Family history of cancer and subsequent risk of cancer: A large-scale population-based prospective study in Japan

Family history (FH) of cancer is an important factor of increased risk of several cancers. Although the association between FH of cancer and concordant cancer risk has been reported in many previous epidemiological studies, no comprehensive prospective study with adjustment for lifestyle habits has evaluated the association of FH of cancer and concordant cancer risk. We investigated the association between FH of cancer and concordant cancer risk in a Japanese population-based prospective study, initiated in 1990 for cohort I and in 1993 for cohort II. We analyzed data on 103,707 eligible subjects without a history of cancer who responded to a self-administered questionnaire including FH of cancer at baseline. Study subjects were followed through 2012 and analyzed using multivariable-adjusted Cox proportional hazards regression models. During 1,802,581 person-years of follow-up, a total of 16,336 newly diagnosed cancers were identified. Any site (Hazard ratios = 1.11 (95% confidence interval = 1.07–1.15]), esophagus (2.11 [1.00–4.45]), stomach (1.36 [1.19–1.55]), liver (1.69 [1.10–2.61]), pancreas (2.63 [1.45–4.79]), lung (1.51 [1.14–2.00]), uterus (1.93 [1.06–3.51]) and bladder cancers (6.06 [2.49–14.74]) with FH of the concordant cancer were associated with an increased risk compared to those without FH. Our findings suggest that having FH of cancer is associated with an increased risk of several concordant cancer incidences in an Asian population. Enquiring about FH of several types of cancer may be important in identifying groups at high-risk of those cancers.     

Efficacy of immunotherapy targeting the neoantigen derived from epidermal growth factor receptor T790M/C797S mutation in non–small cell lung cancer

Lung cancer is the leading cause of cancer‐related deaths worldwide. Epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) often have good clinical activity against non–small cell lung cancer (NSCLC) with activating EGFR mutations. Osimertinib, which is a third‐generation EGFR‐TKI, has a clinical effect even on NSCLC harboring the threonine to methionine change at codon 790 of EGFR (EGFR T790M) mutation that causes TKI resistance. However, most NSCLC patients develop acquired resistance to osimertinib within approximately 1 year, and 40% of these patients have the EGFR T790M and cysteine to serine change at codon 797 (C797S) mutations. Therefore, there is an urgent need for the development of novel treatment strategies for NSCLC patients with the EGFR T790M/C797S mutation. In this study, we identified the EGFR T790M/C797S mutation‐derived peptide (790‐799) (MQLMPFGSLL) that binds the human leukocyte antigen (HLA)‐A*02:01, and successfully established EGFR T790M/C797S‐peptide‐specific CTL clones from human PBMC of HLA‐A2 healthy donors. One established CTL clone demonstrated adequate cytotoxicity against T2 cells pulsed with the EGFR T790M/C797S peptide. This CTL clone also had high reactivity against cancer cells that expressed an endogenous EGFR T790M/C797S peptide using an interferon‐γ (IFN‐γ) enzyme‐linked immunospot (ELISPOT) assay. In addition, we demonstrated using a mouse model that EGFR T790M/C797S peptide‐specific CTL were induced by EGFR T790M/C797S peptide vaccine in vivo. These findings suggest that an immunotherapy targeting a neoantigen derived from EGFR T790M/C797S mutation could be a useful novel therapeutic strategy for NSCLC patients with EGFR‐TKI resistance, especially those resistant to osimertinib.     

The effect of salazosulfapyridine on the in vitro antibody production in murine spleen cells

The effect of salazosulfapyridine (SASP) on the antibody response of murine spleen cells in vitro was studied. SASP inhibited the response to sheep red blood cells (SRBC), a T-cell-dependent (TD) antigen, dose-dependently and was most effective at a dose of 2 x 10(-4) M without cell toxicity. No remarkable inhibition was seen with the main metabolites of SASP, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP). SASP failed to inhibit antibody production to T-cell-independent antigens such as dinitrophenyl-Ficoll or trinitrophenyl (TNP)-lipopolysaccharides, although the response to TNP-keyhole limpet hemocyanin, another TD antigen like SRBC, was inhibited. Further, this drug did not show any depression of the anti-SRBC plaque-forming cell (PFC) response in spleen cells treated with anti-Thy1.2 antibody plus complement. The inhibition of anti-SRBC PFC response by SASP was accompanied by a reduction of interleukin 2 (IL-2) secretion. Our results suggest that SASP may act on T cell populations and may inhibit the T-cell-dependent antibody response partly through a depression of IL-2 production. The active compound appears to be SASP itself, rather than its metabolites.     

Multiple system atrophy variant with severe hippocampal pathology

The striatonigral and olivopontocerebellar systems are known to be vulnerable in multiple system atrophy (MSA), showing neuronal loss, astrogliosis, and alpha-synuclein-immunoreactive inclusions. MSA patients who displayed abundant neuronal cytoplasmic inclusions (NCIs) in the regions other than the striatonigral or olivopontocerebellar system have occasionally been diagnosed with variants of MSA. In this study, we report clinical and pathologic findings of MSA patients characterized by prominent pathologic involvement of the hippocampus. We assessed 146 consecutively autopsied MSA patients. Semi-quantitative analysis of anti-alpha-synuclein immunohistochemistry revealed that 12 of 146 patients (8.2%) had severe NCIs in two or more of the following areas: the hippocampal granule cells, cornu ammonis areas, parahippocampal gyrus, and amygdala. In contrast, the remaining 134 patients did not show severe NCIs in any of these regions. Patients with severe hippocampal involvement showed a higher representation of women (nine women/three men; Fisher's exact test, p = 0.0324), longer disease duration (13.1 ± 5.9 years; Mann–Whitney U-test, p = 0.000157), higher prevalence of cognitive impairment (four patients; Fisher's exact test, p = 0.0222), and lower brain weight (1070.3 ± 168.6 g; Mann–Whitney U-test, p = 0.00911) than other patients. The hippocampal granule cells and cornu ammonis area 1/subiculum almost always showed severe NCIs. The NCIs appeared to be ring-shaped or neurofibrillary tangle-like, fibrous configurations. Three of 12 patients also had dense, round-shaped NCIs that were morphologically similar to pick bodies. The patients with Pick body-like inclusions showed more severe atrophy of the medial temporal lobes and broader spreading of NCIs than those without. Immunohistochemistry for hyperphosphorylated tau and phosphorylated TDP-43 revealed minimal aggregations in the hippocampus of the hippocampal MSA patients. Our observations suggest a pathological variant of MSA that is characterized by severe involvement of hippocampal neurons. This phenotype may reinforce the importance of neuronal alpha-synucleinopathy in the pathogenesis of MSA.     

Adenocarcinoma arising in a colonic interposition following a total gastrectomy: Report of a case

A segment of the transverse colon can be used for gastric reconstruction after a total gastrectomy. This report presents the case of a 68-year-old woman with primary adenocarcinoma of the colon in a segment used for reconstruction after a total gastrectomy. The interposed colon developed colon carcinoma 9 years after the gastric reconstruction. The possibility of a primary carcinoma arising in a gastric colon interposition must be considered when employing the transverse colon as a gastric substitute.     

Comparison between a traditional single still image and a multiframe video image along the z‐axis of the same microscopic field of interest in cytology: Which does contribute to telecytology?

The limitation of cytologic still images is one of the reasons why telecytology has not met with widespread acceptance by the cytology community. Cytologic still image only displays a single depth of field, and this is a particularly acute problem in cytology where the specimen is often much thicker than a single microscopic depth of focus. In this article, we examine the validity of a “z‐axis” video of a microscopic field of interest. After observing videos of fields of interest from 10 cases, five cytotechnologists reached suitable cytologic findings and diagnosed the fields correctly in great majority of cases. Five other cytotechnologists, who looked only at a single representative still image, could not always make a correct diagnosis. The difference between two observer groups was statistically significant by Wilcoxon's matched pairs signed‐rank test. The results indicate that “z‐axis” video of microscopic field of interest provides a similar experience to “focusing through” observation of the specimen under a microscope and may improve an accuracy of primary telecytodiagnosis. And we expect that video image telecytology will strongly influence cytology, especially in education and training. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Aicardi–Goutières syndrome with systemic lupus erythematosus and hypothyroidism

We report a case of Aicardi–Goutières syndrome with systemic lupus erythematosus and hypothyroidism. A 3-year-old girl, diagnosed with Aicardi–Goutières syndrome at 9 months, was transferred to our hospital for fever of unknown origin. Severe spasticity with dystonic posturing and flexion contracture of the limbs were noted. Interstitial pneumonia with pleural effusion was evident. Immunological investigations revealed positive antinuclear antibodies and reduced thyroid function. Prompt treatment with steroids, cyclophosphamide, and levothyroxine sodium hydrate elicited a good response. It is necessary to emphasize that its possible relationship between Aicardi–Goutières syndrome and systemic lupus erythematosus and/or hypothyroidism.