cAMP-dependent protein kinase (PKA) is critical for the expression of some forms of long-term potentiation (LTP) in area CA1 of the mouse hippocampus and for hippocampus-dependent memory. Exposure to spatially enriched environments can modify LTP and improve behavioral memory in rodents, but the molecular bases for the enhanced memory performance seen in enriched animals are undefined. We tested the hypothesis that exposure to a spatially enriched environment may alter the PKA dependence of hippocampal LTP. Hippocampal slices from enriched mice showed enhanced LTP following a single burst of 100-Hz stimulation in the Schaffer collateral pathway of area CA1. In slices from nonenriched mice, this single-burst form of LTP was less robust and was unaffected by Rp-cAMPS, an inhibitor of PKA. In contrast, the enhanced LTP in enriched mice was attenuated by Rp-cAMPS. Enriched slices expressed greater forskolin-induced, cAMP-dependent synaptic facilitation than did slices from nonenriched mice. Enriched mice showed improved memory for contextual fear conditioning, whereas memory for cued fear conditioning was unaffected following enrichment. Our data indicate that exposure of mice to spatial enrichment alters the PKA dependence of LTP and enhances one type of hippocampus-dependent memory. Environmental enrichment can transform the pharmacological profile of hippocampal LTP, possibly by altering the threshold for activity-dependent recruitment of the cAMP-PKA signaling pathway following electrical and chemical stimulation. We suggest that experience-dependent plasticity of the PKA dependence of hippocampal LTP may be important for regulating the efficacy of hippocampus-based memory.

IHC is a reliable screening tool for identification of ALK rearrangement in NSCLC and is antibody dependent. D5F3 (Cell Signaling) and 5A4 (Novocastra) can be used with FISH for identification of IHC-positive cases to reduce screening costs.

Key Points• Induction followed by allotransplantation can achieve long-term disease control in select patients with AML arising from a Ph-MPN.• In this population, transplant should be the goal in patients treated with curative intent, as induction alone provides limited benefit.Leukemic transformation (LT) is a rare but fatal complication of Philadelphia-negative myeloproliferative neoplasms (MPNs) for which optimal treatment strategies are not known. At our center, we have adopted a treatment approach for LT where patients within the transplant age group who have a reasonable fitness level are treated with curative intent and offered induction chemotherapy. Subsequently, those who respond and have a suitable donor are considered for allogeneic hematopoietic cell transplantation (HCT). In this study, we evaluated the clinical outcomes of this treatment approach in 75 patients with LT. The 2-year overall survival (OS) from the time of LT was 15%. A total of 39 patients (52%) were treated with curative intent (induction 6 HCT) and had a 2-y OS of 26% compared with 3% in those noncuratively treated (P < .0001). In the curative intent group, 18 individuals (46%) achieved complete remission (CR) or CR with incomplete recovery and 12 (31%) reverted to a chronic MPN phase, with 17 patients undergoing HCT. Survival of patients posttransplant was significantly improved compared with those who responded to induction but were not transplanted (2-y OS of 47% vs 15%; P 5 .03). Thus, induction chemotherapy followed by HCT has the potential for long-term disease control in select patients with LT preceded by a MPN.

Multicenter standardization study may accelerate the implementation of ALK testing protocols across a country/region. Our data support the use of an appropriately validated IHC assay to screen for ALK+ lung cancers.

Hyalinizing clear cell carcinoma (HCCC) is a rare, low-grade salivary gland tumor with clear cells and hyalinized stroma. Prognosis of HCCC is excellent with few cases metastasizing to the lymph nodes and lung. We present a case of a 61-year-old male with recurrent HCCC on the base of tongue. Histologic examination revealed sheets of clear and eosinophilic cells with a background of a myxoid-like matrix. In addition, large, bizarre malignant cells, focal necrosis, and atypical mitotic figures were identified. By immunohistochemistry, the clear cells were positive for CK18, EMA and vimentin, focally positive for CK7 and CD10, but negative for p63, HMWK, SMA and calponin. A metastatic renal cell carcinoma was considered a possibility but the tumor was called "poorly-differentiated carcinoma, NOS". The patient underwent primary radiotherapy. A recurrence was identified at 10 months follow-up. A biopsy of the recurrent tumor showed clear cell differentiation and a predominant cribriform pattern with focal cords of eosinophilic cells invading the stroma. In contrast to the original tumor, no mitotic figures, atypia or necrosis were identified. The combination of lower grade and different architectural patterns appeared markedly different than the previous biopsy and the immunohistochemical pattern was also different. The recurrent tumor showed diffuse positivity for p63 and HMWK. It was negative for CD10, vimentin, SMA and calponin. Fluorescence in situ hybridization (FISH) analysis was positive for rearrangement of the EWSR1 gene in both samples, confirming that this represented a recurrence of the same tumor. It also confirmed that the initial tumor was a HCCC with high-grade transformation.

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We hypothesize that mechanisms involved in the active suppression of viral antigens may also be involved in the suppression of tumor antigens, and may have resulted in the observed favorable clinical outcome.

PurposeThe purpose of this study was to develop a national program for Canadian diagnostic laboratories to compare DNA-variant interpretations and resolve discordant-variant classifications using the BRCA1 and BRCA2 genes as a case study.MethodsBRCA1 and BRCA2 variant data were uploaded and shared through the Canadian Open Genetics Repository (COGR; http://www.opengenetics.ca). A total of 5,554 variant observations were submitted; classification differences were identified and comparison reports were sent to participating laboratories. Each site had the opportunity to reclassify variants. The data were analyzed before and after the comparison report process to track concordant- or discordant-variant classifications by three different models.ResultsVariant-discordance rates varied by classification model: 38.9% of variants were discordant when using a five-tier model, 26.7% with a three-tier model, and 5.0% with a two-tier model. After the comparison report process, the proportion of discordant variants dropped to 30.7% with the five-tier model, to 14.2% with the three-tier model, and to 0.9% using the two-tier model.ConclusionWe present a Canadian interinstitutional quality improvement program for DNA-variant interpretations. Sharing of variant knowledge by clinical diagnostic laboratories will allow clinicians and patients to make more informed decisions and lead to better patient outcomes.