Outcome of the glutaric aciduria type 1 (GA1) newborn screening program in Manitoba: 1980-2020.

Glutaric aciduria type 1 (GA1) is a severe inherited neurometabolic disorder whose clinical outcome has improved after implementation of newborn screening (NBS) programs and prompt beginning of guideline-directed presymptomatic metabolic treatment. We report the outcome of our 40-year experience with the diagnosis and management of GA1 which has improved but remains suboptimal.

Outcomes for Patients with Residual Stage II/III Breast Cancer Following Neoadjuvant Chemotherapy (AFT-01).

INTRODUCTION: Pathologic complete response (pCR) after neoadjuvant chemotherapy has a demonstrated survival advantage; however, outcomes for non-pCR by receptor status are less understood. We sought to evaluate survival and distant recurrence by receptor status for patients with residual stage II/III breast cancer. METHODS: A stage-stratified random sample of 11,366 patients with stage II-III breast cancer in 2006-2007 was selected from 1217 facilities in the National Cancer Database for a Commission on Cancer Special Study. We identified patients with residual pathologic stage II/III cancer who received standard of care therapy based on receptor status. Distant recurrence and 5-year survival were abstracted and Kaplan-Meier curves were generated by receptor status. Multivariable Cox regression was used to estimate hazard ratios for death and distant recurrence. RESULTS: A total of 734 patients had residual disease; 58%, 28%, and 14% were ER or PR+/Her2neu-, ER and PR-/Her2neu-, and Her2neu+ (any ER/PR), respectively. ER and PR-/Her2neu- cancers had the poorest 5-year overall (52% vs. 82% for Her2neu+ and ER or PR+/Her2neu-, p < 0.0001) and distant recurrence-free survival (57% vs. 72% Her2neu+ and 77% ER or PR+/Her2neu, p < 0.0001). Cox regression models demonstrated a higher likelihood of distant recurrence and death for patients with ER and PR-/Her2neu- disease (HR 2.25, 95% CI 1.56-3.24 and HR 3.19, 95% CI 2.20-4.64 respectively) compared with ER or PR+/Her2neu-. CONCLUSIONS: Patients with residual ER and PR-/Her2neu- cancer have a significant risk of distant recurrence and mortality compared with other breast cancer types, supporting the consideration for additional adjuvant therapy and novel clinical trials in this cohort. Trial registry number ClinicalTrials.gov identifier NCT02171078.

Correction to: Hypophosphatasia: Canadian update on diagnosis and management.

In the article mentioned above an author's name was misspelled.

Hypophosphatasia: Canadian update on diagnosis and management.

Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism caused by loss of function mutations in the ALPL gene. The presentation in children and adults can be extremely variable and natural history is poorly understood particularly in adults. Careful patient evaluation is required with consideration of pharmacologic intervention in individuals meeting criteria for therapy. INTRODUCTION: The purposes of this review are to present current evidence regarding the diagnosis and management of hypophosphatasia in children and adults and provide evidence-based recommendations for management. METHOD: A MEDLINE, EMBASE, and Cochrane database search and literature review was completed. The following consensus recommendations were developed based on the highest level of evidence as well as expert opinion. RESULTS: Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism due to loss of function mutations in the tissue non-specific alkaline phosphatase (ALPL) gene causing reductions in the activity of the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). Deficient levels of alkaline phosphatase result in elevation of inhibitors of mineralization of the skeleton and teeth, principally inorganic pyrophosphate. The impaired skeletal mineralization may result in elevations in serum calcium and phosphate. Clinical features include premature loss of teeth, metatarsal and subtrochanteric fractures as well as fragility fractures. Poor bone healing post fracture has been observed. Myalgias and muscle weakness may also be present. In infancy and childhood, respiratory and neurologic complications can occur. CONCLUSIONS: HPP is associated with significant morbidity and mortality. Pharmacologic intervention can result in significant clinical improvement. This Canadian position paper provides an overview of the musculoskeletal, renal, dental, respiratory, and neurologic manifestations of hypophosphatasia. The current state of the art in the diagnosis and management of hypophosphatasia is presented.

Breast cancer survivor's perspectives on the role different providers play in follow-up care.

IMPORTANCE: Significant variation in the number and types of oncologists that provide breast cancer follow-up exists. However, there is limited understanding regarding breast cancer survivors' preferences for who provides their follow-up. Our objective was to explore breast cancer survivors' perspectives on the goals of breast cancer follow-up, the preferred role for primary care providers, and the perceived roles of different types of oncologists during follow-up. METHODS: A convenience sample of stage 0-III breast cancer survivors was identified and in-depth one-on-one interviews conducted. Data were analyzed using inductive content analysis. RESULTS: Survivors cited a strong preference for oncology-based follow-up within the first 5 years after diagnosis, driven by their need for reassurance that cancer had not recurred. Survivors also thought that their primary care provider needed to be involved. Survivors assumed that oncology follow-up was directed by a standard protocol that included streamlining the follow-up team. Survivors recognized that patients with more complex cancers or challenging treatment courses may require more intensive follow-up and deviate from the standard protocol. Most survivors were comfortable deferring decisions regarding who participated in follow-up to the oncology team. CONCLUSIONS: Most patients think a streamlined approach to oncology-based breast cancer follow-up already occurs, driven by a standard protocol. The use of a standard protocol to provide guidance for which types of oncology providers should participate in breast cancer follow-up will streamline care and represents a significant opportunity to reduce unnecessary variation. This approach is especially critical given patients' strong preferences for oncology-based follow-up.

Successful therapy for protein-losing enteropathy caused by chronic neuronopathic Gaucher disease.

Gaucher disease (OMIM #230800) is caused by ß-glucosidase deficiency and primarily involves the mononuclear phagocyte system (also called Reticuloendothelial System or Macrophage System). The disease is classified into three main phenotypes based on the presence or absence of neurological manifestations: non-neuronopathic (type 1), acute neuronopathic (type 2) and chronic neuronopathic (type 3). Typical manifestations include hepatosplenomegaly, skeletal deformities, hematological abnormalities, interstitial lung fibrosis and neurodegeneration in neuronopathic cases. Mesenteric lymphadenopathy with resultant protein losing enteropathy (PLE) has only been rarely described. Mesenteric lymphadenopathy may lead to intestinal lymphatic obstruction and secondary lymphangiectasia resulting in chronic diarrhea, abdominal pain and weight loss. Fecal protein loss with secondary hypoalbuminemia can be significant. We report a male with Chronic Neuronopathic Gaucher disease (GD) (homozygous for c.1448T > C (NM_000157.3) GBA mutation) who at 16 years of age developed intractable abdominal pain, diarrhea and weight loss. This was caused by PLE secondary to intestinal lymphangiectasia caused by calcified mesenteric lymphadenopathy despite prior long term enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). His older similarly affected sister who had been receiving treatment with ERT and/or SRT remains stable on these treatments with no evidence of mesenteric lymphadenopathy. Medical management with total parenteral nutrition, daily medium chain triglyceride-oil (MCT) supplementation, low dose oral budesonide, continued oral SRT and an increased dose of parenteral ERT has stabilized his condition with resolution of the gastrointestinal symptoms and appropriate weight gain.

A rare case of Niemann-Pick disease type C without neurological involvement in a 66-year-old patient.

UNLABELLED: The case of a 66 year-old female - the oldest known living patient with Niemann-Pick disease type C (NP-C) who remains free of any neurological or psychiatric manifestations 18 years after presentation - is presented. An incidental finding of massive splenomegaly was detected during a routine pelvic ultrasound. The pathology report after splenectomy showed the presence of lipid-laden macrophages. Fibroblasts cultured in LDL-enriched medium revealed abnormal filipin staining consistent with cholesterol-filled vesicles and the rate of cholesterol esterification in response to stimulation of LDL-cholesterol uptake was significantly depressed at 6% of that seen in cells from normal controls, but at a level similar to that observed in an NP-C positive control. Molecular genetic testing later revealed a compound heterozygous mutant NP-C genotype comprising two previously described disease-causing mutations in the NPC1 gene, one in exon 8 (c.1133T>C [V378A]) and one in exon 13 (c.1990G>A [V664M]). These findings confirmed the diagnosis of NP-C. Only three patients with this disorder aged > 53 years have previously been reported, all of whom presented with neurological or neuropsychiatric manifestations. Our patient is the first reported NP-C patient, now in her seventh decade of life, who has to date only manifested splenomegaly. This case highlights the extreme clinical variability of NP-C, and the need to consider this disease in the differential diagnosis of organomegaly, even in the absence of neurological, psychiatric and related clinical signs. SYNOPSIS: An elderly female patient with confirmed NP-C and isolated splenomegaly has remained asymptomatic for neurological, cognitive, psychiatric or ophthalmologic abnormailities into her seventh decade of life.

External validity and reliability of the Psychosocial Assessment Tool (PAT) among Canadian parents of children newly diagnosed with cancer.

BACKGROUND: The Psychosocial Screening Tool (PAT) was developed and validated with a sample of caregivers of children newly diagnosed with cancer in the United States. This study aimed to assess cultural adaptation (Phase 1) and validity and reliability of the revised PAT (PATrev) with a Canadian sample (Phase 2). PROCEDURE: In Phase 1, a convenience sample of seven parents of children who were treated for cancer and six pediatric oncology healthcare experts participated. In Phase 2, 67 parents of children newly diagnosed with cancer from 4 Canadian pediatric cancer centers participated. To assess reliability and validity of the PATrev, parents completed behavioral (BASC-2) and quality of life (PedsQL) instruments about the child and an anxiety inventory (STAI) about themselves. RESULTS: The PAT required minor changes to be culturally adapted for the Canadian population. The PATrev had strong inter-rater (0.77) test-retest (0.75), and internal consistency reliability (0.85), as well as moderate to strong validity comparing PATrev child's problems and PedsQL total (-0.49), PedsQL anxiety (-0.47), BASC-2 internalizing (0.64), behavioral (0.63), and adaptive scores (-0.56). PATrev discriminative validity was confirmed with BASC-2 scores (AUR scores of 0.70-0.74). PATrev parental stressors were strongly correlated to STAI scores (0.53). Finally, agreement between PATrev child's problems and parental anxiety scores was moderate (0.47). CONCLUSION: This study supports the original PAT, demonstrates PATrev is a reliable and valid psychosocial screening tool, and provides unique evidence regarding early psychosocial risk in the family, which have important implications for guiding psychosocial practice.

Does the use of the revised psychosocial assessment tool (PATrev) result in improved quality of life and reduced psychosocial risk in Canadian families with a child newly diagnosed with cancer?

OBJECTIVES: Early psychosocial screening may guide interventions and ameliorate the adverse psychosocial effects of childhood cancer. The revised psychosocial assessment tool provides risk information - Universal (typical distress), Targeted (additional specific distress), and Clinical (severe distress) - about the child with cancer and his or her family. This pilot study investigated the benefits of providing a summary of family psychosocial risk information to the medical team treating the newly diagnosed child (Experimental Group, EG). METHOD: We conducted a pilot randomized control trial with a sample of 67 parents, comparing the EG to the control group (CG) on parental perception of family psychosocial difficulties (revised psychosocial assessment tool risk levels), child behavior (behavior assessment scale for children-2), pediatric quality of life (PedsQL), and parental anxiety (state-anxiety scale of the state-trait anxiety inventory ), 2-4 weeks after diagnosis (Time 1) and 6 months later (Time 2). RESULTS: Compared to the CG, participants in the EG had significantly reduced targeted and clinical risk (p < 0.001), and improved pain related PedsQL at Time 2 (p < 0.05). Scores for PedsQL total and nearly all subscales improved over time in both groups (p < 0.05 to p < 0.001). No changes in behavior scores were noted. CONCLUSION: Preliminary findings suggest that providing a summary of the Psychosocial Assessment Tool to the treating team shortly after diagnosis may help reduce family wide psychosocial risk 6 months later and improve quality of life related to pain for children who are undergoing treatment for cancer.

Retrospective TREC testing of newborns with Severe Combined Immunodeficiency and other primary immunodeficiency diseases.

In Manitoba, Canada, the overall incidence of Severe Combined Immunodeficiency (SCID) is three-fold higher than the national average, with SCID overrepresented in two population groups: Mennonites and First Nations of Northern Cree ancestries. T-cell receptor excision circle (TREC) assay is being used increasingly for neonatal screening for SCID in North America. However, the majority of SCID patients in Manitoba are T-cell-positive. Therefore it is likely that the TREC assay will not identify these infants. The goal of this study was to blindly and retrospectively perform TREC analysis in confirmed SCID patients using archived Guthrie cards. Thirteen SCID patients were tested: 5 T-negative SCID (3 with adenosine deaminase deficiency, 1 with CD3δ deficiency, and 1 unclassified) and 8 T-positive SCID (5 with zeta chain-associated protein kinase (ZAP70) deficiency and 3 with inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKKß) deficiency). As a non-SCID patient group, 5 Primary Immunodeficiency Disease (PID) patients were studied: 1 T-negative PID (cartilage-hair hypoplasia) and 4 T-positive PID (2 common immune deficiency (CID), 1 Wiskott-Aldrich syndrome, and 1 X-linked lymphoproliferative disease). Both patient groups required hematopoietic stem cell transplantation. In addition, randomly-selected de-identified controls (n = 982) were tested. Results: all T-negative SCID and PID had zero TRECs. Low-TRECs were identified in 2 ZAP70 siblings, 1 CID patient as well as 5 preterm, 1 twin, and 4 de-identified controls. Conclusions: TREC method will identify T-negative SCID and T-negative PID. To identify other SCID babies, newborn screening in Manitoba must include supplemental targeted screening for ethnic-specific mutations.

Randomized trial of cisplatin versus firocoxib versus cisplatin/firocoxib in dogs with transitional cell carcinoma of the urinary bladder.

BACKGROUND: Cisplatin combined with a nonselective cyclooxygenase (cox) inhibitor has potent antitumor activity against transitional cell carcinoma (TCC) in dogs, but this treatment is limited by renal toxicosis. Cox-2 is expressed in TCC, but only in limited sites within the kidney. A cox-2 inhibitor could enhance the antitumor activity of cisplatin with potentially fewer adverse effects on the kidney. HYPOTHESIS: Cisplatin/cox-2 inhibitor treatment will have greater antitumor activity but no more renal toxicosis than cisplatin alone in dogs with TCC. ANIMALS: Forty-four dogs with naturally occurring urinary bladder TCC. METHODS: Dogs were randomized to receive cisplatin (60 mg/m(2) IV q21d), firocoxib (5 mg/kg PO q24h), or the combination. Tumor measurements were determined before and at 6-week intervals during treatment. Renal function was monitored by serum creatinine concentration, iohexol clearance, and urine specific gravity. Toxicoses were graded according to Veterinary Co-Operative Oncology Group (VCOG) criteria. RESULTS: The remission rate with cisplatin/firocoxib (57%) was significantly (P = .021) higher than that with cisplatin alone (13%). Renal and gastrointestinal toxicoses were common in dogs receiving cisplatin, but there were no significant differences between dogs receiving cisplatin or cisplatin/firocoxib. Firocoxib alone induced partial remission or stable disease in 20 and 33% of dogs, respectively. CONCLUSIONS: Firocoxib significantly enhanced the antitumor activity of cisplatin resulting in partial remission in more than half of the cases. The toxicoses inherent to cisplatin, however, were noted in dogs receiving this combination. Firocoxib had antitumor effects as a single agent and can be considered a palliative treatment for dogs with TCC.

Results from a search for light-mass dark matter with a p-type point contact germanium detector.

We report on several features in the energy spectrum from an ultralow-noise germanium detector operated deep underground. By implementing a new technique able to reject surface events, a number of cosmogenic peaks can be observed for the first time. We discuss an irreducible excess of bulklike events below 3 keV in ionization energy. These could be caused by unknown backgrounds, but also dark matter interactions consistent with DAMA/LIBRA. It is not yet possible to determine their origin. Improved constraints are placed on a cosmological origin for the DAMA/LIBRA effect.

LC-MS/MS progress in newborn screening.

Newborn screening programs detect treatable disorders in infants before they become symptomatic. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has greatly increased the screening possibilities by monitoring levels of amino acids and acylcarnitines. After the initial screening step, LC-MS/MS can also be used in screening positive samples as a second tier test to differentiate between true and false positive samples. As the list of disorders screened for by LC-tandem MS increases, questions arise about screening for untreatable disorders, such as some lysosomal storage diseases (LSDs). For LSDs screening methods are being developed and tested more quickly than treatments are becoming available. This goes against one of the main tenets of newborn screening which requires that a treatment be available. LC-MS/MS can detect several disorders with a single injection, which is important in high throughput laboratories. Measuring different amino acids and acylcarnitines can be used to detect up to 45 different inherited disorders depending on how diseases are counted. The LSD assays are designed in a similar way to detect multiple disorders with common sample preparation and a single injection. The clinical implications of applying this technology to NBS on a large scale in many jurisdictions across the world are discussed.

Does neoadjuvant bevacizumab increase surgical complications in breast surgery?

BACKGROUND: Neoadjuvant chemotherapy is being increasingly used in operable breast cancer. There are limited data on the safety of bevacizumab (bev) in the neoadjuvant setting. We sought to explore the safety of neoadjuvant cisplatin/bev in a protocol for triple negative breast cancer (TNBC). MATERIALS AND METHODS: A total of 51 patients with confirmed TNBC were enrolled in a single-arm trial of neoadjuvant cisplatin plus bev. Of the 51 patients, 28 with confirmed TNBC were enrolled in our trial of single-agent neoadjuvant cisplatin. Two-sided Fisher exact test were used for comparing the 2 trials. RESULTS: The 51 patients received neoadjuvant protocol therapy with cisplatin/bev and underwent definitive local therapy. Breast conserving therapy (BCT) was performed in 29 (57%) and mastectomy with or without reconstruction in 22 (43%). Postoperative complications were reported in 22 patients (43%); 4 (8%) required explanation of expanders. Also, 28 patients completed neoadjuvant cisplatin therapy. BCT was performed in 13 (46%) and mastectomy with or without reconstruction in 15 (54%). Postoperative complications were reported in 11 patients (39%). None of the 5 reconstructions were lost. We compared all toxicities between the two trials (P = .81 NS), and wound healing related complications between the two trials (P = .10 NS). CONCLUSIONS: Cisplatin/bevacizumab and cisplatin alone neoadjuvant therapy resulted in a significant number of postoperative complications. Specifically, use of expanders/implants may be problematic for patients treated with bev. However, this was a single-arm trial; randomized controlled studies will be needed to determine the optimal use of bevacizumab in the timing of breast cancer surgery.

A novel COMP mutation in an Inuit patient with pseudoachondroplasia and severe short stature.

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia, generally identified clinically at two years of age due to decreased linear growth and a waddling gait. Radiographic features include small and irregular epiphyses, with metaphyseal changes of the long bones and characteristic vertebral changes. Mutations in the COMP gene cause PSACH and some cases of multiple epiphyseal dysplasia. Mutations generally cluster in the calmodulin-like repeat regions of the gene. Mutations in exon 13 (encoding the seventh calmodulin-like repeat) have been associated with severe short stature (-6 SD) in PSACH. We examined an Inuit boy with PSACH and severe short stature. Height essentially remained at -1 SD on the PSACH growth curve (-7.5 SD on a normal growth curve at 10.5 years). Analysis of COMP in our patient revealed a previously undescribed heterozygous A>T substitution in exon 8, at nucleotide 812. This change in the sequence resulted in replacement of a highly conserved and negatively charged aspartic acid with an uncharged, hydrophobic valine at amino acid position 271. Both unaffected parents were negative for this genetic change. This exon encodes the first calmodulin-like repeat, which has not been previously implicated in severe short stature. We propose that this novel missense substitution is responsible for the phenotype of this patient.

Experimental constraints on a dark matter origin for the DAMA annual modulation effect.

A claim for evidence of dark matter interactions in the DAMA experiment has been recently reinforced. We employ a new type of germanium detector to conclusively rule out a standard isothermal galactic halo of weakly interacting massive particles as the explanation for the annual modulation effect leading to the claim. Bounds are similarly imposed on a suggestion that dark pseudoscalars might lead to the effect. We describe the sensitivity to light dark matter particles achievable with our device, in particular, to next-to-minimal supersymmetric model candidates.

Genetic testing of children at risk for adult onset conditions: when is testing indicated?

We report a family with an extensive history of colon cancer consistent with hereditary nonpolyposis colorectal cancer (HNPCC). A specific disease causing mutation was identified in affected individuals; p.W714X MLH1 mutation. Given the very young age of onset of cancer in some affected family members, with the youngest affected individual being 19 years of age, genetic counseling was recommended to children as young as 9 years. Ethical issues arose when affected families requested genetic testing for their underage children. Here we describe and debate the value of offering molecular testing for this adult onset disorder to several children in this particular family. We also examine possible molecular causes for the very young age of onset in some family members.

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) presenting with acute fulminant hepatic failure.

We report on two Aboriginal patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Both presented with acute hepatic failure with severe hypertransaminasemia and coagulopathy, prompting evaluation for emergent liver transplantation. The diagnosis of HHH syndrome was based on the presence of typical metabolic abnormalities. A protein-restricted diet and L-arginine or L-citrulline supplementation were immediately started, with rapid normalization of liver function test results and other biochemical abnormalities. Molecular analysis of the SLC25A15 gene showed that the two patients were homozygous for the common French Canadian mutation (F188Delta). The diagnosis of HHH syndrome should be considered in patients with unexplained fulminant hepatic failure. There does not appear to be a genotype-phenotype correlation for this presentation, inasmuch as the only other reported patient presenting with this picture had two different point mutations. Early identification and prompt treatment of these patients is crucial to avoid liver transplantation and can be life saving.