The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia.

CXCR4(WHIM) somatic mutations are common Waldenstrom's Macroglobulinemia (WM), and are associated with clinical resistance to ibrutinib. We engineered WM cells to express the most common WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis), CXCR(S338X) mutation in WM. Following SDF-1a stimulation, CXCR4(S338X) WM cells exhibited decreased receptor internalization, enhanced and sustained AKT kinase (AKT) and extracellular regulated kinase (ERK) signaling, decreased poly (ADP-ribose) polymerase and caspase 3 cleavage, and decreased Annexin V staining versus CXCR4 wild-type (WT) cells. CXCR4(S338X)-related signaling and survival effects were blocked by the CXCR4 inhibitor AMD3100. SDF-1a-treated CXCR4(S338X) WM cells showed sustained AKT and ERK activation and decreased apoptotic changes versus CXCR4(WT) cells following ibrutinib treatment, findings which were also reversed by AMD3100. AKT or ERK antagonists restored ibrutinib-triggered apoptotic changes in SDF-1a-treated CXCR4(S338X) WM cells demonstrating their role in SDF-1a-mediated ibrutinib resistance. Enhanced bone marrow pAKT staining was also evident in CXCR4(WHIM) versus CXCR4(WT) WM patients, and remained active despite ibrutinib therapy in CXCR4(WHIM) patients. Last, CXCR4(S338X) WM cells showed varying levels of resistance to other WM relevant therapeutics, including bendamustine, fludarabine, bortezomib and idelalisib in the presence of SDF-1a. These studies demonstrate a functional role for CXCR4(WHIM) mutations, and provide a framework for investigation of CXCR4 inhibitors in WM.

Detection of MYD88 L265P in peripheral blood of patients with Waldenström's Macroglobulinemia and IgM monoclonal gammopathy of undetermined significance.

MYD88 L265P is highly prevalent in Waldenstrom's Macroglobulinemia (WM) and IgM monoclonal gammopathy of unknown significance (MGUS). We investigated whether MYD88 L265P could be identified by peripheral blood (PB) allele-specific PCR. MYD88 L265P was detected in untreated WM (114/118; 96.6%); previously treated WM (63/102; 61.8%); and IgM MGUS (5/12; 41.7%) but in none of 3 hyper-IgM or 40 healthy individuals. Median PB MYD88 L265P ΔCt was 3.77, 7.24, 10.89, 12.33 and 14.07 for untreated WM, previously treated WM, IgM MGUS, hyper-IgM and healthy individuals, respectively (P<0.0001). For the 232 IgM MGUS and WM patients, PB MYD88 L265P ΔCt moderately correlated to bone marrow (BM) disease (r=-0.3553; P<0.0001), serum IgM (r=-0.3262; P<0.0001) and hemoglobin (r=0.3005; P<0.0001) levels. PB MYD88 L265P ΔCt and serum IgM correlated similarly with BM disease burden. For positive patients, PB MYD88 L265P ΔCt was <6.5 in 100/114 (88%) untreated WM, and >6.5 in 4/5 (80%) IgM MGUS patients (P=0.0034). Attainment of a negative PB MYD88 L265P mutation status was associated with lower BM disease (P=0.001), serum IgM (P=0.019) and higher hemoglobin (P=0.004) levels in treated patients. These studies show the feasibility for detecting MYD88 L265P by PB examination, and the potential for PB MYD88 L265P ΔCt use in the diagnosis and management of WM patients.

Characterization of familial Waldenstrom's macroglobulinemia.

BACKGROUND: Familial clustering of B-cell disorders among Waldenström's macroglobulinemia (WM) patients has been reported, though the frequency and any differences in disease manifestation for familial patients remain to be defined. PATIENTS AND METHODS: We therefore analyzed clinicopathological data from 257 consecutive and unrelated WM patients. Forty-eight (18.7%) patients had at least one first-degree relative with either WM (n = 13, 5.1%), or another B-cell disorder including non-Hodgkin's lymphoma (n = 9, 3.5%), myeloma (n = 8, 3.1%), chronic lymphocytic leukemia (n = 7, 2.7%), monoclonal gammopathy of unknown significance (n = 5, 1.9%), acute lymphocytic leukemia (n = 3, 1.2%) and Hodgkin's disease (n = 3, 1.2%). Patients with a familial history of WM or a plasma cell disorder (PCD) were diagnosed at a younger age and with greater bone marrow involvement. RESULTS: Deletions in 6q represented the only recurrent structural chromosomal abnormality and were found in 13% of patients, all non-familial cases. Interphase FISH analysis demonstrated deletions in 6q21-22.1 in nearly half of patients, irrespective of familial background. CONCLUSIONS: The above results suggest a high degree of clustering for B-cell disorders among first-degree relatives of patients with WM, along with distinct clinical features at presentation based on familial disease cluster patterns. Genomic studies to delineate genetic predisposition to WM are underway.

Screening for cognitive impairment and dementia in the elderly.

OBJECTIVE: To review the evidence available to support or refute the recommendation to screen for cognitive impairment (cognitive deficits which do not affect daily function) and dementia in primary care. DATA SOURCES: Medline search using terms listed at the end of this article; consultation with experts in the field; review of other published recommendations. STUDY SELECTION: There were no articles which described a randomized controlled trial of screening versus no screening. Studies were therefore chosen which aided in the definition; natural history; interventions and outcomes including possible negative effects. DATA SYNTHESIS: No systematic synthesis was performed. Background papers were circulated to a panel of experts prior to the Canadian Consensus Conference on Dementia and conclusions endorsed by consensus. CONCLUSIONS: 1. There is insufficient evidence to recommend for or against screening for cognitive impairment or dementia. (C); 2. Memory complaints should be evaluated and the individual followed to assess progression. (B); 3. When caregivers or informants describe cognitive decline in an individual, these observations should be taken very seriously; cognitive assessment and careful follow-up are indicated. (A) (See Appendix).

Infective discitis as an uncommon but important cause of back pain in older people.

CASE REPORTS: two elderly patients (aged 70 and 80 years) presented with severe back pain and restriction of spinal movements. Inflammatory markers were raised and in each case computed tomography findings confirmed infective discitis. One patient improved with antibiotics but the second developed paraplegia, a recognized complication of discitis. CONCLUSION: the association of back pain, restricted spinal movements and raised inflammatory markers should act as 'red flags', alerting the clinician to the presence of serious, but potentially treatable pathology.

The recognition, assessment and management of dementing disorders: conclusions from the Canadian Consensus Conference on Dementia.

OBJECTIVE: To develop evidence based consensus statements on which to build clinical practice guidelines for primary care physicians toward the recognition, assessment and management of dementing disorders and to disseminate and evaluate the impact of these statements and guidelines built on these statements. OPTIONS: Structured approach to assessment, including recommended laboratory tests, choices for neuroimaging and referral, management of complications (especially behavioural problems and depression) and use of cognitive enhancing agents. POTENTIAL OUTCOMES: Consistent and improved clinical care of persons with dementia; cost containment by more selective use of laboratory investigations; neuroimaging and referrals; and appropriate use of cognitive enhancing agents. EVIDENCE: Authors of each background paper were entrusted to perform a literature search, discover additional relevant material, including references cited in retrieved articles, consult with other experts in the field and then synthesize information. Standard rules of evidence were applied. Based on this evidence, consensus statements were developed by a group of experts, guided by a steering committee of 8 individuals, from the areas of Neurology, Geriatric Medicine, Psychiatry, Family Medicine, Preventive Health Care and Health Care Systems. VALUES: Recommendations have been developed with particular attention to the context of primary care, and are intended to support family physicians in their ongoing assessment and care of patients with dementia. BENEFITS HARM AND COSTS: Potential for improved clinical care of people with dementia. A dissemination and evaluation strategy will attempt to measure the impact of the recommendations. RECOMMENDATIONS: Forty-eight recommendations are offered that address the following aspects of dementia care: early recognition; importance of careful history and examination in making a positive diagnosis; essential laboratory tests; rules for neuroimaging and referral; disclosure of diagnosis; importance of monitoring and providing support to caregivers; cultural aspects; detection and treatment of depression; observation and management of behavioural disturbances; detection and reporting of unsafe motor vehicle driving; genetic factors and opportunities for preventing dementia; pharmacological treatment with particular emphasis on cognitive enhancing agents. VALIDATION: Four other sets of consensus statement or guidelines have been published recently. These recommendations are generally congruent with our own consensus statements. The consensus statements have been endorsed by relevant bodies in Canada.

Retrospective study of radiotherapy for lung cancer in patients aged 75 years and over.

BACKGROUND: Radiotherapy is widely used in the management of lung cancer but there are few data on its use in elderly patients. METHODS: Retrospective review of case notes of all patients aged 75 years and over referred to a regional centre for radiotherapy with a diagnosis of lung cancer over 1 year. RESULTS: Of 149 patients referred, full information was available on 144 (97%); age range 75-93 years (mean 79). Main referral sources were chest physicians [68 (44%)], general physicians [40 (28%)] and geriatricians [20 (14%)]; all patients were accepted for radiotherapy. One hundred and thirty-four (93%) had palliative treatment with most [129 (90%)] receiving 1-5 fractions over 1 week and 117 (81%) having treatment as an outpatient. Palliation appeared good for haemoptysis but less effective for the more common symptoms of dyspnoea and cough. Side effects were reported by 25 patients (18%) and were usually mild. CONCLUSION: Radiotherapy for lung cancer in this selected group of elderly patients is well tolerated with responses similar to those in younger patients.

A continuing medical education strategy for care of the elderly by the surgical specialties.

As the absolute numbers and percentage of older people rises in Canada, surgeons are required to treat an increasing number of elderly patients. Recognizing the need to enhance the quality of health care for these people by continuing medical education of health care professionals, the Canadian Medical Association sponsored an invitational workshop in May 1992. The workshop group addressing surgery and its specialties identified three essential underprinnings: knowledge of the aging process (altered physiology and response to illness); decision analysis for interventions (risks, benefits and ethical dimensions); and communication skills. Three priorities for continuing education were recommended: improving knowledge of the physiologic changes that impact on the recovery of elderly patients from surgery; management of postoperative care; and improved knowledge and skills in prescribing medications for older surgical patients. Strategies to implement these priorities are outlined.

Candy cigarettes: do they encourage children's smoking?

Candy and bubble gum cigarettes are packaged to resemble cigarette brands, and so they may encourage young children to smoke. Two studies of the role of these products in the development of children's attitudes and behaviors toward smoking were conducted. In the first study, six focus group interviews were conducted with 25 children in three age groups (4 through 5, 6 through 8, and 9 through 11 years old). Children in each group were shown five candy and snack foods and asked about their opinions and experiences with each item. In the second study, 195 seventh-grade students in a southeastern city school system were surveyed about their cigarette smoking and candy cigarette use. In the focus groups, candy cigarettes were recognized by most children. Young children played with the candy cigarettes more than with other candy or snack items and made general references to smoking behaviors. Older children made favorable references to smoking behavior; most knew which stores sold candy cigarettes, and many had chosen to buy and use these items, despite parental disapproval. Candy cigarettes may play a role in the development of children's attitudes toward smoking as an acceptable, favorable, or normative behavior. Elimination of these products should be part of efforts to prevent initiation of smoking by children.

Selection and use of posterior composites in general dental practice.

This study investigated, by means of a directly mailed postal questionnaire to each of the general dental practitioners in a Scottish Health Board area, the use of posterior composites by general dental practitioners and the factors affecting their selection and introduction of these materials into their practices. Three non-restorative practitioners (two-Orthodontics, one-Oral Surgery) were excluded from the study giving a total of 156. Although a relatively small study, a 60 per cent response rate was increased to 70 per cent after telephone follow up. Of the 109 respondents, 30 per cent offered NHS (National Health Service) treatment exclusively and 70 per cent had mixed NHS/private practices. 77 per cent of the respondents claimed to use posterior composites but 7 per cent of those were using anterior composite materials for posterior restorations. 90 per cent of those claiming to use posterior composites placed fewer than five posterior composite restorations per week. In an area with a high proportion of exclusively private practices findings may have differed.

Accidental self-inoculation with Mycobacterium paratuberculosis bacterin (Johne's bacterin) by veterinarians in Wisconsin.

We surveyed Wisconsin veterinarians to assess the frequency and severity of accidental self- and other human exposure to Mycobacterium paratuberculosis bacterin (Johne's bacterin). Of 199 veterinarians administering the bacterin to cattle, 22 reported one or more exposures, including 19 needle-stick exposures, 8 skin surface exposures, and 2 oral mucosa exposures. The mean incidence of needle sticks was 5.5/100 veterinarians/year of bacterin use or 1/1,000 doses administered. The mean total doses given in the needle-stick exposure group was 276 +/- 318 vs 80 +/- 268 in the group without needle-stick exposure, and the mean number of months administering the bacterin was 21.7 and 16.1, respectively; 63% of needle-stick exposures took place during the injection process. Five adverse reactions were reported, and each resulted from needle-stick exposure. The only systemic reaction followed an exposure to the original bacterin formulation of sonically ruptured M paratuberculosis in Freund incomplete adjuvant. The remaining reactions were to the current formulation of whole killed M paratuberculosis in mineral oil and ranged from a small nodule persisting for 4 to 6 months to painful inflammation of a finger persisting for 24 months. We anticipate an increase in incidence of these minimally debilitating injuries as the use and distribution of the bacterin expands. For hand wounds, we recommend conservative management. Surgical intervention should be considered if a granuloma persists and causes the patient functional difficulty.