Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma.

Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of a carcinomatous component (CaC) and a sarcomatous component (SaC). However, the genomic origin and gene signature of ESS remain unclear. Using whole-exome sequencing of laser-capture microdissection (LCM) tumor samples, we determined that CaC and SaC showed high mutational commonality, with the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden; paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK-RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. Prognostic associations were found for CDC27, LRP2, APC, and SNAPC4. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. © 2024 The Pathological Society of Great Britain and Ireland.

Cytomorphologic and molecular characterization of spindle cell carcinoid tumors of the lung.

BACKGROUND: Spindle cell carcinoid tumor (SCCT) is a rare variant of lung carcinoid tumor consisting predominantly or exclusively of spindle cells. To the authors' knowledge, this is the first study to date investigating the molecular characteristics of SCCTs. METHODS: Eighty-five carcinoid tumors initially diagnosed by fine-needle aspiration over a period of 10 years were reviewed. The final diagnostic classification was based on resection specimens. Six SCCTs were identified and characterized based on cytomorphology, and immunohistochemical and molecular features. RESULTS: Most patients with SCCT were Caucasian (100.0%), women (83.3%), asymptomatic (66.7%), and nonsmokers (83.3%). The median age at diagnosis was 78.0 years (range, 58.2-80.3 years). A higher proportion of patients who had SCCT were diagnosed with distant metastasis. The smears were cellular and demonstrated clean backgrounds without necrosis or mitotic activity. SCCTs comprised of bipolar-to-elongated cells with finely granular chromatin, inconspicuous nucleoli, scant cytoplasm, and minimal atypia or pleomorphism. The tumor cells sometimes appeared boomerang-shaped and might mimic granulomas or blood vessels. SCCTs showed strong expression for pan-cytokeratin, synaptophysin, chromogranin, and CD56, with weak TTF-1 and a very low Ki-67 proliferation index. All SCCTs had low tumor mutational burden and were microsatellite-stable. One case showed multiple whole-gene losses in chromosome 11, whereas another harbored duplication in ARID1A. Two cases demonstrated gains in chromosomes 17, one of which also showed gains in chromosome 18. None had a single nucleotide mutation. CONCLUSIONS: SCCT is a rare subset of lung carcinoid tumors. These tumors harbor unique cytologic, prognostic, and molecular features that may have significant diagnostic and clinical implications.

CCDC68 Maintains Mitotic Checkpoint Activation by Promoting CDC20 Integration into the MCC.

The spindle assembly checkpoint (SAC) ensures chromosome segregation fidelity by manipulating unattached kinetochore-dependent assembly of the mitotic checkpoint complex (MCC). The MCC binds to and inhibits the anaphase promoting complex/cyclosome (APC/C) to postpone mitotic exit. However, the mechanism by which unattached kinetochores mediate MCC formation is not yet fully understood. Here, it is shown that CCDC68 is an outer kinetochore protein that preferentially localizes to unattached kinetochores. Furthermore, CCDC68 interacts with the SAC factor CDC20 to inhibit its autoubiquitination and MCC disassembly. Therefore, CCDC68 restrains APC/C activation to ensure a robust SAC and allow sufficient time for chromosome alignment, thus ensuring chromosomal stability. Hence, the study reveals that CCDC68 is required for CDC20-dependent MCC stabilization to maintain mitotic checkpoint activation.

Diagnostic Maze: Malignant Phyllodes Tumor Mimicking Metaplastic Breast Carcinoma.

Phyllodes tumors (PTs) are uncommon breast tumors. They represent a spectrum of benign to malignant neoplasms. These erratic tumors have traits ranging from fibroadenomas on one end of the spectrum to sarcomas on the other end. The presentation of PT is variable, thus posing a diagnostic difficulty. Malignant PTs are often associated with recurrence, poor prognosis, and adverse disease outcomes. The recent genetic studies produced by genome sequencing offer information about the molecular pathophysiology of PT, aid in enhancing diagnostic precision, and suggest possible therapeutic targets in cases of malignant PT. Planning a treatment modality and prognostication requires meticulous histopathological sampling, as it relies on a correct histopathological diagnosis. There are no definitive guidelines for surgical management and targeted therapy for malignant PTs due to the rarity of these cases and very little available literature on these topics. Here in this article, we address a malignant PT in a 74-year-old female that presented as a breast mass mimicking metaplastic breast carcinoma histologically. This article also illuminates how immunohistochemistry plays a vital role in the diagnosis of this tumor.

Quantity and Distribution of Muscle Spindles in Animal and Human Muscles.

Muscle spindles have unique anatomical characteristics that can be directly affected by the surrounding tissues under physiological and pathological conditions. Understanding their spatial distribution and density in different muscles is imperative to unravel the complexity of motor function. In the present study, the distribution and number/density of muscle spindles in human and animal muscles were reviewed. We identified 56 articles focusing on muscle spindle distribution; 13 articles focused on human muscles and 43 focused on animal muscles. The results demonstrate that spindles are located at the nerve entry points and along distributed vessels and they relate to the intramuscular connective tissue. Muscles' deep layers and middle segments are the main topographic distribution areas. Eleven articles on humans and thirty-three articles on animals (totaling forty-four articles) focusing on muscle spindle quantity and density were identified. Hand and head muscles, such as the pronator teres/medial pterygoid muscle/masseter/flexor digitorum, were most commonly studied in the human studies. For animals, whole-body musculature was studied. The present study summarized the spindle quantity in 77 human and 189 animal muscles. We identified well-studied muscles and any as-yet unfound data. The current data fail to clarify the relationship between quantity/density and muscle characteristics. The intricate distribution of the muscle spindles and their density and quantity throughout the body present some unique patterns or correlations, according to the current data. However, it remains unclear whether muscles with fine motor control have more muscle spindles since the study standards are inconsistent and data on numerous muscles are missing. This study provides a comprehensive and exhaustive approach for clinicians and researchers to determine muscle spindle status.

Rotation Error Prediction of CNC Spindle Based on Short-Time Fourier Transform of Vibration Sensor Signals and Improved Weighted Residual Network.

The spindle rotation error of computer numerical control (CNC) equipment directly reflects the machining quality of the workpiece and is a key indicator reflecting the performance and reliability of CNC equipment. Existing rotation error prediction methods do not consider the importance of different sensor data. This study developed an adaptive weighted deep residual network (ResNet) for predicting spindle rotation errors, thereby establishing accurate mapping between easily obtainable vibration information and difficult-to-obtain rotation errors. Firstly, multi-sensor data are collected by a vibration sensor, and Short-time Fourier Transform (STFT) is adopted to extract the feature information in the original data. Then, an adaptive feature recalibration unit with residual connection is constructed based on the attention weighting operation. By stacking multiple residual blocks and attention weighting units, the data of different channels are adaptively weighted to highlight important information and suppress redundancy information. The weight visualization results indicate that the adaptive weighted ResNet (AWResNet) can learn a set of weights for channel recalibration. The comparison results indicate that AWResNet has higher prediction accuracy than other deep learning models and can be used for spindle rotation error prediction.

CD34-Negative Malignant Renal Solitary Fibrous Tumor: Case Report and Diagnostic Insights.

Solitary fibrous tumors (SFTs) are rare fibroblastic neoplasms with diverse biological behaviors and widespread distribution. Primary renal SFTs are uncommon, and their malignant variants, especially those that are CD34 negative, are even rarer. This study presents a case of malignant renal SFT in a 57-year-old female, focusing on its immunomorphological features. On gross examination, the tumor's large size (11.5 cm) was remarkable. Microscopic analysis showed high cellularity, diffuse sheets of moderately pleomorphic ovoid cells, prominent staghorn vessels, tumor cell necrosis, and a high mitotic count. Immunohistochemistry revealed strong positivity for STAT6, vimentin, and Bcl-2 and, notably, negativity for CD34. The presence of the NAB2::STAT6 gene fusion was confirmed through fluorescence in situ hybridization. This case emphasizes the need to consider SFT in the differential diagnosis of unusual renal tumors, even when CD34 is negative. The infrequency, morphological diversity, and resemblance to other tumors make diagnosing renal SFTs challenging. Accurate identification and classification as benign or malignant are crucial for proper clinical management and prognosis.

Giant paratesticular spindle cell lipoma: A rare case report.

INTRODUCTION: Spindle cell lipoma (SCL) is a rare condition primarily occurring in subcutaneous tissue. Only 4 cases of paratesticular SCL have been reported. CASE PRESENTATION: A 51-year-old man presented with a painless mass in his left testicle that has grown for nine years. Physical examination revealed a soft, smooth-surfaced left scrotal mass measuring 30 × 30 cm, which did not transilluminate. A contrast-enhanced abdominal-pelvic CT scan showed a paratesticular mass measuring 31.1 × 15.1 × 30.5 cm extending to the spermatic cord. Preoperative tumor markers, including Alpha-Fetoprotein (AFP), Human Chorionic Gonadotropin (HCG), and Lactate Dehydrogenase (LDH), were within normal ranges. Surgical exploration and excision successfully removed the tumor, measuring 39.0 × 37.0 × 16.0 cm and weighing 10 kg, revealing a spindle cell lipoma on pathology examination. Immunohistochemistry testing for CD34 was positive. Three months post-surgery, the patient was in good health with normal sexual function. DISCUSSION: Paratesticular SCL is a benign neoplasm. Distinguishing spindle cell lipoma from liposarcoma radiologically is challenging. Therefore, a biopsy and histopathological examination are essential. CD34 Immunohistochemistry aids in determining SCL from liposarcoma. Complete excision following thorough preoperative preparation and accurate diagnostic procedures is recommended. CONCLUSION: Paratesticular SCL cases are rare, with good preoperative preparation and accurate post-operative diagnosis; good results will likely be expected, and this case report will likely contribute to ongoing research to enhance the understanding and management of paratesticular SCL cases.

Targeting polo-like kinase 1 to treat kidney diseases.

Globally, ∼850 million individuals suffer from some form of kidney disease. This staggering figure underscores the importance of continued research and innovation in the field of nephrology to develop effective treatments and improve overall global kidney health. In current research, the polo-like kinase (Plk) family has emerged as a group of highly conserved enzyme kinases vital for proper cell cycle regulation. Plks are defined by their N-terminal kinase domain and C-terminal polo-box domain, which regulate their catalytic activity, subcellular localization, and substrate recognition. Among the Plk family members, Plk1 has garnered significant attention due to its pivotal role in regulating multiple mitotic processes, particularly in the kidneys. It is a crucial serine-threonine (Ser-Thr) kinase involved in cell division and genomic stability. In this review, we delve into the types and functions of Plks, focusing on Plk1's significance in processes such as cell proliferation, spindle assembly, and DNA damage repair. The review also underscores Plk1's vital contributions to maintaining kidney homeostasis, elucidating its involvement in nuclear envelope breakdown, anaphase-promoting complex/cyclosome activation, and the regulation of mRNA translation machinery. Furthermore, the review discusses how Plk1 contributes to the development and progression of kidney diseases, emphasizing its overexpression in conditions such as acute kidney injury, chronic kidney disease, and so forth. It also highlights the importance of exploring Plk1 modulators as targeted therapies for kidney diseases in future. This review will help in understanding the role of Plk1 in kidney disease development, paving the way for the discovery and development of novel therapeutic approaches to manage kidney diseases effectively.

Impairment of α-tubulin and F-actin interactions of GJB3 induces aneuploidy in urothelial cells and promotes bladder cancer cell invasion.

BACKGROUND: We have previously identified an unsuspected role for GJB3 showing that the deficiency of this connexin protein induces aneuploidy in human and murine cells and accelerates cell transformation as well as tumor formation in xenograft models. The molecular mechanisms by which loss of GJB3 leads to aneuploidy and cancer initiation and progression remain unsolved. METHODS: GJB3 expression levels were determined by RT-qPCR and Western blot. The consequences of GJB3 knockdown on genome instability were assessed by metaphase chromosome counting, multinucleation of cells, by micronuclei formation and by the determination of spindle orientation. Interactions of GJB3 with α-tubulin and F-actin was analyzed by immunoprecipitation and immunocytochemistry. Consequences of GJB3 deficiency on microtubule and actin dynamics were measured by live cell imaging and fluorescence recovery after photobleaching experiments, respectively. Immunohistochemistry was used to determine GJB3 levels on human and murine bladder cancer tissue sections. Bladder cancer in mice was chemically induced by BBN-treatment. RESULTS: We find that GJB3 is highly expressed in the ureter and bladder epithelium, but it is downregulated in invasive bladder cancer cell lines and during tumor progression in both human and mouse bladder cancer. Downregulation of GJB3 expression leads to aneuploidy and genomic instability in karyotypically stable urothelial cells and experimental modulation of GJB3 levels alters the migration and invasive capacity of bladder cancer cell lines. Importantly, GJB3 interacts both with α-tubulin and F-actin. The impairment of these interactions alters the dynamics of these cytoskeletal components and leads to defective spindle orientation. CONCLUSION: We conclude that deregulated microtubule and actin dynamics have an impact on proper chromosome separation and tumor cell invasion and migration. Consequently, these observations indicate a possible role for GJB3 in the onset and spreading of bladder cancer and demonstrate a molecular link between enhanced aneuploidy and invasive capacity cancer cells during tumor cell dissemination.

Jejunal Undifferentiated Spindle Cell Sarcoma with Intussusception Revealed by 18F-FDG PET/CT.

Spindle cell sarcoma is a malignant tumor with low incidence. They can occur in the soft tissue, bone, or viscera. The characteristics of morphology, density, and metabolism of spindle cell sarcoma are related to the location of the lesion. A 61-year-old woman presented with vomiting after eating for 2 weeks. Signs of peritoneal irritation were involved, but no response for symptomatic treatment included antiemetic and antispasmodic therapy. Abdominal computed tomography (CT) indicated a mass in the intestinal tract in the pelvic cavity. Then, 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/CT was performed, which interestingly detected a jejunal malignancy mass in the left upper abdomen with annular high uptake of 18F-FDG, which was complicated by intussusception and intestinal obstruction. Finally, the jejunal mass was pathologically clarified as an undifferentiated spindle cell sarcoma.

Extracellular signal-regulated protein kinase 5 modulates the spindle assembly to coordinate the oocyte meiotic maturation.

Extracellular signal-regulated protein kinase 5 (Erk5), a member of the mitogen-activated protein kinase (MAPK) family, is ubiquitously expressed in all eukaryotic cells and is implicated in the various mitotic processes such as cell survival, proliferation, migration, and differentiation. However, the potential functional roles of Erk5 in oocyte meiosis have not been fully determined. In this study, we document that ERK5 participates in the meiotic maturation of mouse oocytes by regulating the spindle assembly to ensure the meiotic progression. We unexpectedly found that phosphorylated ERK5 was localized in the spindle pole region at metaphase I and II stages by immunostaining analysis. Inhibition of ERK5 activity using its specific inhibitor XMD8-92 dramatically reduced the incidence of first polar body extrusion. In addition, inhibition of ERK5 evoked the spindle assembly checkpoint to arrest oocytes at metaphase I stage by impairing the spindle assembly, chromosome alignment and kinetochore-microtubule attachment. Mechanically, over-strengthened microtubule stability was shown to disrupt the microtubule dynamics and thus compromise the spindle assembly in ERK5-inhibited oocytes. Conversely, overexpression of ERK5 caused decreased level of acetylated α-tubulin and spindle defects. Collectively, we conclude that ERK5 plays an important role in the oocyte meiotic maturation by regulating microtubule dynamics and spindle assembly.

Mucinous tubular and spindle renal cell carcinoma revealed by a trauma of the kidney: a case report.

BACKGROUND: Mucinous tubular and spindle cell carcinoma is a rare renal tumor. It has been recognized as a distinct entity in the 2004 World Health Organization tumor classification. Since then, several dozen of these tumor have been reported with additional complementary morphologic characteristics, immunohistochemical profile, and molecular genetic features that have further clarified its clinicopathologic aspects. CASE PRESENTATION: We report the case of a 52-year-old male African patient who was found to have a mucinous tubular and spindle renal cell carcinoma on a nephrectomy specimen for a severe kidney trauma. CONCLUSIONS: This tumor has a histological spectrum ranging from low to high grade, which includes sarcomatoid differentiation that can confer the tumor an aggressive clinical course.

Pleomorphic leiomyosarcoma of the maxilla with metastasis to the colon: A case report.

BACKGROUND: Pleomorphic leiomyosarcomas make up around 8.6% of all leiomyosarcomas. They behave aggressively and often have poor prognoses. They can affect the gastrointestinal tract and retroperitoneum. To date, pleomorphic leiomyosarcoma involving the mesocolon have been reported in nine patients. CASE SUMMARY: The patient was a 44-year-old man with a history of pleomorphic leiomyosarcoma of the left maxilla with metastasis to the lung and liver. His most recent positron emission tomography-computed tomography (PET-CT) scan showed uptake in the ascending and transverse colons. A colonoscopy revealed a 5.0 cm × 3.5 cm × 3.0 cm pedunculated polyp in the ascending colon. The polyp was removed using hot snare polypectomy technique and retrieved with Rothnet. Histopathologic examination of the polyp showed a metastatic pleomorphic leiomyosarcoma. CONCLUSION: Uptake(s) on PET-CT in a patient with pleomorphic leiomyosarcoma should raise suspicion for metastasis.

Use of Tumor-Infiltrating Lymphocyte (TIL) Cell Therapy For Spindle Cell Carcinoma of the Breast: A Case Report.

BACKGROUND: Spindle cell carcinoma (SCC) of the breast is a rare type of metaplastic carcinoma with poor prognosis, high recurrence, and distant metastasis. Mammectomy, chemotherapy, radiotherapy, and endocrine therapy are the preferred choices of treatments. Tumor-infiltrating lymphocyte (TIL) therapy, which utilizes the patient's immune cells from the solid tumor micro-environment to eradicate cancer cells, has shown promising results in treating advanced solid tumors. However, its use for SCC of the breast has not been reported. CASE PRESENTATION: Here, we present a case of combining TIL therapy with personalized chemotherapy and endocrine therapy for the treatment of SCC of the breast. A 36-year-old Chinese woman presented with a palpable nodule (32 mm) on her left breast. Based on histological and immunohistochemical analysis of breast biopsy and surgical specimens, she was diagnosed with SCC of the breast (stage IIA). The patient received concurrent personalized chemotherapy, TIL therapy, and endocrine therapy following mammectomy. She showed no severe side effects during therapy, and did not present local recurrence or distant metastasis after follow-up for at least 14 months. CONCLUSION: To our knowledge, this is the first case report, which demonstrated that TIL therapy combined with chemotherapy/endocrine therapy after mastectomy is safe and effective for SCC of the breast.

Five years of disease-free survival in a case of recurrent, post-op, grade 3, stage 2, Malignant Spindle Cell Melanoma treated with Ayurvedic medicines: A case report.

Malignant spindle cell melanoma is a rare cancer with a questionable prognosis because of limited published case reports. This article discusses a male patient with a history of Spindle cell melanoma tumor, Rt heel, Grade 3 (Gr 3) Stage 2 (St 2) seen in our OPD treated with supporting herbo-mineral combination of Ayurvedic medicine. Such types of cancers are of concern and can be more troublesome to the patient. The initial chief complaint of the patient was a palpable corn-like growth in the right heel, which was surgically removed at that time. When it recurred after one year, it was investigated thoroughly and it was found malignant, and then operated again. The patient came to us after his second operation. After appropriate analysis based on Ayurvedic and modern parameters, the patient was treated with Ayurved treatment. As there was no other treatment suggested by oncologists, he was on supportive Ayurvedic treatment only. Ayurvedic treatment continued for 2 years afterwards. The treatment module showed complete relief in the symptoms (100%), by the end of treatment. Follow-up PET scans showed further improvement and a complete reversal of residual disease was observed. The last PET scan did not show any evidence of abnormality. To date, there has been no recurrence and the patient has been living completely normally for the last almost 5 years (karnofsky score 90/100). It can be concluded that the addition of Ayurvedic treatment might have helped this patient of malignant spindle cell melanoma for regression of residual disease, prevention of metastasis to date, and a good quality of life. We have observed 5+ years of disease-free survival and near-normal quality of life for this patient, and still ongoing.

Predicting Infertility: How Genetic Variants in Oocyte Spindle Genes Affect Egg Quality.

Successful reproduction relies on the union of a single chromosomally normal egg and sperm. Chromosomally normal eggs develop from precursor cells, called oocytes, that have undergone accurate chromosome segregation. The process of chromosome segregation is governed by the oocyte spindle, a unique cytoskeletal machine that splits chromatin content of the meiotically dividing oocyte. The oocyte spindle develops and functions in an idiosyncratic process, which is vulnerable to genetic variation in spindle-associated proteins. Human genetic variants in several spindle-associated proteins are associated with poor clinical fertility outcomes, suggesting that heritable etiologies for oocyte dysfunction leading to infertility exist and that the spindle is a crux for female fertility. This chapter examines the mammalian oocyte spindle through the lens of human genetic variation, covering the genes TUBB8, TACC3, CEP120, AURKA, AURKC, AURKB, BUB1B, and CDC20. Specifically, it explores how patient-identified variants perturb spindle development and function, and it links these molecular changes in the oocyte to their cognate clinical consequences, such as oocyte maturation arrest, elevated egg aneuploidy, primary ovarian insufficiency, and recurrent pregnancy loss. This discussion demonstrates that small genetic errors in oocyte meiosis can result in remarkably far-ranging embryonic consequences, and thus reveals the importance of the oocyte's fine machinery in sustaining life.