Current status and prospects of artificial intelligence in breast cancer pathology: convolutional neural networks to prospective Vision Transformers.

Breast cancer is the most prevalent cancer among women, and its diagnosis requires the accurate identification and classification of histological features for effective patient management. Artificial intelligence, particularly through deep learning, represents the next frontier in cancer diagnosis and management. Notably, the use of convolutional neural networks and emerging Vision Transformers (ViT) has been reported to automate pathologists' tasks, including tumor detection and classification, in addition to improving the efficiency of pathology services. Deep learning applications have also been extended to the prediction of protein expression, molecular subtype, mutation status, therapeutic efficacy, and outcome prediction directly from hematoxylin and eosin-stained slides, bypassing the need for immunohistochemistry or genetic testing. This review explores the current status and prospects of deep learning in breast cancer diagnosis with a focus on whole-slide image analysis. Artificial intelligence applications are increasingly applied to many tasks in breast pathology ranging from disease diagnosis to outcome prediction, thus serving as valuable tools for assisting pathologists and supporting breast cancer management.

Comparison of pain-relieving effects by number of irradiations, through propensity score matching and the international consensus endpoint.

Background: Palliative radiotherapy for bone metastases utilizes various dose fractionation schedules. The pain-relieving effects of a single fraction (SF) and multiple fractions (MF) are largely debated due to the difficulty in matching patients' backgrounds and in assessing the effectiveness of pain relief. This study aimed to compare the pain-relieving effects of SF and MF palliative radiotherapy for bone metastases using propensity score matching and the international consensus endpoint (ICE). Materials and methods: Our study included 195 patients irradiated for bone metastasis. The primary endpoint was the pain-relieving effects used by ICE. In addition, the evaluation was performed by using responder (complete response/partial response) and non-responder (pain progression/indeterminate response) categorization. The secondary endpoints were the discharge or transfer rate at one month after irradiation and postirradiation pathological fracture rate. Propensity score matching was used to adjust patient's characteristics and reduce selection bias. Results: After adapting propensity score matching, the total number of patients was 74. There was no significant difference in the pain-relieving effects between SF and MF (p = 0.184). There were no significant differences in them between SF and MF when using responder and non-responder categorization (p = 0.163). Furthermore, there were no differences in the discharge or transfer rates (p = 0.693) and pathological fracture rates (p = 1.00). Conclusions: The combination of propensity score matching and ICE revealed no significant difference in the pain-relieving effects between SF and MF for bone metastases, thus, SF has no significant disadvantage compared to MF in pain-relieving effects.

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

PURPOSE: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). METHODS: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. RESULTS: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. CONCLUSIONS: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.

Single-layered assembly of vanadium pentoxide nanowires on graphene for nanowire-based lithography technique.

Graphene nanoribbon (GNR)-based materials are a promising device material because of their potential high carrier mobility and atomically thin structure. Various approaches have been reported for preparing the GNR-based materials, from bottom-up chemical synthetic procedures to top-down fabrication techniques using lithography of graphene. However, it is still difficult to prepare a large-scale GNR-based material. Here, we develop a procedure to prepare a large-scale GNR network using networked single-layer inorganic nanowires. Vanadium pentoxide (V2O5) nanowires were assembled on graphene with an interfacial layer of a cationic polymer via electrostatic interaction. A large-scale nanowire network can be prepared on graphene and is stable enough for applying an oxygen plasma. Using plasma etching, a networked graphene structure can be generated. Removing the nanowires results in a networked flat structure whose both surface morphology and Raman spectrum indicate a GNR networked structure. The field-effect device indicates the semiconducting character of the GNR networked structure. This work would be useful for fabricating a large-scale GNR-based material as a platform for GNR junctions for physics and electronic circuits.

Does local injection of reveromycin A inhibit tooth movement without causing systemic side effects?

OBJECTIVE: To determine the feasibility of local inhibition of osteoclast activity and control of tooth movement with local intraoral reveromycin A (RMA) injection in model mice for experimental tooth movement. MATERIALS AND METHODS: Eight-week-old wild-type mice (n = 6 per group) were divided into four groups consisting of two non-RMA groups that received normal saline for 14 (14-day non-RMA group) or 21 consecutive days (21-day non-RMA group) and 2 RMA groups that received RMA (1.0 mg/kg of weight) for 14 (14-day RMA group) or 21 consecutive days (21-day RMA group). RMA was injected locally into the buccal mucosa of the left first maxillary molar twice daily starting 3 days before placement of the 10-gf Ni-Ti closed coil spring. Tooth movement distance was analysed using micro-computed tomography. The effects on surrounding alveolar bone were evaluated by measuring the ratio of bone surface area to tissue surface area with haematoxylin-eosin-stained sections and counting the number of osteoclasts in periodontal tissue with TRAP-stained sections. Blood tests were performed and bone volume and trabecular separation at the tibial neck were measured to analyse systemic side effects. RESULTS: Local RMA injection inhibited tooth movement by 40.6 per cent, promoted alveolar bone volume maintenance by 37.4 per cent, and inhibited osteoclast activity around the tooth root at 21 days by 40.8 per cent. Systemic effects on osteoclasts or osteoblasts were not observed. CONCLUSION: Local injection of RMA enabled control of tooth movement without systemic side effects in a mouse model.

Predictive Factors of Postendoscopic Submucosal Dissection Electrocoagulation Syndrome and the Utility of Computed Tomography Scan after Esophageal Endoscopic Submucosal Dissection.

BACKGROUND/AIMS: Recently, postendoscopic submucosal dissection electrocoagulation syndrome (PEECS) has attracted attention. However, the criteria for computed tomography (CT) scanning following esophageal endoscopic submucosal dissection (ESD) are unclear. In this study, we aimed to identify the predictive factors of PEECS and the usefulness of CT scanning after esophageal ESD. METHODS: A total of 245 lesions in 223 patients who underwent esophageal ESD between February 2008 and October 2018 were retrospectively analyzed. Patients with double cancers, those who experienced procedural accidents, such as aspiration pneumonitis or perforation, and those who were unable to undergo CT were excluded from the study. PEECS evaluation items included body temperature (≤37.7°C = 1 point, ≥37.8°C = 2 points), white blood cell count (<10,800/µL = 1 point, ≥10,800/µL = 2 points), and chest pain (numerical rating scale [NRS] ≤4 = 1 point, NRS ≥5 = 2 points). Scores of ≥5 points were categorized as the PEECS-positive group, and scores of ≤4 points were categorized as the PEECS-negative group. The degree of mediastinal emphysema on CT was stratified into 5 grades, in which grades 0 and 1 were considered as the "low-grade" group, and grades 2, 3, and 4 were considered as the "high-grade" group. We analyzed the prognostic factors of high-grade mediastinal emphysema, including the presence or absence of PEECS. RESULTS: The PEECS-positive group comprised 18 out of the 163 patients (11.0%), and mediastinal emphysema was stratified into grades 0 (94), 1 (51), 2 (12), 3 (5), and 4 (1 patient). Three independent risk factors for the onset of PEECS were identified, as follows: resected area ≥750 mm2 (OR 7.28, 95% CI 1.42-37.33, p = 0.017), treatment duration ≥75 min (OR 10.26, 95% CI 1.20-87.77, p = 0.034), and muscle layer exposure (OR 10.92, 95% CI 2.22-53.74, p = 0.003). Two independent predictive factors of high-grade mediastinal emphysema were identified, which were PEECS positivity (OR 4.31, 95% CI 1.29-14.41, p = 0.018), and muscle layer exposure (OR 4.08, 95% CI 1.18-14.06, p = 0.026). CONCLUSIONS: A large resected area, prolonged treatment duration, and muscle layer exposure are risk factors for the onset of PEECS. Mediastinal emphysema was observed in 43% of patients following ESD. When marked clinical symptoms of PEECS appear, high-grade mediastinal emphysema may be observed, and therefore CT should be performed in these cases.

Time-varying synchronous cell ensembles during consummatory periods correlate with variable numbers of place cell spikes.

Spike rates of a hippocampal place cell are not constant and vary even when an animal visits an identical place field with nearly identical behavior. As one potential neurophysiological source underlying place cell spiking variability, we focused on the temporally fluctuating activity states of neuronal ensembles. Spike patterns of hippocampal neurons were recorded from rats performing a linear track task. Within a single consummatory period, similar sets of neurons were more frequently recruited in synchronous firing events, whereas different synchronized firing patterns of neuronal populations tended to be identified in different consummatory periods. A linear regression analysis indicated that the time-varying activation patterns of neuronal populations during consummatory periods are correlated with the spike rates of a place cell within its place field during running. These findings suggest that place cell in-field spiking is not only triggered by static inputs that represent external environments but also strongly depends on the time-varying internal states of neuronal populations.

Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia.

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

Effect of reduced-intensity conditioning and the risk of late-onset non-infectious pulmonary complications in pediatric patients.

OBJECTIVE: Late-onset non-infectious pulmonary complications (LONIPCs) contribute to higher morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we investigated the risk factors of LONIPCs in pediatric patients. METHOD: Between 2001 and 2011, 74 pediatric patients (range, 7 months to 22.7 years old; median 6.5 years old), including 29 with a primary immunodeficiency, underwent 80 allo-HSCTs at our institution. Sixty-seven patients who survived more than 3 months after allo-HSCT were analyzed retrospectively. The median follow-up period was 1 973 days (range, 126-5 145 days). RESULTS: Nine patients (13.4%) developed LONIPCs between 90 and 3 578 days after allo-HSCT. A myeloablative conditioning (MAC) regimen and chronic GVHD were determined as significant risk factors of LONIPCs. None of 18 patients who received the reduced-intensity conditioning (RIC) regimen developed LONIPCs, although there was no difference in overall survival between the MAC and RIC regimen. Notably, two immunodeficient patients who received busulfan-based MAC regimen under 2 years old developed LONIPC with no history of chronic GVHD after 5 years and 10 years from SCT, respectively, suggesting the direct toxicity of busulfan. CONCLUSION: Our study's findings indicate that the RIC regimen reduces the risk of LONIPCs in pediatric patients.

Black Tea High-Molecular-Weight Polyphenol-Rich Fraction Promotes Hypertrophy during Functional Overload in Mice.

Mitochondria activation factor (MAF) is a high-molecular-weight polyphenol extracted from black tea that stimulates training-induced 5' adenosine monophosphate-activated protein kinase (AMPK) activation and improves endurance capacity. Originally, MAF was purified from black tea using butanol and acetone, making it unsuitable for food preparation. Hence, we extracted a MAF-rich sample "E80" from black tea, using ethanol and water only. Here, we examined the effects of E80 on resistance training. Eight-week old C57BL/6 mice were fed with a normal diet or a diet containing 0.5% E80 for 4, 7 and 14 days under conditions of functional overload. It was found that E80 administration promoted overload-induced hypertrophy and induced phosphorylation of the Akt/mammalian target of rapamycin (mTOR) pathway proteins, such as Akt, P70 ribosomal protein S6 kinase (p70S6K), and S6 in the plantaris muscle. Therefore, functional overload and E80 administration accelerated mTOR signaling and increased protein synthesis in the muscle, thereby inducing hypertrophy.

EWSR1/ELF5 induces acute myeloid leukemia by inhibiting p53/p21 pathway.

The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the association of EWSR1 chimeric fusion genes with leukemia has rarely been reported. We identified a novel EWSR1-associated chimeric fusion gene in a patient with acute myeloid leukemia harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired-end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation-specific transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21-dependent pathway. The injection of EWSR1/ELF5-transduced NIH3T3 cells into NSG-SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5.

Haploidentical Bone Marrow Transplantation With Clofarabine and Busulfan Conditioning for a Child With Multiple Recurrent Acute Lymphoblastic Leukemia.

Outcome of children with acute lymphoblastic leukemia (ALL) has improved over the years, but not for those with multiple recurrences because of high therapy resistance and heavily pretreated history that potentially cause physical damages. We describe the case of an 11-year-old boy with a third relapse of ALL and a history of 2 allogeneic bone marrow transplantations. He was successfully treated with clofarabine combination chemotherapy and achieved a fourth remission at 16 months following haploidentical bone marrow transplantation with conditioning regimen of clofarabine and busulfan. Clofarabine/busulfan conditioning might be a preferable option for children with multiple recurrent ALL, and warrants further investigation.

Difference in visual motion representation between cortical areas MT and MST during ocular following responses.

The middle temporal (MT) and medial superior temporal (MST) areas are successive stations of the visual motion-processing stream and project in parallel to the pontine nucleus, which is closely associated with rapid stabilization of gaze. We recorded the neural activities of MT and MST neurons of monkeys during short-latency ocular following responses (OFRs) elicited by large-field sinusoidal gratings with different spatial frequencies drifting at different temporal frequencies, and examined the dependence on spatiotemporal frequency. The results indicate that most MT/MST neurons were tuned almost separately for spatial and temporal frequencies of motion stimuli. The difference between MT and MST neurons was particularly striking for the optimal spatial frequency (higher for MT and lower for MST). The spatiotemporal frequency dependence of the OFRs could be reproduced by a weighted sum of the population activities of the MT and MST neurons. We conclude that MT and MST neurons work as spatiotemporal frequency sensors that extract motions of finer and coarser visual features and that both areas contribute to generation of OFRs.

Secondary cancers among children with acute lymphoblastic leukaemia treated by the Tokyo Children's Cancer Study Group protocols: a retrospective cohort study.

With improvement in survival, it is important to evaluate the impact of treatment on secondary cancers in acute lymphoblastic leukaemia (ALL) survivors. A retrospective cohort study comprising 2918 children diagnosed with ALL and enrolled on Tokyo Children's Cancer Study Group (TCCSG) protocols between 1984 and 2005 was conducted to evaluate the incidence of secondary cancers and associated factors including treatment protocol, cranial irradiation and other characteristics of the primary ALL. Thirty-seven patients developed secondary cancers, including acute myeloid leukaemia (n = 11), myelodysplastic syndrome (n = 5), non-Hodgkin lymphoma (n = 2), brain tumours (n = 13) and other solid carcinomas (n = 6) within a median follow-up duration of 9·5 years. The cumulative incidence of any secondary cancers was 1·0% (95% confidence interval (CI), 0·7-1·4%) at 10 years and 2·4% (95% CI, 1·5-3·7%) at 20 years, respectively. Standardized incidence rate ratio of secondary cancers was 9·3 (95% CI, 6·5-12·8). Multivariate analyses showed an increased risk of secondary cancers associated with the recent treatment protocol and cranial irradiation. There was no evidence of a reduction in secondary cancer incidence despite marked decreases in cranial irradiation use in the recent protocols.

Pain management during bone marrow aspiration and biopsy in pediatric cancer patients.

BACKGROUND: The pain associated with bone marrow aspiration and biopsy (BMAB) has an enormous impact on pediatric cancer patients and their families, but no specific reference standards for sedation and analgesia have been developed in Japan. To determine the problems associated with pain management during BMAB, a cross-sectional investigation was conducted. METHODS: A survey was sent in October 2011 to data managers in institutions belonging to the Tokyo Children's Cancer Study Group, addressing the non-pharmacological and pharmacological pain management for BMAB performed on pediatric cancer inpatients between January 2010 and December 2010. RESULTS: The eligible response rate was 41 of 57 institutions (71.9%). Non-pharmacological pain intervention was provided in 68% of surveyed institutions. All institutions provided pharmacological pain management. In most institutions, sedation/analgesia was performed by pediatric oncologists in a treatment room in the ward. Standards for pain management were developed and utilized in only four institutions. Other means of pain management were provided in various settings. Twelve institutions reported insufficient sedation/analgesia. In total, 80% of institutions reported some adverse events. Two serious adverse events were reported in cases of underlying or complicated conditions. No serious long-term consequences were reported. CONCLUSIONS: Significant issues were identified regarding the efficacy and safety of pain management. Adverse events can occur in any institution. Children with underlying or complicated conditions are at high risk for serious adverse events. Therefore, adequate and systematic assessment, patient monitoring, preparation and treatment for adverse events, and cooperation with skilled specialists of pediatric oncology, anesthesiology, and intensive care are essential.

Obturator Hernia in a Patient Undergoing Hemodialysis.

Obturator hernia is a rare condition that commonly affects frail older women. A 54-year-old woman presented to our hospital with left hip joint pain. She had suffered a left pubic bone fracture and commenced maintenance hemodialysis. Pelvic computed tomography (CT) showed an incarcerated small intestine through the left obturator foramen, while abdominal CT showed marked intestinal dilatation. She underwent emergency laparotomy, and the incarcerated small intestine was found to be necrotic. Partial small intestinal resection and bilateral obturator hernioplasty were performed. Because obturator hernia is a potentially fatal condition, early detection and treatment are important.

Irreversible leukoencephalopathy after reduced-intensity stem cell transplantation in a dyskeratosis congenita patient with TINF2 mutation.

Hematopoietic stem cell transplantation (HSCT) for dyskeratosis congenita (DC) is challenging due to severe treatment-related adverse effects. Development of pulmonary fibrosis or veno-occlusive disease is well described in DC. However, neurological complication after HSCT has not been reported. A 9-year-old Japanese male with DC harboring the TINF2 mutation received reduced-intensity HSCT. Unfortunately, patient developed posterior reversible encephalopathy syndrome-like symptoms plausibly result by combination of thrombotic microangiopathy, graft-versus-host disease, and persistent hypertension and has been persisted mental retardation. Therefore, to decrease risk in DC cases after HSCT, strict control of hypertension, graft-versus-host disease, and thrombotic microangiopathy is required.