Impact of deep learning on radiologists and radiology residents in detecting breast cancer on CT: a cross-vendor test study.

AIM: To investigate the effect of deep learning on the diagnostic performance of radiologists and radiology residents in detecting breast cancers on computed tomography (CT). MATERIALS AND METHODS: In this retrospective study, patients undergoing contrast-enhanced chest CT between January 2010 and December 2020 using equipment from two vendors were included. Patients with confirmed breast cancer were categorised as the training (n=201) and validation (n=26) group and the testing group (n=30) using processed CT images from either vendor. The trained deep-learning model was applied to test group patients with (30 females; mean age = 59.2 ± 15.8 years) and without (19 males, 21 females; mean age = 64 ± 15.9 years) breast cancer. Image-based diagnostic performance of the deep-learning model was evaluated with the area under the receiver operating characteristic curve (AUC). Two radiologists and three radiology residents were asked to detect malignant lesions by recording a four-point diagnostic confidence score before and after referring to the result from the deep-learning model, and their diagnostic performance was evaluated using jackknife alternative free-response receiver operating characteristic analysis by calculating the figure of merit (FOM). RESULTS: The AUCs of the trained deep-learning model on the validation and test data were 0.976 and 0.967, respectively. After referencing with the result of the deep learning model, the FOMs of readers significantly improved (reader 1/2/3/4/5: from 0.933/0.962/0.883/0.944/0.867 to 0.958/0.968/0.917/0.947/0.900; p=0.038). CONCLUSION: Deep learning can help radiologists and radiology residents detect breast cancer on CT.

Dynamic Contrast-Enhanced MRI Parameters and Normalized ADC Values Could Aid Differentiation of Skull Base Osteomyelitis from Nasopharyngeal Cancer.

BACKGROUND AND PURPOSE: The skull base osteomyelitis sometimes can be difficult to distinguish from nasopharyngeal cancer. This study aimed to investigate the differences between skull base osteomyelitis and nasopharyngeal cancer using dynamic contrast-enhanced MR imaging and normalized ADC values. MATERIALS AND METHODS: This study included 8 and 12 patients with skull base osteomyelitis and nasopharyngeal cancer, respectively, who underwent dynamic contrast-enhanced MR imaging and DWI before primary treatment. Quantitative dynamic contrast-enhanced MR imaging parameters and ADC values of the ROIs were analyzed. Normalized ADC parameters were calculated by dividing the ROIs of the lesion by that of the spinal cord. RESULTS: The rate transfer constant between extravascular extracellular space and blood plasma per minute (Kep) was significantly lower in patients with skull base osteomyelitis than in those with nasopharyngeal cancer (median, 0.43 versus 0.57; P = .04). The optimal cutoff value of Kep was 0.48 (area under the curve, 0.78; 95% CI, 0.55-1). The normalized mean ADC was significantly higher in patients with skull base osteomyelitis than in those with nasopharyngeal cancer (median, 1.90 versus 0.87; P < .001). The cutoff value of normalized mean ADC was 1.55 (area under the curve, 0.96; 95% CI, 0.87-1). The area under the curve of the combination of dynamic contrast-enhanced MR imaging parameters (Kep and extravascular extracellular space volume per unit tissue volume) was 0.89 (95% CI, 0.73-1), and the area under the curve of the combination of dynamic contrast-enhanced MR imaging parameters and normalized mean ADC value was 0.98 (95% CI, 0.93-1). CONCLUSIONS: Quantitative dynamic contrast-enhanced MR imaging parameters and normalized ADC values may be useful in differentiating skull base osteomyelitis and nasopharyngeal cancer. The combination of dynamic contrast-enhanced MR imaging parameters and normalized ADC values outperformed each measure in isolation.

Differentiation of Skull Base Chondrosarcomas, Chordomas, and Metastases: Utility of DWI and Dynamic Contrast-Enhanced Perfusion MR Imaging.

BACKGROUND AND PURPOSE: Differentiation of skull base tumors, including chondrosarcomas, chordomas, and metastases, on conventional imaging remains a challenge. We aimed to test the utility of DWI and dynamic contrast-enhanced MR imaging for skull base tumors. MATERIALS AND METHODS: Fifty-nine patients with chondrosarcomas, chordomas, or metastases between January 2015 and October 2021 were included in this retrospective study. Pretreatment normalized mean ADC and dynamic contrast-enhanced MR imaging parameters were calculated. The Kruskal-Wallis H test for all tumor types and the Mann-Whitney U test for each pair of tumors were used. RESULTS: Fifteen chondrosarcomas (9 men; median age, 62 years), 14 chordomas (6 men; median age, 47 years), and 30 metastases (11 men; median age, 61 years) were included in this study. Fractional plasma volume helped distinguish all 3 tumor types (P = .003, <.001, and <.001, respectively), whereas the normalized mean ADC was useful in distinguishing chondrosarcomas from chordomas and metastases (P < .001 and P < .001, respectively); fractional volume of extracellular space, in distinguishing chondrosarcomas from metastases (P = .02); and forward volume transfer constant, in distinguishing metastases from chondrosarcomas/chondroma (P = .002 and .002, respectively) using the Kruskal-Wallis H test. The diagnostic performances of fractional plasma volume for each pair of tumors showed areas under curve of 0.86-0.99 (95% CI, 0.70-1.0); the forward volume transfer constant differentiated metastases from chondrosarcomas/chordomas with areas under curve of 0.82 and 0.82 (95% CI, 0.67-0.98), respectively; and the normalized mean ADC distinguished chondrosarcomas from chordomas/metastases with areas under curve of 0.96 and 0.95 (95% CI, 0.88-1.0), respectively. CONCLUSIONS: DWI and dynamic contrast-enhanced MR imaging sequences can be beneficial for differentiating the 3 common skull base tumors.

Normalized Parameters of Dynamic Contrast-Enhanced Perfusion MRI and DWI-ADC for Differentiation between Posttreatment Changes and Recurrence in Head and Neck Cancer.

BACKGROUND AND PURPOSE: Differentiating recurrence from benign posttreatment changes has clinical importance in the imaging follow-up of head and neck cancer. This study aimed to investigate the utility of normalized dynamic contrast-enhanced MR imaging and ADC for their differentiation. MATERIALS AND METHODS: This study included 51 patients with a history of head and neck cancer who underwent follow-up dynamic contrast-enhanced MR imaging with DWI-ADC, of whom 25 had recurrences and 26 had benign posttreatment changes. Quantitative and semiquantitative dynamic contrast-enhanced MR imaging parameters and ADC of the ROI and reference region were analyzed. Normalized dynamic contrast-enhanced MR imaging parameters and normalized DWI-ADC parameters were calculated by dividing the ROI by the reference region. RESULTS: Normalized plasma volume, volume transfer constant between extravascular extracellular space and blood plasma per minute (K trans), area under the curve, and wash-in were significantly higher in patients with recurrence than in those with benign posttreatment change (P = .003 to <.001). The normalized mean ADC was significantly lower in patients with recurrence than in those with benign posttreatment change (P < .001). The area under the receiver operating characteristic curve of the combination of normalized dynamic contrast-enhanced MR imaging parameters with significance (normalized plasma volume, normalized extravascular extracellular space volume per unit tissue volume, normalized K trans, normalized area under the curve, and normalized wash-in) and normalized mean ADC was 0.97 (95% CI, 0.93-1). CONCLUSIONS: Normalized dynamic contrast-enhanced MR imaging parameters, normalized mean ADC, and their combination were effective in differentiating recurrence and benign posttreatment changes in head and neck cancer.

ADC for Differentiation between Posttreatment Changes and Recurrence in Head and Neck Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Previous studies reported that the ADC values of recurrent head and neck cancer lesions are lower than those of posttreatment changes, however, the utility of ADC to differentiate them has not been definitively summarized and established. PURPOSE: Our aim was to evaluate the diagnostic benefit of ADC calculated from diffusion-weighted imaging in differentiating recurrent lesions from posttreatment changes in head and neck cancer. DATA SOURCES: MEDLINE, Scopus, and EMBASE data bases were searched for studies. STUDY SELECTION: The review identified 6 prospective studies with a total of 365 patients (402 lesions) who were eligible for the meta-analysis. DATA ANALYSIS: Forest plots were used to assess the mean difference in ADC values. Heterogeneity among the studies was evaluated using the Cochrane Q test and the I2 statistic. DATA SYNTHESIS: Among included studies, the overall mean of ADC values of recurrent lesions was 1.03 × 10-3mm2/s and that of the posttreatment changes was 1.51 × 10-3mm2/s. The ADC value of recurrence was significantly less than that of posttreatment changes in head and neck cancer (pooled mean difference: -0.45; 95% CI, -0.59-0.32, P < .0001) with heterogeneity among studies. The threshold of ADC values between recurrent lesions and posttreatment changes was suggested to be 1.10 × 10-3mm2/s. LIMITATIONS: Given the heterogeneity of the data of the study, the conclusions should be interpreted with caution. CONCLUSIONS: The ADC values in recurrent head and neck cancers are lower than those of posttreatment changes, and the threshold of ADC values between them was suggested.

Prognostic Factors of Stroke-Like Migraine Attacks after Radiation Therapy (SMART) Syndrome.

BACKGROUND AND PURPOSE: Prognostic factors of stroke-like migraine attacks after radiation therapy (SMART) syndrome have not been fully explored. This study aimed to assess clinical and imaging features to predict the clinical outcome of SMART syndrome. MATERIALS AND METHODS: We retrospectively reviewed the clinical manifestations and imaging findings of 20 patients with SMART syndrome (median age, 48 years; 5 women) from January 2016 to January 2020 at 4 medical centers. Patient demographics and MR imaging features at the time of diagnosis were reviewed. This cohort was divided into 2 groups based on the degree of clinical improvement (completely versus incompletely recovered). The numeric and categoric variables were compared as appropriate. RESULTS: There were statistically significant differences between the completely recovered group (n = 11; median age, 44 years; 2 women) and the incompletely recovered group (n = 9; median age, 55 years; 3 women) in age, months of follow-up, and the presence of steroid treatment at diagnosis (P = .028, .002, and .01, respectively). Regarding MR imaging features, there were statistically significant differences in the presence of linear subcortical WM susceptibility abnormality, restricted diffusion, and subcortical WM edematous changes in the acute SMART region (3/11 versus 8/9, P = .01; 0/11 versus 4/9, P = .026; and 2/11 versus 7/9, P = .022, respectively). Follow-up MRIs showed persistent susceptibility abnormality (11/11) and subcortical WM edematous changes (9/9), with resolution of restricted diffusion (4/4). CONCLUSIONS: Age, use of steroid treatment at the diagnosis of SMART syndrome, and MR imaging findings of abnormal susceptibility signal, restricted diffusion, and subcortical WM change in the acute SMART region can be prognostic factors in SMART syndrome.

Alcohol abuse has a potential association with unfavourable clinical course and brain atrophy in patients with status epilepticus.

AIM: To evaluate chronological changes on serial magnetic resonance imaging (MRI) examinations and clinical prognosis in patients with status epilepticus (SE), as well as the effect of alcohol abuse and heavy alcohol use on clinicoradiological findings. MATERIALS AND METHODS: This retrospective, single-centre study was approved by the institutional review board. Among 345 patients with seizures between January 2010 and October 2021, 27 patients with SE who had undergone both initial MRI (within a week after onset) and follow-up MRI (within 1 month after the initial MRI) were included. Five and three patients with concurrent or previous alcohol abuse and heavy alcohol-use history were included, respectively, and they were classified into the AL (Alcohol use) group. The remaining 19 patients were classified into the non-AL group. Two neuroradiologists independently evaluated both initial and follow-up MRI examinations of each patient; MRI findings were compared between the AL and non-AL groups using Fisher's exact test. In 15 patients, including four patients from the AL group, clinical information 6 months after the onset of SE was available; this information was compared between the two groups. RESULTS: Brain atrophy (5/8 versus 2/19, p=0.011; odds ratio, 12.29 [95% confidence interval, 1.32-189.2]) and unfavourable clinical course with uncontrollable seizures (3/4 versus 1/11, p=0.033; odds ratio, 30[1.43-638.19]) were significantly more frequent in the AL group than in the non-AL group. CONCLUSION: Among patients with SE, alcohol abuse and heavy alcohol-use history were associated with unfavourable seizure control and brain atrophy.

Pretreatment ADC Histogram Analysis as a Prognostic Imaging Biomarker for Patients with Recurrent Glioblastoma Treated with Bevacizumab: A Systematic Review and Meta-analysis.

BACKGROUND: The mean ADC value of the lower Gaussian curve (ADCL) derived from the bi-Gaussian curve-fitting histogram analysis has been reported as a predictive/prognostic imaging biomarker in patients with recurrent glioblastoma treated with bevacizumab; however, its systematic summary has been lacking. PURPOSE: We applied a systematic review and meta-analysis to investigate the predictive/prognostic performance of ADCL in patients with recurrent glioblastoma treated with bevacizumab. DATA SOURCES: We performed a literature search using PubMed, Scopus, and EMBASE. STUDY SELECTION: A total of 1344 abstracts were screened, of which 83 articles were considered potentially relevant. Data were finally extracted from 6 studies including 578 patients. DATA ANALYSIS: Forest plots were generated to illustrate the hazard ratios of overall survival and progression-free survival. The heterogeneity across the studies was assessed using the Cochrane Q test and I2 values. DATA SYNTHESIS: The pooled hazard ratios for overall survival and progression-free survival in patients with an ADCL lower than the cutoff values were 1.89 (95% CI, 1.53-2.31) and 1.98 (95% CI, 1.54-2.55) with low heterogeneity among the studies. Subgroup analysis of the bevacizumab-free cohort showed a pooled hazard ratio for overall survival of 1.20 (95% CI, 1.08-1.34) with low heterogeneity. LIMITATIONS: The conclusions are limited by the difference in the definition of recurrence among the included studies. CONCLUSIONS: This systematic review with meta-analysis supports the prognostic value of ADCL in patients with recurrent glioblastoma treated with bevacizumab, with a low ADCL demonstrating decreased overall survival and progression-free survival. On the other hand, the predictive role of ADCL for bevacizumab treatment was not confirmed.

Hypoxic hepatitis with marked elevation of serum ferritin probably due to activation of intrahepatic macrophages: another form of hypoxic hepatitis hitherto not reported?

BACKGROUND AND STUDY AIMS: Hypoxic hepatitis (HH) is an acute liver injury that develops in patients with underlying diseases, such as heart failure, respiratory failure, septic/toxic shock. However, some patients do not have underlying diseases or episodes which are known to result in HH. Here, we analyzed the clinical characteristics of this particular patient group (called 'unknown HH' hereafter) to understand its pathogenesis. PATIENTS AND METHODS: Between October 2010 and January 2016, 157 consecutive patients with acute liver injury were admitted to our hospital. Among these patients, 15 patients were categorized as unknown HH. Medical histories and blood test results of unknown HH were analyzed. RESULTS: Among 15 patients of unknown HH, 11 were habitual drinkers and all experienced one of digestive symptoms which might result in mild hypovolemia such as vomiting, diarrhea, appetite loss, and epigastralgia. All patients of unknown HH presented marked elevation of serum ferritin concentration paralleled with aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) concentrations. The serum levels of ferritin, ALT, LDH, and prothrombin time-international normalized ratio (PT-INR) were rapidly decreased during hospitalization and all 15 patients of unknown HH recovered without any complication. CONCLUSIONS: We found the particular group of HH with marked elevation of serum ferritin probably due to intrahepatic macrophage activation. Anti-inflammatory treatments might be effective for this group of hypoxic hepatitis.

Primary bone adult T cell lymphoma with multiple skeletal lesions and debilitating painful osteolysis: a case report.

There have been only a limited number of reports on primary adult T cell lymphoma/leukemia (ATL) in the bone. This is a case report of a 75-year-old patient initially reporting multiple bone pains that were attributed to osteolytic ATL. The patient developed spontaneous chest/back pain and visited a local hospital. Laboratory tests showed high levels of alkaline phosphatase (ALP), and computed tomography (CT) revealed skeletal lesions with osteolysis. Although multiple myeloma was initially suspected, the results of bone marrow aspiration and bone biopsy were inconsistent. After he was referred to our hospital, mild hypercalcemia (10.4 mg/dL) with low-normal intact parathyroid hormone (PTH) (27 pg/mL), low parathyroid hormone-related protein (PTHrP), and elevated 1,25-dihydroxy vitamin D (1,25OH2D) levels (136 pg/mL) narrowed the differential diagnosis down to lymphomatous and granulomatous diseases, and then, the high serum soluble IL-2 receptor (3,450 U/mL) and the flower cells recognized in the peripheral blood sample suggested the involvement of ATL. Finally, the reevaluation of the iliac bone biopsy sample led us to the histological diagnosis of ATL infiltration in the bone. The subsequent two courses of chemotherapy in addition to denosumab resulted in an objective partial metabolic response indicated in 18-fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Although very rare, the bone involvement of ATL could be used for the differential diagnosis for local osteolytic bone pain in addition to multiple myeloma and metastatic bone diseases.

MRI Findings of Immune Checkpoint Inhibitor-Induced Hypophysitis: Possible Association with Fibrosis.

BACKGROUND AND PURPOSE: Hypophysitis is one of the well-known adverse effects of immune checkpoint inhibitors. Immune checkpoint inhibitor-induced hypophysitis frequently causes irreversible hypopituitarism, which requires long-term hormone replacement. Despite the high frequency and clinical significance, characteristic MR imaging findings of immune checkpoint inhibitor-induced hypophysitis have not been established. In the present study, we aimed to review and extract the MR imaging features of immune checkpoint inhibitor-induced hypophysitis. MATERIALS AND METHODS: This retrospective international multicenter study comprised 20 patients with melanoma who were being treated with immune checkpoint inhibitors and clinically diagnosed with immune checkpoint inhibitor-induced hypophysitis. Three radiologists evaluated the following MR imaging findings: enlargement of the pituitary gland and stalk; homogeneity of enhancement of the pituitary gland; presence/absence of a well-defined poorly enhanced area and, if present, its location, shape, and signal intensity in T2WI; and enhancement pattern in contrast-enhanced dynamic MR imaging. Clinical symptoms and hormone levels were also recorded. RESULTS: Enlargement of the pituitary gland and stalk was observed in 12 and 20 patients, respectively. Nineteen patients showed poorly enhanced lesions (geographic hypoenhancing lesions) in the anterior lobe, and 11 of these lesions showed hypointensity on T2WI. Thyrotropin deficiency and corticotropin deficiency were observed in 19/20 and 12/17 patients, respectively, which persisted in 12/19 and 10/12 patients, respectively, throughout the study period. CONCLUSIONS: Pituitary geographic hypoenhancing lesions in the anterior lobe of the pituitary gland are characteristic and frequent MR imaging findings of immune checkpoint inhibitor-induced hypophysitis. They reflect fibrosis and are useful in distinguishing immune checkpoint inhibitor-induced hypophysitis from other types of hypophysitis/tumors.

Antiviral activity of hypothiocyanite produced by lactoperoxidase against influenza A and B viruses and mode of its antiviral action.

Hypothiocyanite (OSCN-) is a natural component of human saliva and is produced by the lactoperoxidase (LPO)/thiocyanate/hydrogen peroxide (H2O2) system. OSCN- has been previously shown to exhibit antiviral activity against influenza viruses (IFV) A/H1N1/2009 and A/H1N2/2009 in vitro as well as antimicrobial and antifungal activities. We elucidated the antiviral activity of OSCN- against both IFV types A and B and the mode of its antiviral action. OSCN- was produced constantly at 900 ± 200 µmol/l in Na3PO4 buffer solution containing NaSCN and LPO in the presence of H2O2 as an original OSCN- solution. In a plaque reduction assay, IFV A/PR/8/34 (H1N1), A/Fukushima/13/43 (H3N2), B/Singapore/222/97, and B/Fukushima/15/93 were exposed to various concentrations of OSCN- for 0 to 30 min before adsorption to MDCK cells, and plaque formation was examined. OSCN- exhibited significant similar antiviral activities against all four viruses without cytotoxicity, and the EC50 values for them were from 57 ± 16 to 148 ± 27 µmol/l regardless of the exposure times. The exposure of MDCK cells to OSCN- before viral adsorption did not affect its anti-IFV activity (EC50: more than 450 µmol/l), but the exposure after viral adsorption affected it moderately (EC50: 380 ± 40 µmol/l). Moreover, the exposure of virus particles to OSCN- at 450 µmol/l did not affect the hemagglutinin activity of IFV in hemagglutination inhibition assay. These results suggest that the attachment of OSCN- to the viral envelope critically contributes to the mode of antiviral action of OSCN- without interfering with viral adsorption. Keywords: hypothiocyanite; influenza virus type A; influenza virus type B; lactoperoxidase; antiviral activity.

High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG.

High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

T-705 (Favipiravir) suppresses tumor necrosis factor α production in response to influenza virus infection: A beneficial feature of T-705 as an anti-influenza drug.

Influenza virus infection induces the production of various cytokines, which play important roles in the pathogenesis of infection. Among the cytokines induced by influenza, tumor necrosis factor α (TNF-α) production has been correlated with the severity of lung lesions. We investigated the effects of T-705 (Favipiravir, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) on cytokine production due to influenza virus infection in vitro and in vivo, compared with oseltamivir or GS 4071, an active form of oseltamivir. TNF-α production in mouse macrophage-derived P388D1 cells infected with the influenza virus was lower following treatment with T-705 at concentrations of 0.3 to 100 µg/ml than treatment with GS 4071 at the same concentrations. The effect of treatment with T-705 on the cytokine production induced by the influenza virus infection was investigated in mouse influenza virus infection model. At 48 h post-infection (p.i.) T-705 significantly suppressed the viral load in the lungs and TNF-α production in the airways of infected mice even when viral loads were high. Furthermore, T-705 suppressed only TNF-α production from the early phase of infection. In this study, T-705 showed the antiviral activity of reducing pulmonary viral load compared with oseltamivir, thereby suppressing the TNF-α production. This feature of T-705 is benefit against severe influenza infection.

Loss of p53 induces leukemic transformation in a murine model of Jak2 V617F-driven polycythemia vera.

As leukemic transformation of myeloproliferative neoplasms (MPNs) worsens the clinical outcome, reducing the inherent risk of the critical event in MPN cases could be beneficial. Among genetic alterations concerning the transformation, the frequent one is TP53 mutation. Here we show that retroviral overexpression of Jak2 V617F mutant into wild-type p53 murine bone marrow cells induced polycythemia vera (PV) in the recipient mice, whereas Jak2 V617F-transduced p53-null mice developed lethal leukemia after the preceding PV phase. The leukemic mice had severe anemia, hepatosplenomegaly, pulmonary hemorrhage and expansion of dysplastic erythroid progenitors. Primitive leukemia cells (c-kit+Sca1+Lin- (KSL) and CD34-CD16/32-c-kit+Sca1-Lin- (megakaryocyte-erythroid progenitor; MEP)) and erythroid progenitors (CD71+) from Jak2 V617F-transduced p53-null leukemic mice had leukemia-initiating capacity, however, myeloid differentiated populations (Mac-1+) could not recapitulate the disease. Interestingly, recipients transplanted with CD71+ cells rapidly developed erythroid leukemia, which was in sharp contrast to leukemic KSL cells to cause lethal leukemia after the polycythemic state. The leukemic CD71+ cells were more sensitive to INCB18424, a potent JAK inhibitor, than KSL cells. p53 restoration could ameliorate Jak2 V617F-transduced p53-null erythroleukemia. Taken together, our results show that p53 loss is sufficient for inducing leukemic transformation in Jak2 V617F-positive MPN.

Metabolic Regulation of Apoptosis in Cancer.

Apoptosis is a cellular suicide program that plays a critical role in development and human diseases, including cancer. Cancer cells evade apoptosis, thereby enabling excessive proliferation, survival under hypoxic conditions, and acquired resistance to therapeutic agents. Among various mechanisms that contribute to the evasion of apoptosis in cancer, metabolism is emerging as one of the key factors. Cellular metabolites can regulate functions of pro- and antiapoptotic proteins. In turn, p53, a regulator of apoptosis, also controls metabolism by limiting glycolysis and facilitating mitochondrial respiration. Consequently, with dysregulated metabolism and p53 inactivation, cancer cells are well-equipped to disable the apoptotic machinery. In this article, we review how cellular apoptosis is regulated and how metabolism can influence the signaling pathways leading to apoptosis, especially focusing on how glucose and lipid metabolism are altered in cancer cells and how these alterations can impact the apoptotic pathways.

Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.