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In clinical practice, urethral diseases are not as frequent as conditions affecting other components of the urinary system. Radiological imaging tests, such as retrograde urethrography, CT, MRI, and PET/CT, along with patient history, are crucial for accurately assessing relatively rare urethral lesions. This article aimed to provide a comprehensive overview of urethral lesions, from traumatic changes to neoplasms, and discuss the multimodal imaging findings of various urethral lesions that radiologists should know. To this end, the normal imaging anatomy of the urethra and a step-by-step approach that can be used in clinical practice have been presented to help in the systematic understanding of urethral lesions., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Triple-negative breast cancer (TNBC) lacks the expression of hormone and HER2 receptors and is highly malignant with no effective therapeutic targets. In TNBC, the cancer stem-like cell (CSC) population is considered to be the main cause of resistance to treatment. Thus, the therapeutic targeting of this population could substantially improve patient survival. Here, we identify the RNA-binding protein ZCCHC24 as enriched in the mesenchymal-like TNBC population. ZCCHC24 promotes the expression of a set of genes related to tumorigenicity and treatment resistance by directly binding to the cis-element "UGUWHWWA" in their mRNAs, thereby stabilizing them. One of the ZCCHC24 targets, ZEB1, is a transcription factor that promotes the expression of cancer stemness genes and reciprocally induces ZCCHC24 expression. ZCCHC24 knockdown by siRNAs shows a therapeutic effect and reduces the mesenchymal-like cell population in TNBC patient-derived xenografts. ZCCHC24 knockdown also has additive effects with the BET inhibitor JQ1 in suppressing tumor growth in TNBC patient-derived xenografts., (© 2024. The Author(s).)

An 83-year-old woman presented with disturbance of consciousness and hand tremor. She had taken lithium carbonate 300 mg/day for bipolar disorder and magnesium oxide 660 mg/day for constipation. Blood tests revealed lithium poisoning, hypermagnesemia and acute kidney injury. Computed tomography showed colonic obstruction caused by cancer of the descending colon. In the outpatient section, her blood pressure decreased to 89/54 mmHg, and her heart rate dropped to 40 bpm. We considered that the obstructive ileus induced intravascular dehydration, which led to toxic serum concentrations of lithium and magnesium, triggering the emergence of severe arrythmia induced by sinus dysfunction. The patient was treated with fluid resuscitation and hemodialysis, followed by endoscopic stent replacement for the descending colon cancer obstruction. These treatments improved her general condition and alleviated the lithium poisoning, hypermagnesemia and colonic obstruction. Such a case is considered extremely rare., Competing Interests: We have no conflict of interest to declare., (© The Author(s) 2024. Published by Oxford University Press.)

Increasing pieces of evidence have suggested that astrocyte function has a strong influence on neuronal activity and plasticity, both in physiological and pathophysiological situations. In epilepsy, astrocytes have been shown to respond to epileptic neuronal seizures; however, whether they can act as a trigger for seizures has not been determined. Here, using the copper implantation method, spontaneous neuronal hyperactivity episodes were reliably induced during the week following implantation. With near 24-h continuous recording for over 1 week of the local field potential with in vivo electrophysiology and astrocyte cytosolic Ca 2+ with the fiber photometry method, spontaneous occurrences of seizure episodes were captured. Approximately 1 day after the implantation, isolated aberrant astrocyte Ca 2+ events were often observed before they were accompanied by neuronal hyperactivity, suggesting the role of astrocytes in epileptogenesis. Within a single developed episode, astrocyte Ca 2+ increase preceded the neuronal hyperactivity by ~20 s, suggesting that actions originating from astrocytes could be the trigger for the occurrence of epileptic seizures. Astrocyte-specific stimulation by channelrhodopsin-2 or deep-brain direct current stimulation was capable of inducing neuronal hyperactivity. Injection of an astrocyte-specific metabolic inhibitor, fluorocitrate, was able to significantly reduce the magnitude of spontaneously occurring neuronal hyperactivity. These results suggest that astrocytes have a role in triggering individual seizures and the reciprocal astrocyte-neuron interactions likely amplify and exacerbate seizures. Therefore, future epilepsy treatment could be targeted at astrocytes to achieve epilepsy control., (© 2024 The Authors. GLIA published by Wiley Periodicals LLC.)

Background: Fine bubble (FB) bathing has shown benefits on a mouse model of atopic dermatitis (AD). However, its efficacy in dogs with AD remains to be evaluated., Objective: This study aimed to assess the clinical effectiveness of FB bathing in dogs with AD., Animals: Seventeen dogs with AD whose clinical presentation showed a Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) score of <40., Materials and Methods: The dogs were randomly assigned to either the FB bathing group or the shampoo group. The treatments were administered once a week as per the instructions, in a trial totalling 4 weeks. Evaluations were conducted on Day (D)0 and D28 to assess the outcomes of the trial. The severity of AD was measured using the CADESI-04 and the pruritus Visual Analog Scale (PVAS). The skin barrier function parameters, transepidermal water loss (TEWL) and stratum corneum hydration were measured before and after the treatment., Results: Both treatment groups demonstrated a decreasing trend in CADESI-04 scores, yet the FB group exhibited significant improvement in comparison to the shampoo group after 1 month of trial. There were no significant changes in PVAS scores in either group. No significant difference was found in skin barrier function parameters between the two treatments, although TEWL slightly decreased in the FB group and slightly increased in the shampoo group after treatment., Conclusions and Clinical Relevance: These results suggested that FB treatment provides benefits for dogs with AD and offers an alternative topical treatment option with a lesser impact on skin barrier function compared to frequent shampooing., (© 2024 Vet Derm Tokyo Dermatological and Laboratory Service for Animals. Veterinary Dermatology published by John Wiley & Sons Ltd on behalf of ESVD and ACVD.)

Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer; therefore, new therapeutic approaches are required to improve the prognosis of LSCC. Although immunotherapies targeting B7 family molecules were explored as treatments for several cancer types, the expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated in detail. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression using 110 surgically resected pathological specimens retrospectively. We examined the correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells. High B7-H3 expression in tumor cells was associated with a better prognosis and a significant increase in the number of CD163 + PD-L1 + macrophages. Quantitative analysis revealed that there is a positive correlation between B7-H3 and PD-L1 expression in tumor and stromal cells, as well as in intratumoral tumor-infiltrating lymphocytes and tumor-associated macrophages in the same cells. CD68 + , CD163 + , and CK + cells with PD-L1 + phenotypes had higher B7-H3 expression compared to PD-L1 - cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. New therapeutic strategies are needed for the treatment of refractory DLBCL. 4-Hydroxy-2-nonenal (4-HNE) is a cytotoxic lipid peroxidation marker, which alters intracellular signaling and induces genetic mutations. Lipid peroxidation is associated with nonapoptotic cell death, called ferroptosis. However, the relationship between 4-HNE accumulation and feroptotic regulators in DLBCL has not been fully evaluated. Here, we aimed to evaluate the accumulation of lipid peroxide and the expression of ferroptosis suppressor protein 1 (FSP1) in DLBCL using immunohistochemistry. We found a significant increase in the expression of FSP1 in cases with nuclear 4-HNE accumulation (P = .021). Both nuclear and cytoplasmic 4-HNE accumulation and FSP1 positivity were independent predictors of worse prognosis. In vitro exposure to 4-HNE resulted in its concentration- and time-dependent intracellular accumulation and increased expression of FSP1. Furthermore, short-term (0.25 and 1.0 μM) or long-term (0.25 μM) exposure to 4-HNE induced resistance to not only apoptosis but also ferroptosis. Taken together, regulation of FSP1 through 4-HNE accumulation may attenuate resistance to cell death in treatment-resistant DLBCL and might help develop novel therapeutic strategies for refractory DLBCL., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

A woman in her 70s, initially suspected of having fibroadenoma due to a well-defined mass in her breast, underwent regular mammography and ultrasound screenings. Over several years, no appreciable alterations in the mass were observed, maintaining the fibroadenoma diagnosis. However, in the fourth year, an ultrasound indicated slight enlargement and peripheral irregularities in the mass, even though the mammography images at that time showed no alterations. Interestingly, mammography images over time showed the gradual disappearance of previously observed arterial calcification around the mass. Pathological examination eventually identified the mass as invasive ductal carcinoma. Although the patient had breast tissue arterial calcification typical of atherosclerosis, none was present around the tumor-associated arteries. This case highlights the importance of monitoring arterial calcification changes in mammography, suggesting that they are crucial indicators in breast cancer diagnosis, beyond observing size and shape alterations.

Objectives: The aim is to evaluate the prevention and development of cervical cancer in systemic lupus erythematosus (SLE) patients in Japan and its background based on a questionnaire survey., Methods: The questionnaire was handed to 460 adult female SLE patients at 12 medical institutions. The participants were grouped by age, and data related to their human papillomavirus vaccination status, age at first coitus, cervical cancer screening, and diagnosis of cervical cancer were analysed., Results: A total of 320 responses were received. Patients aged 35-54 years included a higher proportion of patients whose age at first coitus was <20 years. This group also showed a higher rate of cervical cancer/dysplasia. Only nine patients had a human papillomavirus vaccination history. Adequate frequency of cervical cancer screening was slightly higher (52.1%) among SLE patients than in the Japanese general population. However, 23% of the patients had never undergone examination, primarily because of a feeling of troublesome. The incidence of cervical cancer was significantly higher among SLE patients. One reason for this may be associated with the use of immunosuppressants, although the difference was not significant., Conclusions: SLE patients are at a higher risk of cervical cancer and dysplasia. Rheumatologists should proactively recommend vaccination and screening examinations for SLE female patients., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: Cardiac amyloidosis is a fatal disease of severe heart failure caused by the accumulation of amyloid in the myocardium. This disease is often advanced by the time cardiac symptoms appear; therefore, early detection and treatment are critical for a good prognosis. Recently, it has been suggested that cardiac amyloidosis is implicated in several orthopedic diseases, including carpal tunnel syndrome (CTS), which is often reported to precede cardiac dysfunction. Shoulder disease has also been suggested to be associated with cardiac amyloidosis; however, there have been no reports investigating the rate of amyloid deposition in shoulder specimens and the simultaneous prevalence of cardiac amyloidosis. Herein, we investigated the prevalence of intraoperative specimen amyloid deposition and cardiac amyloidosis in shoulder disease and CTS to determine the usefulness of shoulder specimen screening as a predictor of cardiac amyloidosis development., Methods: A total of 41 patients undergoing arthroscopic shoulder surgery and 33 patients undergoing CTS surgery were enrolled in this study. The shoulder group included rotator cuff tears, contracture of the shoulder, synovitis, and calcific tendonitis. In the shoulder group, a small sample of synovium and the long head of the biceps brachii tendon were harvested, while the transverse carpal ligament was harvested from the CTS group. The intraoperative specimens were pathologically examined for amyloid deposition, and patients with amyloid deposition were examined for the presence of cardiac amyloidosis by cardiac evaluation., Results: In the shoulder group, three cases (7.3%) of transthyretin amyloid deposition were found, all of which involved rotator cuff tears. None of these three cases with amyloid deposition were associated with cardiac amyloidosis. When examining the specimens, the amyloid deposition rate in the long head of the biceps brachii tendon was higher than that in the synovium. In the CTS group, 12 cases (36.4%) of transthyretin amyloid deposition were observed. Of these cases, seven underwent cardiac evaluation and two were identified with cardiac amyloidosis., Conclusion: While the prevalence of amyloid deposition and cardiac amyloidosis in the CTS group was consistent with previous reports, the shoulder group showed a lower deposition rate and no concomitant cardiac amyloidosis. Therefore, it remains debatable whether investigating amyloid deposition in samples obtained from shoulder surgery is beneficial for the early detection of cardiac amyloidosis., (© 2023 The Authors.)

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) is useful for preoperatively diagnosing various pancreatic tumors. Although there is a risk of complications, such as pancreatitis, this procedure achieves the crucial need of reducing unnecessary invasive surgery for benign lesions. Herein, we reported a surgically resected case of pancreatic hamartoma in the pancreatic head whose retrospective analysis revealed that the specimens obtained via EUS-FNAB contained hamartoma fragments. Pancreatic hamartoma is an extremely rare benign disease that is exceptionally difficult to diagnose before surgical resection owing to its rarity and lack of established imaging findings. To the best of our knowledge, the preoperative diagnosis of pancreatic hamartoma via EUS-FNAB specimens has not been reported to date. Herein, postoperative EUS-FNAB evaluation revealed a collection of pancreatic hamartoma lesions, although the initial diagnosis was pancreatic tissue with focal atrophy and fibrosis. Diagnosis using EUS-FNAB can be challenging owing to the very small sample size. If mature acini and ducts with fibrous stroma without islets are observed in the EUS-FNAB specimen, pancreatic hamartoma should be considered as a differential diagnosis. Thus, careful follow-up or reexamination of EUS-FNAB should be considered instead of surgery if a benign lesion is suspected preoperatively., (© 2023 Wiley Periodicals LLC.)

Accumulation of 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation, has various favorable and unfavorable effects on cancer cells; however, the clinicopathological significance of its accumulation in hepatocellular carcinoma (HCC) and its metabolic pathway remain unknown. This study analyzed 4-HNE accumulation and its clinicopathological significance in HCC. Of the 221 cases, 160 showed relatively low accumulation of 4-HNE in HCC tissues, which was an independent prognostic predictor. No correlation was found between 4-HNE accumulation and the expression of the antioxidant enzymes glutathione peroxidase 4, ferroptosis suppressor protein 1, and guanosine triphosphate cyclohydrolase 1. Therefore, we hypothesized that 4-HNE metabolism is up-regulated in HCC. A database search was focused on the transcriptional regulation of aldo-keto reductases, alcohol dehydrogenases, and glutathione-S-transferases, which are the metabolic enzymes of 4-HNE, and seven candidate transcription factor genes were selected. Among the candidate genes, the knockdown of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) increased 4-HNE accumulation. Immunohistochemical analysis revealed an inverse correlation between 4-HNE accumulation and SMARCA4 expression. These results suggest that SMARCA4 regulates 4-HNE metabolism in HCC. Therefore, targeting SMARCA4 provides a basis for a new therapeutic strategy for HCC via 4-HNE accumulation and increased cytotoxicity.

Comprehensive screenings to clarify indirect cell-cell interactions, such as those in the tumor microenvironment, especially comprehensive assessments of supporting cells' effects, are challenging. Therefore, in this study, indirect CRISPR screening for drug resistance with cell-cell interactions was invented. The photoconvertible fluorescent protein Dendra2 was inducted to supporting cells and explored the drug resistance responsible factors of supporting cells with CRISPR screenings. Random mutated supporting cells co-cultured with leukemic cells induced drug resistance with cell-cell interactions. Supporting cells responsible for drug resistance were isolated with green-to-red photoconversion, and 39 candidate genes were identified. Knocking out C9orf89, MAGI2, MLPH, or RHBDD2 in supporting cells reduced the ratio of apoptosis of cancer cells. In addition, the low expression of RHBDD2 in supporting cells, specifically fibroblasts, of clinical pancreatic cancer showed a shortened prognosis, and a negative correlation with CXCL12 was observed. Indirect CRISPR screening was established to isolate the responsible elements of cell-cell interactions. This screening method could reveal unknown mechanisms in all kinds of cell-cell interactions by revealing live phenotype-inducible cells, and it could be a platform for discovering new targets of drugs for conventional chemotherapies., (© 2023. The Author(s).)

Purpose: To retrospectively compare the clinical and pathological characteristics of breast masses and non-mass lesions that underwent ultrasound (US)-guided 16-gauge spring-loaded core needle biopsy (CNB) or 12-gauge spring-loaded vacuum-assisted biopsy (VAB)., Methods: We retrospectively compared the results from US-guided diagnostic breast biopsy performed with a 16-gauge CNB (Magnum™) or a 12-gauge VAB (Celero ® ). The patients' backgrounds and pathological features for each device were examined., Results: In 453 patients with 500 lesions, 373 lesions underwent CNB and 127 underwent VAB. The positive biopsy rate (positive predictive value 3) was significantly higher for VAB (92/127; 72.4%) than for CNB (231/373; 61.9%) (P = 0.032). Non-mass lesions were biopsied more frequently with VAB (57/127; 47.4%) than with CNB (27/378; 7.14%) (P = 0.000). The upgrade rate from high-risk to malignant lesions was significantly higher for CNB (5/19; 26.3%) than for VAB (1/8; 12.5%) (P = 0.043). There were five (1.34%) specimen failures with CNB and one (0.78%) with VAB, 18 (4.82%) re-biopsies with CNB and three (2.36%) with VAB, and 11/21 (52.4%) upgrades from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) with CNB and 11/30 (36.7%) with VAB. Although these rates tended to be higher with CNB than with VAB, the difference was not significant., Conclusion: Although VAB had a significantly higher rate of non-mass lesion biopsies, the upgrade rate from high-risk to malignant lesions was significantly lower for VAB than for CNB. US-guided 12-gauge spring-loaded VAB may be more appropriate for biopsy of non-mass lesions., (© 2023. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

We investigated whether 18 F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography images restored via deep learning (DL) improved image quality and affected axillary lymph node (ALN) metastasis diagnosis in patients with breast cancer. Using a five-point scale, two readers compared the image quality of DL-PET and conventional PET (cPET) in 53 consecutive patients from September 2020 to October 2021. Visually analyzed ipsilateral ALNs were rated on a three-point scale. The standard uptake values SUV max and SUV peak were calculated for breast cancer regions of interest. For "depiction of primary lesion", reader 2 scored DL-PET significantly higher than cPET. For "noise", "clarity of mammary gland", and "overall image quality", both readers scored DL-PET significantly higher than cPET. The SUV max and SUV peak for primary lesions and normal breasts were significantly higher in DL-PET than in cPET ( p < 0.001). Considering the ALN metastasis scores 1 and 2 as negative and 3 as positive, the McNemar test revealed no significant difference between cPET and DL-PET scores for either reader ( p = 0.250, 0.625). DL-PET improved visual image quality for breast cancer compared with cPET. SUV max and SUV peak were significantly higher in DL-PET than in cPET. DL-PET and cPET exhibited comparable diagnostic abilities for ALN metastasis.

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint inhibitors, acts as a suppressive signal for the surrounding immune system; however, its expression and effect on TAMs and the clinical outcome in breast cancer are unknown. In this study, we used high-throughput multiple immunohistochemistry to spatially and quantitatively analyze TAMs. We subjected 81 breast cancer specimens to immunostaining for CD68, CD163, PD-1, PD-L1, CD20, and pan-CK. In both stromal and intratumoral areas, the triple-negative subtype had significantly more CD68/CD163, CD68/PD-L1, and CD163/PD-L1 double-positive cells than the estrogen receptor (ER)/progesterone receptor (PR) subtype. Interestingly, a higher number of CD68+/PD-L1+/CK-/CD163- TAMs in the intratumoral area was correlated with a favorable recurrence rate ( p = 0.048). These findings indicated that the specific subpopulation and localization of TAMs in the TME affect clinical outcomes in breast cancer.

Mutations in NRAS constitutively activate cell proliferation signaling in malignant neoplasms, such as leukemia and melanoma, and the clarification of comprehensive downstream genes of NRAS might lead to the control of cell-proliferative signals of NRAS -driven cancers. We previously established that NRAS expression and proliferative activity can be controlled with doxycycline and named as THP-1 B11. Using a CRISPR activation library on THP-1 B11 cells with the NRAS -off state, survival clones were harvested, and 21 candidate genes were identified. By inducting each candidate guide RNA with the CRISPR activation system, DOHH , HIST1H2AC , KRT32 , and TAF6 showed higher cell-proliferative activity. The expression of DOHH , HIST1H2AC, and TAF6 was definitely upregulated with NRAS expression. Furthermore, MEK inhibitors resulted in the decreased expression of DOHH, HIST1H2AC, and TAF6 proteins in parental THP-1 cells. The knockdown of DOHH , HIST1H2AC , and TAF6 was found to reduce proliferation in THP-1 cells, indicating that they are involved in the downstream proliferation of NRAS . These molecules are expected to be new therapeutic targets for NRAS -mutant leukemia cells.

The uptake of 18 F-fluorothymidine ( 18 F-FLT) depends on cells' proliferative rates. We compared the characteristics of 18 F-FLT positron emission tomography/computed tomography (PET/CT) with those of 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/CT for breast cancer. We prospectively diagnosed patients with breast cancer who underwent 18 F-FLT PET/CT and 18 F-FDG PET/CT. Subsequently, significant differences and correlation coefficients of the maximum standardized uptake value (SUVmax) in primary breast cancer and axillary lymph nodes were statistically evaluated. We enrolled eight patients with breast cancer. In six treatment-naive patients, the SUVmax for primary lesions showed a significant difference (mean, 2.1 vs. 4.1, p = 0.031) and a strong correlation ( r = 0.969) between 18 F-FLT and 18 F-FDG. Further, although the SUVmax for the axillary lymph nodes did not show a significant difference between 18 F-FLT and 18 F-FDG (P = 0.246), there was a strong correlation between the two (r = 0.999). In a patient-by-patient study, there were cases in which only 18 F-FDG uptake was observed in lymph nodes and normal breasts. Bone metastases demonstrated lower accumulation than bone marrow on the 18 F-FLT PET/CT. In conclusion, a strong correlation was observed between the 18 F-FLT PET/CT and 18 F-FDG PET/CT uptake. Differences in the biochemical characteristics of 18 F-FLT and 18 F-FDG were reflected in the accumulation differences for breast cancer, metastatic lesions, and normal organs.

Background: With sentinel node metastasis in breast cancer (BC) patients, axillary lymph node (ALN) dissection is often omitted from cases with breast-conserving surgery. Omission of lymph node dissection reduces the invasiveness of surgery to the patient, but it also obscures the number of metastases to non-sentinel nodes. The possibility of finding ≥ 4 lymph nodes (pN2a/pN3a) preoperatively is important given the ramifications for postoperative treatment., Aim: To search for clinicopathological factors that predicts upstaging from N0 to pN2a/pN3a., Methods: Patients who were sentinel lymph node (SLN)-positive and underwent ALN dissection between September 2007 and August 2018 were selected by retrospective chart review. All patients had BC diagnosed preoperatively as N0 with axillary evaluation by fluorodeoxyglucose (FDG) positron emission tomography/computed tomography and ultrasound (US) examination. When suspicious FDG accumulation was found in ALN, the presence of metastasis was reevaluated by second US. We examined predictors of upstaging from N0 to pN2a/pN3a., Results: Among 135 patients, we identified 1-3 ALNs (pN1) in 113 patients and ³4 ALNs (pN2a/pN3a) in 22 patients. Multivariate analysis identified the total number of SLN metastasis, the maximal diameter of metastasis in the SLN (SLNDmax), and FDG accumulation of ALN as predictors of upstaging to pN2a/pN3a., Conclusion: We identified factors involved in upstaging from N0 to pN2a/pN3a. The SLNDmax and number of SLN metastasis are predictors of ≥ 4 ALNs (pN2a/pN3a) and predictors of metastasis to non-sentinel nodes, which have been reported in the past. Attention should be given to axillary accumulations of FDG, even when faint., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Hematopoiesis is maintained by the interaction of hematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (MSCs) in bone marrow microenvironments, called niches. Certain genetic mutations in MSCs, not HSCs, provoke some hematopoietic neoplasms, such as myelodysplastic syndrome. An in vivo bone marrow niche model using human MSC cell lines with specific genetic mutations and bone scaffolds is necessary to elucidate these interactions and the disease onset. We focused on decellularized bone (DCB) as a useful bone scaffold and attempted to induce human MSCs (UE7T-9 cells) into the DCB. Using the CRISPR activation library, we identified SHC4 upregulation as a candidate factor, with the SHC4 overexpression in UE7T-9 cells activating their migratory ability and upregulating genes to promote hematopoietic cell migration. This is the first study to apply the CRISPR library to engraft cells into decellularized biomaterials. SHC4 overexpression is essential for engrafting UE7T-9 cells into DCB, and it might be the first step toward creating an in vivo human-mouse hybrid bone marrow niche model.

In breast cancer (BC), the development of cancer immunotherapy including immune checkpoint inhibitors has progressed. Tumor infiltrating lymphocytes (TILs) is one of the important factors for an immune response between tumor cells and immune cells in the tumor microenvironment, and the presence of TILs has been identified as predictors of response to chemotherapy. However, because complex mechanisms underlies the crosstalk between immune cells and cancer cells, the relationship between immune profiles in the tumor microenvironment and the efficacy of the immune checkpoint blocked has been unclear. Moreover, in many cases of breast cancer, the quantitative analysis of TILs and immuno-modification markers in a single tissue section are not studied. Therefore, we quantified detailed subsets of tumor infiltrating lymphocytes (TILs) from BC tissues and compared among BC subtypes. The TILs of BC tissues from 86 patients were classified using multiplex immunohistochemistry and an artificial intelligence-based analysis system based on T-cell subset markers, immunomodification markers, and the localization of TILs. The levels of CD4/PD1 and CD8/PD1 double-positive stromal TILs were significantly lower in the HER2- BC subtype (p <0.01 and p <0.05, respectively). In triple-negative breast cancer (TNBC), single marker-positive intratumoral TILs did not affect prognosis, however CD4/PDL1, CD8/PD1, and CD8/PDL1 double-positive TILs were significantly associated with TNBC recurrence (p<0.05, p<0.01, and p<0.001, respectively). TIL profiles differed among different BC subtypes, suggesting that the localization of TILs and their tumor-specific subsets influence the BC microenvironment., Competing Interests: Author KK was employed by Daiichi Sankyo, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hayashi, Nogawa, Kobayashi, Asakawa, Ohata, Kitagawa, Kubota, Takahashi, Yamada, Oda, Nakagawa, Uetake, Onishi, Kinowaki, Kurata, Kitagawa and Yamamoto.)

Comprehensive genomic profiling (CGP) provides information regarding cancer-related genetic aberrations. However, its clinical utility in recurrent/metastatic head and neck cancer (R/M HNC) remains unknown. Additionally, predictive biomarkers for immune checkpoint inhibitors (ICIs) should be fully elucidated because of their low response rate. Here, we analyzed the clinical utility of CGP and identified predictive biomarkers that respond to ICIs in R/M HNC. We evaluated over 1100 cases of HNC using the nationwide genetic clinical database established by the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and 54 cases in an institution-based study. The C-CAT database revealed that 23% of the cases were candidates for clinical trials, and 5% received biomarker-matched therapy, including NTRK fusion. Our institution-based study showed that 9% of SCC cases and 25% of salivary gland cancer cases received targeted agents. In SCC cases, the tumor mutational burden (TMB) high (≥10 Mut/Mb) group showed long-term survival (>2 years) in response to ICI therapy, whereas the PD-L1 combined positive score showed no significant difference in progression-free survival. In multivariate analysis, CCND1 amplification was associated with a lower response to ICIs. Our results indicate that CGP may be useful in identifying prognostic biomarkers for immunotherapy in patients with HNC.

MYC is a major oncogene that plays an important role in cell proliferation in human cancers. Therefore, the mechanism behind MYC regulation is a viable therapeutic target for the treatment of cancer. Comprehensive and efficient screening of MYC regulators is needed, and we had previously established a promoter screening system using fluorescent proteins and the CRISPR library. For the efficient identification of candidate genes, a database was used, for which mRNA expression was correlated with MYC using datasets featuring "Similar" and "Not exactly similar" contexts. INTS14 and ERI2 were identified using datasets featuring the "Similar" context group, and INTS14 and ERI2 were capable of enhancing MYC promoter activity. In further database analysis of human cancers, a higher expression of MYC mRNA was observed in the INTS14 mRNA high-expressing prostate and liver cancers. The knockdown of INTS14 in prostate cell lines resulted in decreased MYC mRNA and protein expression and also induced G0/1 arrest. This study confirmed that CRISPR screening combined with context-matched database screening is effective in identifying genes that regulate the MYC promoter. This method can be applied to other genes and is expected to be useful in identifying the regulators of other proto-oncogenes.

In haematological malignancies, such as malignant lymphoma, reprogramming of fatty acid metabolism favours tumour cell survival and drug resistance. Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), an enzyme involved in fatty acid beta-oxidation (FAO), is overexpressed in high-grade lymphoma and is a predictor of poor prognosis in diffuse large B-cell lymphoma (DLBCL). HADHB forms a heterodimer with HADHA and functions as an FAO enzyme together with HADHA; however, the relevance of its expression in malignant lymphoma is unknown. In this study, we investigated the roles and antitumour effects of HADHB expression in malignant lymphoma. Immunohistochemical analysis showed that HADHB was frequently overexpressed in the high-grade lymphoma subtype. HADHB overexpression was observed in 68% (87/128) of DLBCL cases and was an independent predictor of poor prognosis (p=0.001). In vitro analysis demonstrated that HADHB knockdown suppressed cell proliferation in LCL-K and MD901 cells (p<0.05). Additionally, treatment with the FAO inhibitor, ranolazine, increased cell death in control cells compared with that in HADHB knockdown LCL-K and MD901 cells (p<0.01). Cell death was also suppressed by the ferroptosis inhibitor, ferrosatin-1, in LCL-K and MD901 cells (p<0.05). Collectively, these findings provide basic evidence for the development of new cell death-based therapies for refractory malignant lymphoma. We plan to perform prospective studies and preclinical studies using animal models to confirm these results., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Introduction: Clinical sequencing has provided molecular and therapeutic insights into the field of clinical oncology. However, despite its significance, its clinical utility in Japanese patients remains unknown. Here, we examined the clinical utility of tissue-based clinical sequencing with FoundationOne® CDx and FoundationOne® Heme. Between August 2018 and August 2019, 130 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne® CDx or FoundationOne® Heme., Results: The median age of 130 patients was 60.5 years (range: 3 to 84 years), and among them, 64 were males and 66 were females. Major cancer types were gastrointestinal cancer (23 cases) and hepatic, biliary, and pancreatic cancer (21 cases). A molecular tumor board had been completed on all 130 cases by October 31, 2019. The median number of gene alterations detected by Foundation testing, excluding variants of unknown significance (VUS) was 4 (ranged 0 to 21) per case. Of the 130 cases, one or more alterations were found in 123 cases (94.6%), and in 114 cases (87.7%), actionable alterations with candidates for therapeutic agents were found. In 29 (22.3%) of them, treatment corresponding to the gene alteration was performed. Regarding secondary findings, 13 cases (10%) had an alteration suspected of a hereditary tumor. Of the 13 cases, only one case received a definite diagnosis of hereditary tumor., Conclusions: Our study showed that clinical sequencing might be useful for detecting gene alterations in various cancer types and exploring treatment options. However, many issues still need to be improved., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Lung squamous cell carcinoma (LSCC) exhibits poor response to treatment compared with other lung cancer subtypes, resulting in worse prognosis. Therefore, new therapeutic strategies are required for advanced LSCC. Ferroptosis is a recently discovered nonapoptotic cell death caused by intracellular lipid peroxidation that can bring about effective cell death in cancer cells resistant to apoptosis. Hence, ferroptosis is a potential therapeutic strategy for refractory cancer., Materials and Methods: In this study, we performed clinicopathological and molecular analyses on tumor specimens from 270 patients with squamous cell lung cancer, focusing on the expression of glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), which are known to be key regulators of ferroptosis, and the accumulation of 4-hydroxynoneral (4-HNE), a lipid peroxidation marker., Results: Immunohistochemistry revealed that patients with low 4-HNE accumulation and low levels of GPX4 or FSP1 had significantly worse prognoses than other patients (P = 0.001). This stratification was an independent prognostic predictor (P = 0.003). A dramatic cell death synergistic effect was observed on LSCC-derived LK-2 and EBC1 cells treated with GPX4 and FSP1 inhibitors. This effect was completely inhibited by treatment with the ferroptosis inhibitor. Notably, this was not the case in LK-2 cells treated with the apoptosis inhibitor, and in these cells, ferroptosis was induced., Conclusion: Ferroptosis regulators GPX4 and FSP1 are associated with lung squamous cell cancer cancer's prognosis. We present the clinicopathological and molecular basis of novel therapeutic strategies for refractory LSCC., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Lymphoproliferative disorder (LPD) has been shown to occur after treatment with methotrexate (MTX). Currently, MTX-LPD has become widely recognized, but its mechanism and prognostic factors remain unclear., Case Presentation: We report the first case of Epstein-Barr virus (EBV)-associated MTX-LPD of the breast. A 63-year-old Asian woman with long-term rheumatoid arthritis presented to our facility with intermittent fever. A physical examination revealed a 3-cm lump in her left breast. She had been taking MTX for the past 15 years. Laboratory studies revealed slightly elevated levels of EBV-viral capsid antigen antibody immunoglobulin G and EBV nuclear antibody. Contrast-enhanced computer tomography revealed a mass in the left breast, a subcutaneous nodule in the abdomen, a mass in the left lung, and a nodule in the left retroperitoneum. The definitive diagnosis was consistent with MTX-LPD merging into an EBV-positive, diffuse large B-cell lymphoma. Six months following the withdrawal of MTX, the breast mass had markedly shrunk and the patient remained in good health for 1 year with no evidence of relapse of LPD., Conclusion: MTX-LPD rarely occurs in the breast, and it is difficult to diagnose because there have only been six reported cases of breast MTX-LPD reported in the literature. EBV-positive MTX-LPD tends to regress spontaneously after MTX withdrawal, and our case also had similar results. It is important to make an appropriate diagnosis of MTX-LPD of the breast based on imaging and pathology to determine the appropriate treatment protocol for this rare disorder., (© 2022. The Author(s).)

Background and objectives: In the treatment of the special type of breast cancer (STBC), the choice of chemotherapeutic agents is often based on the characteristic features of the histological type. On the other hand, the surgical strategy is usually determined by the tumor size and presence of lymph node metastasis, and the indication for immediate reconstruction is rarely discussed based on the histological type. The prognoses of STBC and invasive ductal carcinoma of the breast (IDC) patients who underwent subcutaneous mastectomy (SCM) with immediate reconstruction at our institution were compared. Materials and Methods: A total of 254 patients with SCM with immediate reconstruction from 1998 to 2018 were included; their tumor diameter or induration was less than 25 mm, and it was not in close proximity to the skin. Preoperative chemotherapy and non-invasive cancer cases were excluded. Results: The number of patients was 166 for skin-sparing mastectomy (SSM) and 88 for nipple-sparing mastectomy (NSM). The reconstructive techniques were deep inferior epigastric artery perforator flap (DIEP) reconstruction in 43 cases, latissimus dorsi flap reconstruction (LDflap) in 63 cases, tissue expander (TE) in 117 cases, and transverse rectus abdominis myocutaneous flap/vertical rectus abdominis myocutaneous flap (TRAM/VRAM) reconstruction in 31 cases. The histological types of breast cancer were 211 IDC and 43 STBC; 17 were mucinous carcinoma (MUC), 17 were invasive lobular carcinoma (ILC), 6 were apocrine carcinoma, 1 was tubular carcinoma, and 2 were invasive micropapillary carcinoma. There was no difference in local recurrence or disease-free survival (LRFS, DFS) between IDC and STBC, and overall survival (OS) was significantly longer in STBC. OS was better in the STBC group because SCM with immediate reconstruction was performed for STBC, which is a histological type with a relatively good prognosis. Highly malignant histological types, such as squamous cell carcinoma or metaplastic carcinoma, were totally absent in this study. Conclusions: The indications for SCM with immediate reconstruction for relatively common STBCs such as MUC and ILC can be the same as for IDC.

The introduction of the guidelines has resulted in an increase of laparoscopic surgeries performed, but the rate of early surgery was still low. Here, the initial effect of the introduction of the guideline was confirmed in single center, and factors disturbing early cholecystectomy were analyzed. This study included 141 patients who were treated for acute cholecystitis from January 2010 to October 2014 at Kanazawa Medical Center. Each patient was assigned into a group according to when they received treatment. Patients in Group A were treated before the Tokyo Guidelines were introduced (n = 48 cases), those in Group B were treated after the introduction of the guidelines (93 cases). After the introduction of the guidelines, early laparoscopic cholecystectomy was significantly increased (P < 0.001), however, the rate of early operations was still 38.7% only. There are many cases with cardiovascular disease in delayed group, the prevalence had reached 50% as compared with early group of 24% (P < 0.01). Approximately 25% of patients continued antiplatelet or anticoagulant therapy. In the early days of guidelines introduction, the factor which most disturbed early surgery was the coexistence of cardiovascular disease. These contents could be described in the next revision of the guidelines., (© 2022. The Author(s).)

Denosumab is the world's first human monoclonal antibody for the treatment of osteoporosis and shares an active pathway with bisphosphonates, strongly suppressing osteoclast activities. This is the first case report describing a possible relationship between the development of osteonecrosis of external auditory canal and denosumab administration. We herein report an 81-year-old woman diagnosed with left osteonecrosis of external auditory canal who had a history of denosumab administration. She underwent left radical mastoidectomy due to being refractory to conservative treatment. No major complications or recurrence were observed in the left ear after surgery, but bone erosion in the right ear has continued to progress slowly despite the cessation of denosumab administration. Otolaryngologists should be aware of the association between osteonecrosis of external auditory canal and denosumab administration and consider performing long-term observation even after cessation., (Copyright © 2020. Published by Elsevier B.V.)

BLNK (BASH/SLP-65) encodes an adaptor protein that plays an important role in B-cell receptor (BCR) signaling. Loss-of-function mutations in this gene are observed in human pre-B acute lymphoblastic leukemia (ALL), and a subset of Blnk knock-out (KO) mice develop pre-B-ALL. To understand the molecular mechanism of the Blnk mutation-associated pre-B-ALL development, retroviral tagging was applied to KO mice using the Moloney murine leukemia virus (MoMLV). The Blnk mutation that significantly accelerated the onset of MoMLV-induced leukemia and increased the incidence of pre-B-ALL Cebpb was identified as a frequent site of retroviral integration, suggesting that its upregulation cooperates with Blnk mutations. Transgenic expression of the liver-enriched activator protein (LAP) isoform of Cebpb reduced the number of mature B-lymphocytes in the bone marrow and inhibited differentiation at the pre-BI stage. Furthermore, LAP expression significantly accelerated leukemogenesis in Blnk KO mice and alone acted as a B-cell oncogene. Furthermore, an inverse relationship between BLNK and C/EBPβ expression was also noted in human pre-B-ALL cases, and the high level of CEBPB expression was associated with short survival periods in patients with BLNK-downregulated pre-B-ALL. These results indicate the association between the C/EBPβ transcriptional network and BCR signaling in pre-B-ALL development and leukemogenesis. This study gives insight into ALL progression and suggests that the BCR/C/EBPβ pathway can be a therapeutic target., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The clinical utility of plasma cell-free DNA in precision cancer medicine has not been established. A pilot study was conducted to investigate the clinical utility of comprehensive genomic profiling by liquid biopsy in a Japanese population., Methods: In this PROFILE study, 102 patients with advanced solid tumors who showed progression with standard systemic therapy underwent liquid biopsy between August 2017 and February 2020. Liquid biopsy was performed using Guardant360., Results: Of the 102 patients, 56 were women, and the median age was 65 years. Regarding the types of cancer, 31 were hepatobiliary and pancreatic cancer, 17 were gastrointestinal cancer, and 13 were breast cancer. Frequently altered genes were TP53 (53.9%, 46/102), KRAS (25.5%, 26/102), PIK3CA (19.6%, 20/102), and EGFR (17.6%, 18/102). At least one genetic aberration was detected in 92 patients (90.2%). Actionable mutation was discovered in 88 patients (86.3%), and 67 patients (65.7%) were clinical trial candidates. Of the 102 patients, 22 (21.6%) were able to receive biomarker-matched therapy. Their best responses were as follows: 1 complete response, 3 partial responses, 7 stable diseases, and 11 progressive diseases. Additionally, the treated patients were divided on the basis of matching scores (≥ 50% vs. < 50%). The patients were divided into high and low groups. The high group had a higher disease control rate (DCR) of 75% compared with 20% in the low group (P = 0.010)., Conclusions: The results indicate that liquid biopsy is useful for identifying actionable mutations associated with the clinical response of selected patients., (© 2021. Society of Surgical Oncology.)

Decorin (DCN), an extracellular matrix proteoglycan found in tumor surrounding tissues, is a natural inhibitor of tumor cell proliferation and invasion. We conducted a cross-sectional observation study to evaluate the association of the pathological stage with the levels of DCN in plasma or tumor surrounding tissue. Among 118 patients who underwent breast surgery, 35 were designated as carcinoma in situ (Stage 0), 39 were Stage I, and 44 were Stage II or III. The stromal expression of DCN was quantified using a semiquantitative digital image analysis after immunohistochemical staining. The concentration of DCN was evaluated with a specific ELISA. As we have previously shown, stromal DCN expression was attenuated in the patients with Stage I, whereas stromal and plasma DCN was elevated paradoxically in those with Stage II/III. The elevated plasma DCN is an independent predictive factor of Stage II/III by the multivariate logistic regression analysis. The plasma level of DCN was negatively correlated with stromal DCN expression only in patients with advanced disease (Stage II/III). The plasma level of DCN could become a useful biomarker for patients in the advanced stages. Extensive studies and further assessments are warranted for evaluating the prognostic significance and tumor characteristics to understand the clinical significances of stromal and systemic DCN.

CRISPR/Cas has emerged as an excelle nt gene-editing technology and is used worldwide for research. The CRISPR library is an ideal tool for identifying essential genes and synthetic lethality targeted for cancer therapies in human cancers. Synthetic lethality is defined as multiple genetic abnormalities that, when present individually, do not affect function or survival, but when present together, are lethal. Recently, many CRISPR libraries are available, and the latest libraries are more accurate and can be applied to few cells. However, it is easier to efficiently search for cancer targets with their own screenings by effectively using databases of CRISPR screenings, such as Depmap portal, PICKLES (Pooled In-Vitro CRISPR Knockout Library Essentiality Screens), iCSDB, Project Score database, and CRISP-view. This review will suggest recent optimal CRISPR libraries and effective databases for Novel Approaches in the Discovery and Design of Targeted Therapies.

Abstract: The oncological safety of immediate breast reconstruction (IBR) in lymph node-positive patients is unclear. In the present study, the impact of IBR on recurrence based on data of patients with axillary lymph node metastases only was examined.The subjects were 232 patients who underwent breast surgery. The patients were grouped into 2 cohorts: non-IBR patients who underwent mastectomy with axillary lymph node dissection; and IBR patients with tissue expander or flap transfer and axillary lymph node dissection. The Non-IBR group included 165 patients, and the IBR group included 67 patients. For the comparison of oncological outcomes between the 2 groups, propensity score matching was performed. The propensity scores were calculated by logistic regression analysis, including age, tumor staging, human epidermal growth factor receptor 2 status, and estrogen receptor status. There was no difference in locoregional recurrence-free survival (LRRFS) between the non-IBR and IBR groups. The 5-year LRRFS rate was 78.9% in the non-IBR group and 85.1% in the IBR group. There was no difference in recurrence-free survival (RFS) between the non-IBR and IBR groups. The 5-year RFS rate was 75.6% in the non-IBR group and 78.8% in the IBR group. In all patients, the 5-year LRRFS rate was 77.3%, and the RFS rate was 70.5%. Multivariate Cox regression analysis to identify factors affecting RFS in all patients showed that estrogen receptor status and high nuclear grade were significant prognostic factors; IBR was irrelevant.This is the first report of an analysis using propensity score matching limited to node-positive breast cancer patients, and it showed that IBR is relatively safe in such patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Indocyanine green angiography enables real-time visualization of blood vessels at depths of up to 10 mm beneath the body surface, thereby aiding the evaluation of the viability of skin flaps and predicting necrosis in surgical fields requiring good tissue perfusion. Although skin-flap necrosis also occurs in mastectomy without reconstruction, most studies have focused on reconstructive plastic surgery. Several patients undergoing mastectomy are eligible for postoperative adjuvant therapy, but complications can lead to delays in treatment and thus require prevention. However, a lack of a standard protocol for evaluating skin-flap perfusion using indocyanine green necessitates the study of its characteristics to facilitate comparison of the perfusion rate among individuals., Methods: This retrospective study focused on the characteristics of indocyanine green and established a protocol for indocyanine green angiography using laser-assisted imaging (SPY system) to predict postoperative skin-flap necrosis from intraoperative images of 30 patients who underwent mastectomy without reconstruction., Results: Our protocol predicted postoperative skin-flap necrosis as follows. First, the intravenous dose and concentration were set at 2.5 mg/mL and 0.05 mg/kg, respectively. Second, the timing of measurement was set to 100 s after the entry of indocyanine green into the skin (plateau phase); the analysis pattern was set to single frame. Third, comparisons among individuals were made using relative values., Conclusions: We analyzed the area of postoperative flap necrosis using this protocol. We found that the intraoperative images showed decreased perfusion in that area, which was useful in predicting skin-flap necrosis, as reported by previous breast reconstruction studies., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)