7%) have died. Median TFS and OS for all patients were 6.9 and 9.3 years, respectively. The mean percentage of abnormal nuclei in the three groups was 44%, 53%, and 47% for 13q-x1 only, mosaic 13q-x1/13q-x2, or 13q-x2 only, respectively (p=0.22). No significant difference in age or gender was observed based on whether 13q- occurred as a heterozygous or homozygous deletion, or was mosaic. Likewise, no significant difference in survival (p=0.313, see Table) or time to treatment (p=0.53) was found among the three groups. Five year OS rates for the 13q- x1 only, 13q- x2 only, and mosaic 13q- x1/13q- x2 are 85%, 95%, and 83%, respectively Median time to treatment for 13q-x1 was not reached, and for the mosaic13q-x1/13q-x2 and 13q-x2 groups median time to treatment was 6.9 and 4.9 years, respectively. Conclusions: The presence of deletion in one versus two 13q- chromosomes in CLL patients appears to have no significant impact on treatment free or overall survival. This observation supports the grouping of CLL patients with isolated 13q- of one or both alleles into a single risk category as originally proposed in the risk categorization by Dohner et al. Taking the present findings together with those of Dohner et al and Dewald et al, we propose a hierarchical risk model of FISH abnormalities in CLL as 17p- à 11q- à 6q- à +12 à normal à 13q-, from most to least aggressive. The 13q- group would now include 13q-x1, 13q-x2, and the mosaic subgroups.

Abstract Background: The biology, pathology and clinical course of CD5+ chronic B cell lymphoproliferative disorders (CD5+ B-CLPD) excluding chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) and mantle cell lymphoma (MCL) are poorly defined. These patients could either have a leukemic variant of a known B cell malignancy or a novel disease entity. Objective: To define the clinical features and pathology of CD5+ B-CLPD, compare these features to CLL, and test the hypothesis that at least some of these patients have a unique B cell malignancy. Methods: The study was conducted with Institutional Review Board permission. We studied 231 patients evaluated in the Division of Hematology at Mayo Clinic Rochester between 1996 and 2008 who had CD5+ monoclonal B cell population in the peripheral blood and/or bone marrow, and in whom CLL and MCL was not diagnosed after flow cytometry, histology and interphase fluorescence in situ hybridization (FISH) examinations. Data were abstracted from patient records and from the Mayo Clinic CLL database. Statistical analysis: To compare differences in characteristics between CD5+ and CLL patients, χ2 statistics were used for qualitative variables (gender, treatment, vital status) and t-tests were used for quantitative variables (age). We performed survival and time to treatment analyses with results displayed using Kaplan-Meier curves and p-values calculated using a log-rank test. Results: We analyzed data on 231 CD5+ B-CLPD patients diagnosed between 7/1/1976 and 5/2/2008 and 1572 CLL patients diagnosed in the same time period. Median follow-up from diagnosis was 2.5 years (range 0 to 25.1 years) for the CD5+ patients and 5.2 years (range 0 to 29.9 years) for CLL patients. CD5+ B-CLPD patients had a median age at diagnosis of 68 years (range 30–94 years) with male predominance (61.5%). One hundred and nine of 231 (52.4%) patients received treatment for their CD5+ B-CLPD and 162 (70.1%) patients were alive at the time of last follow-up. As a group, CD5+ B-CLPD patients had a similar male predominance to CLL but were older at diagnosis. CD5+ B-CLPD patients required their first treatment significantly sooner than CLL patients (median 2.0 years vs. 6.8 years, (p< 0.001) and a higher percentage of CD5+ B-CLPD patients required treatment (52.4% vs. 37.5%, p<0.0001). In addition, CD5+ B-CLPD patients had a shorter survival from diagnosis than CLL patients (median 8.4 years vs. 12.5 years, p<0.001). In 60 patients the CD5+ B-CLPD disease was the leukemic phase of a known lymphoma (lymphoplasmacytic lymphoma, n=34; nodal marginal zone lymphoma, n=6; splenic marginal zone lymphoma, n=16; MALT lymphoma, n=4), 46 patients had incomplete data, and 125 patients did not have pathological and flow cytometry features of a known lymphoid malignancy. Next we compared clinical outcome among the 125 patients with unclassifiable CD5+ B-CLPD to the CLL patients. The unclassifiable CD5+B-CLPD patients were older at diagnosis (median 69 vs. 65 years, p=0.0003) but there were no significant differences in time to treatment (median 9.0 years vs. 6.8 years, p=0.93) or the proportion of patients receiving treatment (30% vs. 37.5%, p=0.11). The survival from diagnosis was shorter for unclassifiable CD5+ B-CLPD patients (median 6.3 vs. 12.5 years, p<0.001). Conclusions: In this large series of CD5+ B-CLPD patients we found that a large subset did not meet diagnostic criteria for known B-cell malignancies and could have a novel disease. This will need to be investigated further. We reviewed the pathology of all available archived tissue and intend to examine additional clinical and prognostic information including molecular prognostic markers. Our data provide a clinical rationale for the careful differentiation between patients with CLL and CD5+ B-CLPD.

Neuromuscular dysfunction is common in old age. A hallmark of aging is the aggregation of damaged cytoplasmic structures, especially in post‐mitotic cells like motor neurons. Autophagy flux may be impaired as a result of deficits in the formation of double membrane autophagosomes, the fusion of autophagosomes with lysosomes, or lysosome‐based degradation. Our overarching hypothesis is that autophagy contributes to neuromuscular dysfunction in old age, and that this effect occurs in motor neurons. We evaluated changes in expression levels of core autophagy proteins necessary for the initiation (Beclin1) and elongation (LC3‐I, LC3‐II, ATG7 and ATG5‐ATG12 complex) phases of autophagsome formation, as well as lysosome degradation (assessed by p62 clearance), in adult male and female C57BL/6 mice at 6, 18, and 24 months of age (reflecting 100%, 90% and 75% survival, respectively). Protein expression was analyzed by Western blotting in the cervical spinal cord segments C2–C6. Expression of p62 was reduced in the cervical spinal cord of adult mice at 18 months compared to 24 months, suggesting increased clearance and autophagy flux at 18 months of age. There was no evidence of an effect of age on the expression of the other autophagy markers. In separate animals, immunohistochemical (IHC) analyses of the C2‐C6 segments was used to determine the relative expression of LC3 and p62 in gray and white matter regions. Across all age groups, LC3 and p62 immunoreactivity was evident in the gray matter with minimal expression in the white matter. The ratio of both LC3 and p62 in motor neurons vs. gray matter was compared using a mixed linear model with animal as a random effect. No effect of sex was evident. Increased expression of both LC3 and p62 was evident in choline acetyl transferase (ChAT)‐positive motor neurons (~2–3 fold) compared to the remainder of the gray matter. There was evidence of a difference in relative LC3 and p62 expression in motor neurons across age (F 349,2 =12.5, p<0.001), with a significant increase by 24 months of age (p<0.005). Taken together, these findings suggest that 1) there is an aging effect on autophagy markers in the cervical spinal cord of mice; 2) an increase in autophagy by 18 months of age reflects an increase in autophagosome clearance (reduced p62 expression) not restricted to motor neurons; and, 3) increased motor neuron expression of both LC3 and p62 by 24 months of age reflect autophagsome accumulation and autophagy impairment in motor neurons. These findings are also is in accordance with previous reports suggesting a period of vulnerability between 18 and 24 months of age in mice, where autophagy may play a role in the development of age‐related neuromuscular dysfunction. Support or Funding Information Supported by NIH R01 AG057052.

Objective Cardiovascular adjustments to exercise, including increases in blood pressure (MAP) and heart rate, occur in response to several neural mechanisms. Specifically, stimulation of respiratory (via inspiratory loading (IL)) and locomotor muscle (via subsystolic cuff inflation (CUFF)) neurologic feedback via group III/IV afferents augments the MAP response during exercise. Further, we have recently shown that simultaneous stimulation of the respiratory and locomotor muscle afferents during exercise potentiates the MAP increase compared to when these reflexes are stimulated individually. To date, interventional strategies to attenuate the augmented MAP during IL+CUFF have not been investigated. Previous studies have shown that inspiratory muscle training (IMT) attenuates the IL‐induced increase in MAP at rest in healthy adults. We hypothesized that 8 weeks of IMT will attenuate the IL+CUFF‐induced increase in MAP during exercise in healthy adults. Methods Twenty adults were recruited and randomized to the IMT (n=10) or sham group (n=10). Participants performed 8 weeks of IMT twice a day, 7 days a week at 50% (IMT) or 10% (sham) maximum inspiratory pressure (MIP). On separate visits, participants performed an incremental cycling test to volitional fatigue and a 10 min cycling exercise bout at 40% maximal oxygen uptake Pre‐ and Post‐IMT. The exercise bout consisted of 5 min of spontaneous breathing followed by 5 min of voluntary hyperventilation (i.e. breathing frequency of 40 breaths per min) with IL (30% MIP) and bilateral locomotor subsystolic cuff inflation (80 mmHg). Systolic and diastolic blood pressure (SBP and DBP, respectively) were measured using manual sphygmomanometry and MAP was calculated. SBP and MAP were reported as the change from rest. Dyspnea was measured via Borg scale (1–10). Results After 8 weeks, MIP increased in the IMT (Pre: 99±26 vs. Post: 127±26 cmH 2 O, p<0.05), but not the sham group (Pre: 126±29 vs. Post: 129±28 cmH 2 O, p>0.05). Pre‐IMT, the increase in MAP with IL+CUFF was not different between groups (IMT: 28±6 vs. sham: 31±7 mmHg) (p>0.05). Post‐IMT, the increase in MAP with IL+CUFF was attenuated in IMT, but not sham (IMT: 23±7 vs. sham: 32±5 mmHg) (p<0.05). Pre‐IMT, the increase in SBP with IL+CUFF was not different between groups (IMT: 49±12 vs. sham: 53±16 mmHg) (p>0.05). Post‐IMT, the increase in SBP with IL+CUFF was attenuated in IMT, but not sham (IMT: 42±12 vs. sham: 57±14 mmHg) (both, p<0.05). The increase in DBP with IL+CUFF was not different between groups Pre or Post‐IMT (both, p>0.05). Lastly, dyspnea was not different Pre‐IMT between groups (IMT: 4±3 vs. sham: 4±2 Borg (1–10)) (p>0.05), but was lower in the IMT, but not sham Post‐IMT (IMT: 2±2 vs. sham: 4±1 Borg (1–10)) (p<0.05). Conclusions These data demonstrate that IMT attenuates the MAP response when the respiratory and locomotor afferents are stimulated simultaneously. These findings have important clinical implications for populations that exhibit exaggerated respiratory and locomotor muscle reflexes during exercise. Support or Funding Information This work was supported by the National Institutes of Health [HL126638 to TPO] and American Heart Association [18POST3990251 to JRS].

AbstractDeficient intake of micronutrients involved in one‐carbon metabolism (eg, choline, methionine, vitamin B12 and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under‐investigated in humans. We investigated the association between one‐carbon metabolism‐related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow‐up in the NIH‐AARP study. Dietary intakes and supplement use were ascertained at baseline using a food‐frequency questionnaire. Total intake (diet plus supplements) of the following one‐carbon metabolism‐related micronutrients were calculated: folate, methionine and vitamins B2 (riboflavin), B3 (niacin), B6 and B12. These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16‐year follow‐up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B3 intake was associated with a lower HCC risk (HRQ5 vs Q1 = 0.60; 95% CI = 0.42‐0.85; Ptrend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HRQ5 vs Q1 = 0.32; 95% CI = 0.18‐0.55; Ptrend < .0001). Among participants with >3 years of follow‐up, higher total vitamin B3 intake was again associated with lower risk (HRQ5 vs Q1 = 0.37; 95% CI = 0.20‐0.68; Ptrend = .001), whereas higher total vitamin B6 intake was associated with higher risk (HRQ5 vs Q1 = 2.04; 95% CI = 1.02‐4.07; Ptrend = .04). Restricted cubic spline analyses showed a dose‐response inverse association between total vitamin B3 intake and HCC risk, and dose‐response positive association between total vitamin B6 intake and HCC risk. The study suggests that higher vitamin B3 intake is associated with lower HCC risk, whereas higher vitamin B6 intake is associated with increased risk.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

Summary Chronic pain causes significant suffering, limitation of daily activities and reduced quality of life. Infection from COVID ‐19 is responsible for an ongoing pandemic that causes severe acute respiratory syndrome, leading to systemic complications and death. Led by the World Health Organization, healthcare systems across the world are engaged in limiting the spread of infection. As a result, all elective surgical procedures, outpatient procedures and patient visits, including pain management services, have been postponed or cancelled. This has affected the care of chronic pain patients. Most are elderly with multiple comorbidities, which puts them at risk of COVID ‐19 infection. Important considerations that need to be recognised during this pandemic for chronic pain patients include: ensuring continuity of care and pain medications, especially opioids; use of telemedicine; maintaining biopsychosocial management; use of anti‐inflammatory drugs; use of steroids; and prioritising necessary procedural visits. There are no guidelines to inform physicians and healthcare providers engaged in caring for patients with pain during this period of crisis. We assembled an expert panel of pain physicians, psychologists and researchers from North America and Europe to formulate recommendations to guide practice. As the COVID ‐19 situation continues to evolve rapidly, these recommendations are based on the best available evidence and expert opinion at this present time and may need adapting to local workplace policies.

Reflexes arising from the respiratory and locomotor muscles influence cardiovascular regulation during exercise. However, it is unclear how the respiratory and locomotor muscle reflexes interact when simultaneously stimulated. Herein, we demonstrate that stimulation of the respiratory and locomotor muscle reflexes yielded additive cardiovascular responses during submaximal exercise.