Inflammatory Rhabdomyoblastic Tumor: Clinicopathologic and Molecular Analysis of 13 Cases.

Inflammatory rhabdomyoblastic tumors (IRMTs) are newly recognized skeletal muscle tumors with uncertain malignant potential. We investigated 13 IRMTs using clinicopathologic, genetic, and epigenetic methods. The cohort included 7 men and 6 women, aged 23 to 80 years (median, 50 years), of whom 2 had neurofibromatosis type 1. Most tumors occurred in the deep soft tissues of the lower limbs, head/neck, trunk wall, and retroperitoneum/pelvis. Two tumors involved the hypopharyngeal submucosa as polypoid masses. Eight tumors showed conventional histology of predominantly spindled cells with nuclear atypia, low mitotic activity, and massive inflammatory infiltrates. Three tumors showed atypical histology, including uniform epithelioid or plump cells and mitotically active histiocytes. The remaining 2 tumors demonstrated malignant progression to rhabdomyosarcoma; one had additional IRMT histology and the other was a pure sarcoma. All 11 IRMTs without malignant progression exhibited indolent behavior at a median follow-up of 43 months. One of the 2 patients with IRMTs with malignant progression died of lung metastases. All IRMTs were positive for desmin and PAX7, whereas myogenin and MyoD1 were expressed in a subset of cases. Targeted next-generation sequencing identified pathogenic mutations in NF1 (5/8) and TP53 (4/8). All TP53 mutations co-occurred with NF1 mutations. TP53 variant allele frequency was much lower than that of NF1 in 2 cases. These tumors showed geographic (subclonal) strong p53 immunoreactivity, suggesting the secondary emergence of a TP53-mutant clone. DNA methylation-based copy number analysis conducted in 11 tumors revealed characteristic flat patterns with relative gains, including chromosomes 5, 18, 20, 21, and/or 22 in most cases. Widespread loss of heterozygosity with retained biparental copies of these chromosomes was confirmed in 4 tumors analyzed via allele-specific profiling. Based on unsupervised DNA methylation analysis, none of the 11 tumors tested clustered with existing reference entities but formed a coherent group, although its specificity warrants further study.

Common clinicopathological and immunological features of sarcomatoid carcinoma across organs: A histomorphology-based cross-organ study.

Sarcomatoid carcinoma (SC), which can occur in any organ, is a rare disease. To elucidate common characteristics of SC beyond organs, we evaluated clinicopathological and immunological features of SC defined by the single histological criterion beyond organs compared to randomly matched conventional carcinoma (non-SC) adjusted for the disease stage. Immunological features were assessed by multiplex immunohistochemistry, comparing immune cell density in tumor tissues and tumor programmed death-ligand 1 (PD-L1) expression. A total of 101 patients with SC or non-SC (31 lung, 19 esophagus, 22 pancreas, 15 liver, 4 bile duct, 6 kidney, 2 uterus and 2 ovary) were identified among 7197 patients who underwent surgery at our institute (1997-2020). SC was significantly associated with worse survival (HR: 1.571; 95% CI: 1.084-2.277; P = .017). The frequency of postoperative progression within 6 months was significantly higher for SC patients (54% vs 28%; P = .002). The immune profiling revealed the densities of CD8+ T cells (130 vs 72 cells/mm2 ; P = .004) and tumor-associated macrophages (566 vs 413 cells/mm2 ; P < .0001) and the tumor PD-L1 expression score (40% vs 5%; P < .0001) were significantly higher in SCs than in non-SCs. Among 73 SC patients with postoperative progression, multivariate Cox regression analysis showed that immunotherapy tended to be associated with favorable survival (HR: 0.256; 95% CI: 0.062-1.057; P = .060). Collectively, SCs shared clinicopathological and immunological features across organs. Our study can initiate to standardize the pathological definition of SC and provide a rationale for the investigation and development for this rare disease in a cross-organ manner.

Clinicopathological features and prognostic impact of dirty necrosis in metastatic lung cancers from the colon and rectum.

Dirty necrosis (DN) is a form of tumor necrosis (TN) with prominent neutrophil infiltration and cell detritus in the necrotic foci. This study aimed to characterize the clinicopathological features of DN in metastatic lung cancers of the colon and rectum (MLCRs). A total of 227 patients who underwent pulmonary metastasectomy and complete resection for MLCR were included in this study. TN was evaluated using digitally scanned resection specimens. These slides were immunostained for biomarkers of NETosis (citrullinated histone H3 [citH3] and myeloperoxidase [MPO]), and the area positive for citH3 and MPO was further quantified. TN was observed in 216 cases (95.2%), and 54 (25.0%) of these cases had DN. The presence of TN was not associated with a worse prognosis; however, patients with DN had a significantly shorter overall survival than those without DN (p < 0.01). Furthermore, the presence of DN was a poor prognostic factor in both the univariate and multivariate analyses. Immunohistochemical analysis revealed that the percentage of citH3-positive and MPO-positive areas in the DN-positive cases was significantly higher than that in the DN-negative cases (p < 0.01 and p < 0.01, respectively). In surgically resected MLCR, DN is the characteristic TN subtype associated with poor prognosis and neutrophil extracellular traps (NETs).

Prognostic impact and gene expression analysis of peri-tumoral alveolar macrophage in resected lung adenocarcinoma.

The prognostic significance and role of extratumoral alveolar macrophages (exAMs) in lung adenocarcinoma (LUAD) patients remain unknown. In this study, we investigated the prognostic impact and gene expression of exAMs in LUAD patients. The density of alveolar macrophages (AMs) in the peri-tumoral lung field (p-exAMs) and distant lung field (d-exAMs) was evaluated in 217 LUAD patients with lymph node metastasis. Patients with high p-exAMs showed significantly shorter recurrence-free (RFS) and shorter overall survival (OS) than those with low p-exAMs (p = 0.02 and p = 0.03, respectively), whereas there was no survival difference between patients with high d-exAMs and those with low d-exAMs. Multivariate analysis revealed that high p-exAMs was an independent predictive factor for RFS (HR: 1.54; 95% confidence interval [CI]:1.10-2.16; p = 0.01). Later, we collected AMs from the tumor periphery and distant segments in 13 resected lungs by bronchoalveolar lavage (BAL) procedure and compared mRNA expression. AMs in the tumor periphery expressed significantly higher levels of IL-10 and CCL2 than those in the distant segment (p < 0.01 and p = 0.03, respectively). Additionally, IL-10 and CCL2 significantly induced the growth and migration of the PC9 cells in vitro. This study suggests that p-exAMs should be considered as a tumor-promoting component in the tumor microenvironment.

Efficacy of Preoperative Biopsy in Predicting the Newly Proposed Histologic Grade of Resected Lung Adenocarcinoma.

A novel histologic grading system for invasive lung adenocarcinomas (LUAD) has been newly proposed and adopted by the World Health Organization (WHO) classification. We aimed to evaluate the concordance of newly established grades between preoperative biopsy and surgically resected LUAD samples. Additionally, factors affecting the concordance rate and its prognostic impact were also analyzed. In this study, surgically resected specimens of 222 patients with invasive LUAD and their preoperative biopsies collected between January 2013 and December 2020 were used. We determined the histologic subtypes of preoperative biopsy and surgically resected specimens and classified them separately according to the novel WHO grading system. The overall concordance rate of the novel WHO grades between preoperative biopsy and surgically resected samples was 81.5%, which was higher than that of the predominant subtype. When stratified by grades, the concordance rate of grades 1 (well-differentiated, 84.2%) and 3 (poorly differentiated, 89.1%) was found to be superior compared to grade 2 (moderately differentiated, 66.2%). Overall, the concordance rate was not significantly different from biopsy characteristics, including the number of biopsy samples, biopsy sample size, and tumor area size. On the other hand, the concordance rate of grades 1 and 2 was significantly higher in tumors with smaller invasive diameters, and that of grade 3 was significantly higher in tumors with larger invasive diameters. Preoperative biopsy specimens can predict the novel WHO grades, especially grades 1 and 3 of surgically resected specimens, more accurately than the former grading system, regardless of preoperative biopsy or clinicopathologic characteristics.

Prevalence and characteristics of patients with upper urinary tract urothelial carcinoma having potential Lynch syndrome identified by immunohistochemical universal screening and Amsterdam criteria II.

BACKGROUND: This study aimed to identify patients with upper urinary tract urothelial carcinoma (UTUC) having potential Lynch syndrome (pLS) by immunohistochemistry (IHC) of DNA mismatch repair gene-related proteins (MMRPs) and Amsterdam criteria II and explore their clinical characteristics. METHODS: We retrospectively collected the clinical data of 150 consecutive patients with UTUC who underwent surgical resection at our institution between February 2012 and December 2020, and immunohistochemistry (IHC) of four MMRPs (MLH1, MSH2, MSH6, and PMS2) on all UTUC specimens was performed. Patients who tested positive for Amsterdam criteria (AMS) II and/or IHC screening were classified as having pLS and others as non-pLS, and their characteristics were explored. RESULTS: In this study, 5 (3%) and 6 (4%) patients were positive for AMS II and IHC screening, respectively. Two patient were positive for both AMS II and IHC screening, resulting in 9 (6%) patients with pLS. The pLS group was predominantly female (67% vs. 36%; p = 0.0093) and had more right-sided tumors (100% vs. 43%; p = 0.0009) than the non-pLS group. Of the 6 patients who were positive for IHC screening, 4 showed a combined loss of MSH2/MSH6 (n = 3) and MLH1/PMS2 (n = 1). Other two patients showed single loss of MSH6 and PSM2. CONCLUSIONS: AMS II and IHC screening identified pLS in 6% of patients with UTUC. The IHC screening-positive group tends to have relatively high rate of combined loss, but some patients have single loss. AMS II may overlook patients with LS, and a universal screening may be required for patients with UTUC as well as those with colorectal and endometrial cancer.

Prediction of the Contribution Ratio of a Target Metabolic Enzyme to Clearance from Chemical Structure Information.

The contribution ratio of metabolic enzymes such as cytochrome P450 to in vivo clearance (fraction metabolized: fm) is a pharmacokinetic index that is particularly important for the quantitative evaluation of drug-drug interactions. Since obtaining experimental in vivo fm values is challenging, those derived from in vitro experiments have often been used alternatively. This study aimed to explore the possibility of constructing machine learning models for predicting in vivo fm using chemical structure information alone. We collected in vivo fm values and chemical structures of 319 compounds from a public database with careful manual curation and constructed predictive models using several machine learning methods. The results showed that in vivo fm values can be obtained from structural information alone with a performance comparable to that based on in vitro experimental values and that the prediction accuracy for the compounds involved in CYP induction or inhibition is significantly higher than that by using in vitro values. Our new approach to predicting in vivo fm values in the early stages of drug discovery should help improve the efficiency of the drug optimization process.

The prognostic impact of a high number of peritumoral alveolar macrophages in neuroendocrine carcinoma in the lung.

Alveolar macrophages (AMs) are resident macrophages in the lungs; however, whether the number of AMs plays a role in the lung neuroendocrine tumor (NET) prognosis remains unclear. We counted the number of AMs located around the tumor (peritumoral alveolar macrophages [pAMs]) and the number of AMs located apart from the tumor (distant macrophages; dAMs). In 73 cases of neuroendocrine carcinoma (NEC: small cell lung carcinoma and large cell neuroendocrine carcinoma), the group that contained higher pAMs (≥86/µm2 ) revealed shorter recurrent-free survival (RFS) than those with lower pAMs (<86/µm2 ) (p = 0.005). Bivariate analysis showed that the number of pAMs was an independent predictor of a poor RFS. In contrast, in the carcinoid tumor cohort (n = 29), there was no statistically significant correlation between the two groups with high and low numbers of pAMs in RFS (p = 0.113). Furthermore, we examined the correlation between genomic alterations and the number of pAMs in NEC, but no significant correlation was observed. In conclusion, the number of pAMs is a prognostic factor for NEC in the lung and pAMs may contribute to tumor progression within the peritumoral microenvironment.

Patients with B-cell malignancies experience reduced antibody responses with class switching defect following BNT162b2 SARS-CoV-2 vaccination.

Vaccines having aided in escaping the majority of the population from immunological naïvety, our strategies are now shifting towards an increased focus on identifying and protecting the extremely vulnerable. We here describe the results of testing 12 patients, those with lymphoid malignancies having been targeted their B-cells for therapy with rituximab-containing regimens or a Bruton tyrosine kinase inhibitor, for anti-SARS-CoV-2 spike antibodies after receiving the BNT162b2 mRNA vaccine doses. The interval from last dosing of B-cell depletion therapy to SARS-CoV-2 vaccination was at median 5.3 (range 3.1-6.6) months. Using the 'seroprotection' threshold of 775 [BAU/mL] for the anti-spike antibody titer, our finding points out the crucial unresponsiveness of the targeted population with 0/12 (0%) achieving 'seroprotection'. Although IgG seroconversion was observed in 4/12 (33%), supporting the overall benefit of vaccination, the figures still point out a potential need for optimization of practice. IgA was further less responsive (unsuccessful 'seroconversion' in 11/12 (92%)), implicating an underlying class switch defect. Those with depletion on B-cells are caught at a dilemma between, being too early and too late on receiving SARS-CoV-2 vaccines. They wish to get over their immunological naïvety at the earliest, while, in order to assure quality immune memory, are also required to hold the patience for their B-cells to repopulate. Although it remains an issue whether intensified vaccine schedules and/or regimens will lead to stronger immunogenicity or more effective boosters for non-responders, we shall take advantage of every increasing evidence in order to optimize current options.

Prognostic impact of count of extratumoral lymphatic permeation in lung adenocarcinoma and its relation to the immune microenvironment.

Extratumoral lymphatic permeation (ly-ext) has been reported as an independent poor prognostic factor for lung adenocarcinoma, but whether or not the number of ly-ext foci is associated with prognosis and its relationship to the immune microenvironment is unclear. We counted the number of ly-ext foci on pathological slides from patients with completely resected lung adenocarcinoma with ly-ext, and divided them into two groups: a group with a high number of ly-ext foci (ly-ext high) and one with a low number of ly-ext foci (ly-ext low). Among the patients with ly-ext, only a high number of ly-ext foci was an independent poor prognostic factor. The 3-year recurrence-free survival (RFS) rate of the ly-ext high group was significantly lower than that of the ly-ext low group (14.7% vs. 50.0%, P < 0.01). Then, we analyzed the immune microenvironment of pT1 lung adenocarcinoma with ly-ext (13 cases of ly-ext high and 11 cases of ly-ext low tumor) by immunohistochemistry using antibodies for stem cell markers (aldehyde dehydrogenase 1 A1 and CD44), tumor-promoting mucin (MUC1), tumor-infiltrating lymphocytes (CD4, CD8, FOXP3, and CD79a), and tumor-associated macrophages (CD204). The number of CD8+ TILs within the primary lesion was significantly lower and the number of FOXP3+ TILs within the primary lesion was significantly higher in the ly-ext high group (P < 0.05 and P < 0.01, respectively). Our results indicated that a high number of ly-ext foci was an independent poor prognostic factor. Moreover, tumors with high numbers of ly-ext foci had a more immunosuppressive microenvironment.

Pathologic method for extracting good prognosis group in triple-negative breast cancer after neoadjuvant chemotherapy.

The area of residual tumor (ART) is a prognostic factor in patients treated with neoadjuvant chemotherapy (NAC) for lung, pancreatic, and rectal cancers. This study aimed to evaluate the usefulness of ART as a method for predicting the prognosis of triple-negative breast cancer (TNBC) patients after NAC. We included 143 patients with TNBC treated with NAC. The ART at the maximum cut surface of the residual tumor was measured. We divided the patients into three groups: ART-0 (ART = 0 mm2 ), ART-low (0 mm2  < ART ≤ 136mm2 ), and ART-high (ART > 136 mm2 ), and compared their clinicopathologic factors and prognosis. There were no significant differences in either recurrence-free survival (RFS) or overall survival (OS) between ART-0 and ART-low; however, the ART-high group had significantly shorter RFS and OS than the ART-0 and ART-low groups. Multivariate analysis showed that ART-0 and -low and ypN(-) were independent favorable prognostic factors for RFS. Groups with both ART-low and ypN(-) as well as those with ART-0 and ypN(-) showed significantly longer OS and RFS than the other groups (P < .05). Moreover, there was no significant difference in the RFS and OS between the ART-0 and ypN(-) groups and the ART-low and ypN(-) groups (P = .249 and P = .554, respectively). We concluded that ART is a candidate histopathological evaluation method for predicting the prognosis of TNBC patients treated with NAC. Furthermore, postoperative chemotherapy could be omitted in patients with ART-0 and ypN(-) (pathological complete response) and those with ART-low and ypN(-).

18F-fluorodeoxyglucose uptake in PET is associated with the tumor microenvironment in metastatic lymph nodes and prognosis in N2 lung adenocarcinoma.

Positron emission tomography is a useful technique for diagnosing lymph node (LN) metastasis. This study aimed to elucidate the association between fluorodeoxyglucose accumulation and the microenvironment in metastatic LNs in lung adenocarcinoma. We retrospectively analyzed 62 patients with surgically resected pathological N2 lung adenocarcinoma who underwent preoperative PET. The maximum standardized uptake value (SUVmax ) in the metastatic LNs was measured. Lymph node specimens were immunohistochemically analyzed for CD8+ , FoxP3+ , and CD79a+ lymphocytes, CD204+ tumor-associated macrophages (TAMs), and alpha-smooth muscle actin-positive cancer-associated fibroblasts (αSMA+ CAFs). We compared the clinicopathologic and immunohistochemical characteristics between two groups with high and low LN SUVmax . Using novel 3D hybrid spheroid models, we investigated the change in invasiveness of cancer cells in the presence of CAFs. In the multivariate analyses, LN SUVmax was an independent prognostic factor. The overall survival in the LN SUVmax high group was significantly worse than in the low group (P = .034). In the LN SUVmax high group, metastatic cancer cell invasion of extranodal tissue was more frequent (P = .005) and the number of CD204+ TAMs and αSMA+ CAFs in metastatic LNs was significantly higher than in the low group (P < .001 and P = .002, respectively). Hybrid spheroid models revealed that cancer cells coexisting with CAFs were more invasive than those without CAFs. Our results indicated a strong association between LN SUVmax and poor prognosis in patients with N2 lung adenocarcinoma. Moreover, LN SUVmax was suggested to be associated with the presence of tumor-promoting stromal cells in metastatic LNs.

Sarcomatoid hepatocellular carcinoma is distinct from ordinary hepatocellular carcinoma: Clinicopathologic, transcriptomic and immunologic analyses.

Sarcomatoid hepatocellular carcinoma (SHCC), which was a rare histological subtype of hepatocellular carcinoma (HCC), is currently subclassified as poorly differentiated HCC because of insufficient evidence to define SHCC as a subtype of HCC. We aimed to assess the feasibility of classifying SHCC as a histological subtype of HCC by comprehensively identifying novel and distinct characteristics of SHCC compared to ordinary HCC (OHCC). Fifteen SHCCs (1.4%) defined as HCC with at least a 10% sarcomatous component, 15 randomly disease-stage-matched OHCCs and 163 consecutive OHCCs were extracted from 1106 HCCs in the Pathology Database (1997-2019) of our hospital. SHCC patients showed poor prognosis, and the tumors could be histologically subclassified into the pleomorphic, spindle and giant cell types according to the subtype of carcinomas with sarcomatoid or undifferentiated morphology in other organs. The transcriptomic analysis revealed distinct characteristics of SHCC featuring the upregulation of genes associated with epithelial-to-mesenchymal transition and inflammatory responses. The fluorescent multiplex immunohistochemistry results revealed prominent programmed death-ligand 1 (PD-L1) expression on sarcomatoid tumor cells and higher infiltration of CD4+ and CD8+ T cells in SHCCs compared to OHCCs. The density of CD8+ T cells in the nonsarcomatous component of SHCCs was also higher than that in OHCCs. In conclusion, the comprehensive analyses in our study demonstrated that SHCC is distinct from OHCC in terms of clinicopathologic, transcriptomic and immunologic characteristics. Therefore, it is reasonable to consider SHCC as a histological subtype of HCC.

Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment.

BACKGROUND: The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) with large cell neuroendocrine carcinoma (LCNEC) patients remains unclear. Thus, we performed a retrospective study to examine the relationship between the pretreatment NLR and clinical outcome in advanced LCNEC patients and the impact of the immune-related tumour microenvironment (TME). METHODS: This retrospective study included 63 advanced LCNEC patients who had received chemotherapy. We collected clinical data and investigated the TME status (CD4, CD8, CD20 and FOXP3). RESULTS: The overall survival of the patients with a low NLR (<5) was significantly longer than those with a high NLR (≥5) (14.9 vs. 5.2 months; p < 0.001). A multivariate analysis identified a high NLR as a predictor of a poor prognosis (HR, 3.43; 95% CI, 1.73-6.79; p < 0.001). The NLR was inversely correlated with tumoural and stromal CD8-positive tumour-infiltrating lymphocytes (tumoural: r = -0.648, p = 0.005, stromal: r = -0.490, p = 0.046). CONCLUSIONS: A high NLR was associated with a poor prognosis in advanced LCNEC patients. Our study revealed that the NLR can reflect the TME, at least in part, suggesting that the NLR plays an important role not only as a clinical outcome predictor but also as a tumour immune status indicator.

Pre-conditioning intervention in patients with relapsed or refractory acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation: a KSGCT multicenter retrospective analysis.

The efficacy and clinical significance of pre-conditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute lymphoblastic leukemia (ALL) not in remission remain inconclusive. The purpose of this multicenter retrospective study was to clarify the clinical significance of PCI before HCT in patients with non-remission ALL. Patients with non-remission ALL who received HCT between 2005 and 2015 at 16 institutions were included. PCI was objectively defined and classified to three groups according to the intensity of PCI (no, intensive, or moderate). The study cohort consisted of 104 patients with a median age of 38 (range 17-68). A significant decrease of blast percentage in the peripheral blood (PB) was confirmed in both PCI groups, suggesting that PCIs were effective to stabilize the disease activity. The group with moderate PCI had higher nucleated cell count in the BM compared to the group with intensive PCI or the group without PCI. The overall survival (OS) rates of groups with intensive and no PCI showed comparable and significantly better compared to the group with moderate PCI (P = 0.009). Multivariate analysis demonstrated that the OS of moderate PCI group was significantly worse compared to that of intensive PCI group (HR = 2.43, 95% CI: 1.32-4.14, P = 0.004), while the OS of intensive PCI group was comparable to that of the group without PCI. These results suggest that the intensity of PCI rather than the response to PCI may contribute to improve the transplant outcome in patients with ALL not in remission.

Effect of fumaric acid on the growth of Lactobacillus delbrueckii ssp. bulgaricus during yogurt fermentation.

Yogurt is traditionally fermented by a symbiotic starter culture of Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus. These bacteria exchange metabolites with each other to meet their nutritional demands during protocooperation, resulting in a shorter fermentation time. In this study, we investigated whether fumaric acid functions as a symbiotic agent to promote the growth of Lb. bulgaricus by evaluating 8 strains of Lb. bulgaricus and 7 strains of Strep. thermophilus. All the tested Lb. bulgaricus strains metabolized the added fumaric acid into succinic acid during monoculture in milk, and 6 strains (75%) showed shorter fermentation time compared with the control. The addition of malic acid showed similar trends as that of fumaric acid, indicating that the reverse tricarboxylic acid cycle was functioning in Lb. bulgaricus. All 7 Strep. thermophilus strains tested produced fumaric acid during monoculture in milk. Further, in Lb. bulgaricus 2038, the gene expression of fumarate reductase that converts fumaric acid to succinic acid, was higher in the coculture with Strep. thermophilus 1131 than in the monoculture. These findings indicate that fumaric acid produced by Strep. thermophilus can function as a symbiotic substance during yogurt fermentation to stimulate the growth of Lb. bulgaricus.

Effect of lactose hydrolysis on the milk-fermenting properties of Lactobacillus delbrueckii ssp. bulgaricus 2038 and Streptococcus thermophilus 1131.

Yogurt is a well-known nutritious and probiotic food and is traditionally fermented from milk using the symbiotic starter culture of Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus. However, yogurt consumption may cause health problems in lactose-intolerant individuals, and the demand for lactose-free yogurt has been increasing. The standard method to prepare lactose-free yogurt is to hydrolyze milk by lactase; however, this process has been reported to influence the fermentation properties of starter strains. This study aimed to investigate the fermentation properties of an industrial starter culture of L. bulgaricus 2038 and S. thermophilus 1131 in lactose-hydrolyzed milk and to examine the metabolic changes induced by glucose utilization. We found that the cell number of L. bulgaricus 2038, exopolysaccharide concentration, and viscosity in the coculture of L. bulgaricus 2038 and S. thermophilus 1131 was significantly increased in lactose-hydrolyzed milk compared with that in unhydrolyzed milk. Although the cell number of S. thermophilus 1131 showed no difference, production of formic acid and reduction of dissolved oxygen were enhanced in lactose-hydrolyzed milk. Further, in lactose-hydrolyzed milk, S. thermophilus 1131 was found to have increased the expression of NADH oxidase, which is responsible for oxygen reduction. These results indicated that glucose utilization promoted S. thermophilus 1131 to rapidly reduce the dissolved oxygen amount and produce a high concentration of formic acid, presumably resulting in the increased cell number of L. bulgaricus 2038 in the coculture. Our study provides basic information on the metabolic changes in starter strains in lactose-hydrolyzed milk, and demonstrates that lactose-free yogurt with increased cell number of L. bulgaricus can be prepared without delay in fermentation and decrease in the cell number of S. thermophilus.

Outcomes and Prognostic Factors for Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation: A KSGCT Multicenter Analysis.

A multicenter retrospective study was performed to evaluate the prognostic factors in 104 patients with relapsed or refractory acute lymphoblastic leukemia (ALL), who underwent allogeneic hematopoietic cell transplantation (HCT) between 2005 and 2015. The median age was 38 (range, 17 to 68), and the median blast fraction in peripheral blood and bone marrow was 1% (range, 0 to 99%) and 52% (range, 0 to 100%), respectively. With a median follow-up of 47 months (range, 8.3 to 105 months), overall survival (OS), nonrelapse mortality, and relapse mortality at 1 year were 25%, 44%, and 31%, respectively. Multivariate analysis demonstrated independent predictors for poor OS, including nuclear cell count in the bone marrow ≥10 × 104/µL (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.33 to 3.43; P = .002), elevated lactate dehydrogenase level (HR, 1.66; 95% CI, 1.05 to 2.62; P = .031), and no primary induction failure (HR, 2.05; 95% CI, 1.11 to 3.78; P = .022). A prognostic scoring index was designed based on these survival predictors. At 2 years, OS was 28%, 14%, and 0% for good (score 0 or 1; n = 47), intermediate (score 2; n = 40), and poor (score 3; n = 17), respectively (P < .001). This scoring system may be useful in identifying the patient population for which allogeneic HCT is least beneficial in advanced stages of ALL.

A Prospective, Longitudinal Observation of the Incidence, Treatment, and Survival of Late Acute and Chronic Graft-versus-Host Disease by National Institutes of Health Criteria in a Japanese Cohort.

To prospectively validate the incidence, manifestations, and outcomes of graft-versus-host disease (GVHD) by National Institutes of Health criteria, we recruited 406 hematopoietic stem cell transplantation recipients at 16 transplant centers in Japan from May 2012 to June 2014. The 2-year cumulative incidence of late acute and chronic GVHD was 3.2% (n = 13) and 35.4% (n = 145), with a median onset of 3.6 and 4.7 months after transplant, respectively. The global severity at onset was mild in 30.3%, moderate in 43.5%, and severe in 26.2%. Eighty-two patients were followed up for 2 years, with 79.3% still manifesting GVHD symptoms, and 80.6% (n = 117) of the patients received systemic immunosuppressive treatment (IST), with a 2-year cumulative incidence of IST termination of 33.1%. Severe patients showed a significantly lower rate of IST termination than those with mild and moderate severities (mild, 38.5%; moderate, 40.9%; and severe, 17.2%). The 2-year incidence of nonrelapse mortality (NRM) and relapse was not significantly different according to the severity at onset (NRM: mild [16.6%] versus moderate [8.7%] versus severe [16.1%]; relapse: mild [14.9%] versus moderate [14.7%] versus severe [5.3%]). As a result, 2-year overall survival (OS) and GVHD-specific survival (GSS) were equivalent according to the severity at onset (mild: OS = 81.0%, GSS = 85.7%; moderate: OS = 84.2%, GSS = 92.5%; severe: OS = 83.9%, GSS = 89.2%). Our study helped identify the characteristics of late acute and chronic GVHD in Japanese patients. Further investigation is needed to identify an optimal endpoint for survival prediction.

Clinical status and prognostic factors in Japanese patients with uterine leiomyosarcoma.

OBJECTIVE: Uterine leiomyosarcoma (uLMS) is a rare gynecologic malignancy for which the currently available treatments do not consistently provide long-term disease control. This study aimed to reveal the current clinical status of uLMS to support future clinical trials. METHODS: This study enrolled patients with uLMS treated at 53 Japanese institutions from 2000 to 2012. Central pathological review (CPR) was performed. All cases were confirmed by CPR, and epidemiological features, treatment, and prognosis were analyzed statistically. RESULTS: A total of 307 patients were enrolled. A diagnosis of uLMS was confirmed in 266 patients (86.6%) of patients after CPR, of whom data for 259 were analyzed. Of these, 186 (71.8%) patients underwent complete gross resection as primary therapy. Ninety-eight patients received no additional adjuvant therapy, while docetaxel and gemcitabine was the most frequent regimen among 155 patients treated with adjuvant chemotherapy. In all cases, the median overall survival (OS) was 44.2 months. Multivariate analyses of prognostic factors in all cases identified stage III and IV disease, high serum lactate dehydrogenase level, and menopausal status as poor prognostic factors. However, in stage I cases, high serum lactate dehydrogenase level and no adjuvant treatment were identified as poor prognostic factors. The 5-year OS of patients with stage I uLMS treated with adjuvant chemotherapy was significantly better than that of those without adjuvant treatment (67.8% vs 46.7%, P = 0.0461). CONCLUSIONS: Despite complete removal of the primary lesion, the clinical course of patients with uLMS was poor due to recurrence of distant metastasis. The application of a suitable biomarker and effective adjuvant chemotherapy are required to improve the prognosis of patients with uLMS.