Cytomorphological disparities in invasive breast cancer cells following neoadjuvant endocrine therapy and chemotherapy.

INTRODUCTION: Neoadjuvant endocrine therapy (NAE) offers a breast-conserving surgery rate and clinical response rate similar to those of neoadjuvant chemotherapy (NAC), while presenting fewer adverse events and lower pathological complete response rates. The assessment of pathological response determines degenerative changes and predicts the prognosis of breast cancer treated with NAC. This study clarified the degenerative changes occurring in breast cancer following NAE. METHODS: Our study encompassed two groups: NAE, consisting of 15 patients, and NAC, comprising 18 patients. Tissue samples were obtained from core needle biopsies and surgeries. Nuclear and cell areas were calculated using Autocell analysis. Furthermore, we assessed markers associated with microtubule depolymerization (KIF2A) and initiators of apoptosis (caspase-9). RESULTS: In the NAC group, we observed significant increases in both cytoplasmic and cell areas. These changes in cytoplasm and cells were notably more pronounced in the NAC group compared to the NAE group. Post-treatment, KIF2A exhibited a decrease, with the magnitude of change being greater in the NAE group than in the NAC group. However, no discernible differences were found in caspase-9 expression between the two groups. CONCLUSION: Our findings indicate that NAE induces condensation in cancer cells via cell cycle arrest or apoptosis. Conversely, NAC leads to cell enlargement due to the absence of microtubule depolymerization. These discrepancies underscore the importance of accounting for these distinctions when establishing criteria for evaluating pathological responses.

Pks-positive Escherichia coli in tumor tissue and surrounding normal mucosal tissue of colorectal cancer patients.

A significant association exists between the gut microbiome and colorectal carcinogenesis, as well as cancer progression. It has been reported that Escherichia coli (E. coli) containing polyketide synthetase (pks) island contribute to colorectal carcinogenesis by producing colibactin, a polyketide-peptide genotoxin. However, the functions of pks+ E. coli in initiation, proliferation, and metastasis of colorectal cancer (CRC) remain unclear. We investigated the clinical significance of pks+ E. coli to clarify its functions in CRC. This study included 413 patients with CRC. Pks+ E. coli of tumor tissue and normal mucosal tissue were quantified using droplet digital PCR. Pks+ E. coli was more abundant in Stages 0-I tumor tissue than in normal mucosal tissue or in Stages II-IV tumor tissue. High abundance of pks+ E. coli in tumor tissue was significantly associated with shallower tumor depth (hazard ratio [HR] = 5.0, 95% confidence interval [CI] = 2.3-11.3, p < 0.001) and absence of lymph node metastasis (HR = 3.0, 95% CI = 1.8-5.1, p < 0.001) in multivariable logistic analyses. Pks+ E. coli-low and -negative groups were significantly associated with shorter CRC-specific survival (HR = 6.4, 95% CI = 1.7-25.6, p = 0.005) and shorter relapse-free survival (HR = 3.1, 95% CI = 1.3-7.3, p = 0.01) compared to the pks+ E. coli-high group. Pks+ E. coli was abundant in Stages 0-I CRC and associated with CRC prognosis. These results suggest that pks+ E. coli might contribute to carcinogenesis of CRC but might not be associated with tumor progression.

Japanese Dermatological Association guidelines: Outlines of Japanese clinical guidelines for basal cell carcinoma 2021.

To summarize the current therapies for skin cancers, the Japanese Skin Cancer Society issued the first guidelines for skin cancers, including melanoma, squamous cell carcinoma, basal cell carcinoma (BCC), and extramammary Paget's disease, in 2007. These guidelines were revised in 2015. Herein, we present the English version of the 2021 edition of the Japanese clinical guidelines for BCC. In the latest edition, all procedures were performed according to the Grading of Recommendations, Assessment, Development and Evaluation systems. The clinical questions that could not be answered were selected for further analysis. A comprehensive literature search, systematic review, and recommendations for each clinical question were determined by a multidisciplinary expert panel comprising dermatologists, a plastic and reconstructive surgeon, and a pathologist. Surgical resection is the gold-standard therapy of BCC. Radiotherapy or topical treatments, other than surgical resection, have been used in some cases. Patients with unresectable or metastatic BCC require systemic therapy. Novel agents, such as immune response modifiers or hedgehog pathway inhibitors, are emerging worldwide for the treatment of BCC. Based on these viewpoints, four relevant clinical questions regarding, surgical resection, radiotherapy, topical treatment, and systemic therapy, were raised in this report that aims to help clinicians select suitable therapies for their patients.

Effective Management of Hypertensive Emergencies with Aliskiren Treatment in a Patient Before and After Introducing Hemodialysis Secondary to Scleroderma Renal Crisis-like Condition Under Corticosteroid Treatment for Sjögren Syndrome-associated Multiple Mononeuropathy.

A middle-aged woman presented with hypertensive emergency after corticosteroid treatment for Sjögren syndrome-associated multiple mononeuropathy with suspected systemic sclerosis. Hypertensive heart failure with hyperreninemia improved with antihypertensives, including aliskiren; however, she became hemodialysis-dependent. Clinical findings and biopsy-proven thrombotic microangiopathy indicated conditions resembling scleroderma renal crisis (SRC). Severe hypertension and heart failure with hyperreninemia occurred after stopping aliskiren for hypotension due to diverticular bleeding, which improved after the reintroduction of aliskiren. Aliskiren appears to be effective in managing hypertensive heart failure in patients with SRC. Nevertheless, hemodialysis remained necessary in our case, and whether or not aliskiren can restore the renal function is unclear.

A Case of Axillary Fibroadenoma That Grew Rapidly from Axillary Accessory Breast Tissue over 40 Days.

Axillary accessory breast (AAB) occurs in 2%-6% of women. Like normal breast tissue, ABB can undergo changes, including periodic enlargement that can result in a palpable axillary mass. Fibroadenoma is the most common benign subcutaneous tumor of the breast: it occurs in approximately 25% of women and accounts for 50% of all breast biopsies. However, fibroadenoma in AAB is rare (2.6%). Here, we describe the case of a patient who was diagnosed first with left AAB on the basis of clinical and magnetic imaging resonance findings, and then 40 days later with fibroadenoma in left AAB by histopathology of the resected mass. The tumor, which had been undetectable at the initial visit, had transformed into a clinically obvious, hard, protruding mass at surgery. Thus, fibroadenomas originating from AAB can grow quickly, and imaging-based diagnosis should be confirmed with histology. Treatment should involve complete excision of the fibroadenoma and surrounding AAB.

Rap1 small GTPase is essential for maintaining pulmonary endothelial barrier function in mice.

Vascular permeability is dynamically but tightly controlled by vascular endothelial (VE)-cadherin-mediated endothelial cell-cell junctions to maintain homeostasis. Thus, impairments of VE-cadherin-mediated cell adhesions lead to hyperpermeability, promoting the development and progression of various disease processes. Notably, the lungs are a highly vulnerable organ wherein pulmonary inflammation and infection result in vascular leakage. Herein, we showed that Rap1, a small GTPase, plays an essential role for maintaining pulmonary endothelial barrier function in mice. Endothelial cell-specific Rap1a/Rap1b double knockout mice exhibited severe pulmonary edema. They also showed vascular leakage in the hearts, but not in the brains. En face analyses of the pulmonary arteries and 3D-immunofluorescence analyses of the lungs revealed that Rap1 potentiates VE-cadherin-mediated endothelial cell-cell junctions through dynamic actin cytoskeleton reorganization. Rap1 inhibits formation of cytoplasmic actin bundles perpendicularly binding VE-cadherin adhesions through inhibition of a Rho-ROCK pathway-induced activation of cytoplasmic nonmuscle myosin II (NM-II). Simultaneously, Rap1 induces junctional NM-II activation to create circumferential actin bundles, which anchor and stabilize VE-cadherin at cell-cell junctions. We also showed that the mice carrying only one allele of either Rap1a or Rap1b out of the two Rap1 genes are more vulnerable to lipopolysaccharide (LPS)-induced pulmonary vascular leakage than wild-type mice, while activation of Rap1 by administration of 007, an activator for Epac, attenuates LPS-induced increase in pulmonary endothelial permeability in wild-type mice. Thus, we demonstrate that Rap1 plays an essential role for maintaining pulmonary endothelial barrier functions under physiological conditions and provides protection against inflammation-induced pulmonary vascular leakage.

Discontinuing Hemodialysis through Corticosteroid Treatment in a Patient with Cryofibrinogen-associated Glomerulonephritis.

Cryofibrinogen-associated glomerulonephritis (CryoFiGN) is rare, and its diagnosis is difficult while treatment is not established. We herein report an elderly woman with CryoFiGN who experienced recurrent purpura and nephritic features that subsequently progressed to nephrotic syndrome and required hemodialysis during the 18-month clinical course. The patient was treated with corticosteroids, which led to the discontinuation of hemodialysis. The diagnosis of CryoFiGN was based on the clinical presentation, characteristic glomerular deposits, and results of laser microdissection and liquid chromatography-tandem mass spectrometry of the glomeruli. This case highlights the potential utility of corticosteroids as a treatment option for patients with CryoFiGN, even after hemodialysis.

Slowly Progressive ANCA-associated Glomerulonephritis with Strong Mesangial MPO Deposits Following a Diagnosis of Interstitial Lung Disease: A Case Report.

An elderly woman showed positive conversion of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCAs) following the diagnosis of interstitial lung disease (ILD) and glomerular hematuria and subsequently experienced slowly progressive glomerulonephritis. A kidney biopsy revealed chronic damage and necrotizing crescentic glomerulonephritis with mesangial MPO deposits. After corticosteroid treatment, the patient's urinalysis results and MPO-ANCA titers almost normalized and her renal function stabilized. This case is similar to recently reported cases of slowly progressive ANCA-associated glomerulonephritis. ILD likely triggered the production of MPO-ANCAs, and the accumulation of MPO deposits in the glomeruli may have contributed to the progression of her renal disease.

Elucidation of the mechanism of amyloid A and transthyretin formation using mass spectrometry-based absolute quantification.

Amyloidosis is triggered by the truncation of amyloid precursor proteins, causing organ damages. While previous studies found the truncation of amyloid A (AA) and amyloid transthyretin (ATTR) occurs in C- and N-terminal, respectively, the detailed mechanism of the fibril formation remains unclear. Liquid chromatography mass spectrometry is usually applied for a qualitative purpose, and thus quantification of tryptic peptide residue is difficult. We therefore employed a mass spectrometry-based quantification by isotope-labeled cell-free (MS-QBIC) to analyze the truncation processes in amyloid fibrillogenesis of AA and ATTR using the formalin-fixed paraffin-embedded tissues of autopsy cases. In this study, the process of transthyretin from an 'early fibril state' consisting of full-length ATTR to a 'mature ATTR amyloid fibril' with a truncated low-amyloidogenic segment has been mathematically revealed. The amount of full-length ATTR was nine times higher than in mature fibers. Large cohort studies using MS-QBIC may shed light on the clinical significance of amyloid fibrils.

Comparison of pancreatic enzyme abnormalities and protease-activated receptor-2-positive eosinophils in the duodenum of patients with functional dyspepsia-irritable bowel syndrome overlap with functional dyspepsia alone in Asian populations.

BACKGROUND AND AIM: Some patients with functional gastrointestinal disorders exhibit pancreatic dysfunctions and pancreatic enzyme abnormalities. Thus, we aimed to clarify whether significant differences in clinical characteristics, prevalence of pancreatic enzyme abnormalities, duodenal inflammation, and protease-activated receptor 2 (PAR2) expression levels related to hypersensitivity exist between functional dyspepsia (FD) alone and FD-irritable bowel syndrome (IBS) overlap group. METHODS: Ninety-three patients based on the Rome IV criteria, FD alone (n = 44) and FD overlapped with IBS (n = 49) group were enrolled. The patients scored their own clinical symptoms after consuming high-fat meals. Serum trypsin, PLA2, lipase, p-amylase, and elastase-1 levels were measured. PAR2, eotaxin-3, and TRPV4 mRNA levels in duodenum were determined using real-time polymerase chain reaction methods. PRG2- and PAR2 in the duodenum were evaluated using immunostaining. RESULTS: FD score and global GSRS in patients with FD-IBS overlap were significantly higher than FD alone. Although the prevalence of pancreatic enzyme abnormalities in patients with FD alone was significantly (P < 0.01) higher than that in FD-IBS overlap, the ratio of aggravation of clinical symptoms following high-fat intake in patients with FD-IBS overlap was significantly higher (P = 0.007) than that in patients with FD alone. PAR2- and PRG2-double positive cells were localized in the degranulated eosinophils in the duodenum of patients with FD-IBS overlap. The number of PAR2- and PRG2-double positive cells in FD-IBS overlap was significantly (P < 0.01) higher than FD alone. CONCLUSIONS: Pancreatic enzyme abnormalities and PAR2 expression on degranulated eosinophils infiltrations in the duodenum may be associated with the pathophysiology of patients with FD-IBS overlap in Asian populations.

A Diagnostic and Therapeutic Dilemma Concerning Exostosin 1/Exostosin 2-associated Lupus-like Membranous Nephropathy with Positive Antinuclear Antibody in an Elderly Man with Various Immune Abnormalities.

Exostosin 1 (EXT1) and exostosin 2 (EXT2)-associated membranous nephropathy (MN) may be associated with active autoimmune disease. We encountered an elderly man who presented with EXT1/EXT2-associated lupus-like MN with full house immune deposits, monoclonal gammopathy of uncertain significance and Sjögren's syndrome. The patient exhibited various other immune abnormalities. Although he did not fulfill the criteria of clinical systemic lupus erythematosus (SLE), he met a stand-alone renal criterion of the Systemic Lupus International Collaborating Clinics (SLICC) 2012. Whether or not a stand-alone renal criterion with EXT1/EXT2 positivity, as in the present patient, can efficiently guide decisions regarding the diagnosis and treatment of SLE remains a clinical dilemma.

A novel germline SMAD4 variant detected in a Japanese family with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia.

Juvenile polyposis syndrome (JPS) is an autosomal dominant, inherited disorder caused by pathogenic germline variants of mainly SMAD4 or BMPR1A genes. Some patients with JPS, especially with SMAD4 variants, also develop hereditary, hemorrhagic telangiectasia (HHT). HHT is also an autosomal dominant inherited disorder. Herein, we identified a novel germline pathogenic variant of the SMAD4 in a Japanese family with JPS and HHT. A six-base pair deletion in the SMAD4 gene (NM_005359.6:c.1495_1500delTGCATA) was identified in the patients. Two amino acids are deleted from SMAD4 protein (p.Cys499_Ile500del), which are located in MSH2 domain essential for the binding with SMAD3. This is a novel variant that has not been registered in any database surveyed. Amino acid structural analysis predicted significant changes in the secondary and three-dimensional structures in the vicinity of the two amino acids' deletion. The variant is classified as 'Likely Pathogenic' according to the American College of Medical Genetics and Genomics guidelines.

Downhill Varices in the Hypopharynx of a Patient with a Large Thyroid Tumor: A Case Report.

Downhill varices are usually caused by superior vena cava (SVC) obstruction due to bronchogenic carcinoma or mediastinal tumors. These structures exhibit retrograde blood flow and are located in the proximal esophagus. Varices in the hypopharynx resulting from mediastinal thyroid tumor are extremely rare. A 70-year-old man with a 35-year history of a growing thyroid tumor on the right side of his neck visited a local hospital. Fine-needle aspiration cytology of the tumor revealed benign goiter. Contrast-enhanced computed tomography showed a huge tumor (13 × 10 × 5 cm) in the right to left lobe of the thyroid that extended into the mediastinum. A well-enhanced mass mimicking hypopharyngeal cancer was identified in the hypopharynx. Endoscopic examination showed varices in the postcricoid region, so biopsy was contraindicated. The preoperative diagnosis was adenomatous goiter and hypopharyngeal varices caused by obstruction of the internal jugular and brachiocephalic vein by the goiter. Total thyroidectomy was performed and the hypopharyngeal varices had disappeared by the next day. The histopathological diagnosis of the thyroid tumor was poorly differentiated carcinoma. Mediastinal thyroid tumor rarely causes downhill varices due to SVC obstruction. However, signs of SVC obstruction were absent in this case, and varices were present in the hypopharynx, not in the upper esophagus. Obstructed venous flow from the thyroid plexus might circulate via the superior laryngeal vein and cause varices in the postcricoid region. When a patient with a large mediastinal tumor has a tumor-like lesion in the hypopharynx, downhill varices should be considered before scheduling a biopsy.

Cytological Assessment of Desmoplastic Malignant Pleural Mesothelioma in an Autopsy Case.

INTRODUCTION: Desmoplastic malignant pleural mesothelioma (DMPM) is a sarcoma-type mesothelioma, comprising approximately 5% of malignant pleural mesotheliomas. Although effusion cytology is commonly used as the primary diagnostic approach for mesothelioma, it may not be useful for DMPM because of the presence of desmoplasia and bland cellular atypia. We report a case, and previously undescribed cytological features, of DMPM that was diagnosed during autopsy. CASE PRESENTATION: A man in his 60s with a history of occupational asbestos exposure was referred to our hospital with right chest pain. A chest CT scan showed right pleural effusion. Thirteen months later, the patient died of respiratory failure. During autopsy, scrape-imprint smears were prepared and cytology of pleural effusions was performed. The scrape-imprint smear samples showed spindle cells with mild nuclear atypia and grooves with fibrous stroma. Pleural effusion cytology revealed spindle cells with mild nuclear atypia, as well as grooves with loose epithelial connections. Histological examination of the right pleura showed spindle cells proliferating with dense collagen fibers, as seen in the cytological samples, thus indicating a diagnosis of DMPM, which was confirmed by fluorescence in situ hybridization. CONCLUSION: Cytological procedures such as pleural effusion cytology and scrape-imprinting cytology may help in diagnosing rare tumors such as DMPM.

Solitary Chondrosarcoma of the Right Ring Finger: A Case Report.

We present a case of solitary chondrosarcoma arising from the proximal phalanx of the ring finger in an elderly man. The chondrosarcoma developed over a period of 14 years, during which the phalanx became progressively more deformed. Several radiographic investigations were carried out, but the patient declined further suggested diagnostic examinations (computed tomography, magnetic resonance imaging, biopsy). Eventually, the lesion became significantly enlarged, and radiographs showed osteolytic lesions in the phalangeal bone. Ray amputation of the finger was required to establish a wide resection of the chondrosarcoma. Most osteochondral tumors arising from the phalanges are benign tumors such as enchondromas, but primary chondrogenic malignant bone tumors (chondrosarcomas) occasionally occur. Chondrosarcoma of the phalanx is difficult to distinguish from enchondroma of the phalanx, because histological investigations of the two neoplasms often produce similar findings. Even with a combination of clinical, biopsy, and imaging findings, differentiating these neoplasms is still challenging, because the characteristic clinical and radiological features of chondrosarcoma do not appear until it becomes aggressive and starts to cause destructive changes. Once that happens, radical expanded resection of the tumor is essential. Therefore, longstanding enchondroma-like lesions should be actively treated in elderly patients, even if a definite diagnosis of chondrosarcoma cannot be made.

Use of Ultrasonographic Shear Wave Measurements to Diagnose Thyroid Metastasis from Breast Carcinoma.

A metastatic thyroid tumor (MTT) arising from breast carcinoma (BC) is rare and sometimes difficult to diagnose. We present a case of MTT from BC; we suspected anaplastic thyroid carcinoma at initial presentation. The patient was a 58-year-old female with a hard nodule in the right anterior neck and a history of breast cancer. Computed tomography indicated tumors on both thyroid lobes, and ultrasonography (US) with shear wave measurement (SWM) showed malignant features. We performed fine needle aspiration cytology (FNAC), the results of which led us to strongly suspect MTT from BC. The surgically resected specimen was evaluated histopathologically, including by immunohistochemistry (IHC), and the diagnosis was confirmed. In addition to FNAC and IHC, SWM is useful to diagnose MTT from BC.

N-terminal peptide fragment constitutes core of amyloid deposition of serum amyloid A: An imaging mass spectrometry study.

Serum amyloid A (SAA) is an acute phase protein, which undergoes structural changes and deposits in the extracellular matrix, causing organ damage. Systemic AA amyloidosis is a relatively common amyloid subtype among the more than 30 amyloid subtypes, but the mechanism of amyloid fibril formation remains unclear. In this study, we investigated the tissue distribution of SAA derived peptides in formalin-fixed paraffin embedded (FFPE) specimens of human myocardium with amyloidosis using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). In the whole SAA protein, four trypsin-digested peptides in the range of SAA2-67 were visualized and the N-terminal peptide; SAA2-15, was selectively localized in the Congo red-positive region. The C-terminal peptides; SAA47-62, SAA48-62, and SAA63-67 were detected not only in the Congo red-positive region but also in the surrounding negative region. Our results demonstrate that the N-terminal SAA2-15 plays a critical role in the formation of AA amyloid fibril, as previously reported. Roles of the C-terminal peptides require further investigation.

A Patient with Acute Kidney Injury Associated with Massive Proteinuria and Acute Hyperuricemia after Epileptic Seizures.

A 25-year-old man presented with acute kidney injury (AKI), massive proteinuria and hyperuricemia after epileptic seizures. His AKI improved along with the disappearance of proteinuria after corticosteroid treatment. A kidney biopsy revealed no significant glomerular abnormalities, but varying degrees of tubular injury, such as proximal tubular simplification, mild distal tubular proliferation, and Tamm-Horsfall protein-like material accumulation with extravasation into the interstitium, were noted. A further analysis revealed the intratubular depositions of uric acid crystals, indicating the involvement of acute uric acid nephropathy associated with seizures. Our patient's condition is rare, and the clinicopathological aspects of the diagnostic challenges are discussed.