RESUMEN

Phosphatidylinositol 4,5-bisphosphate 3-kinases (PI3K) are a family of kinases whose activity affects pathways needed for basic cell functions. As a result, PI3K is one of the most mutated genes in all human cancers and serves as an ideal therapeutic target for cancer treatment. Expanding on work done by other groups we improved protein yield to produce stable and pure protein using a variety of modifications including improved solubility tag, novel expression modalities, and optimized purification protocol and buffer. By these means, we achieved a 40-fold increase in yield for p110α/p85α and a 3-fold increase in p110α. We also used these protocols to produce comparable constructs of the ß and δ isoforms of PI3K. Increased yield enhanced the efficiency of our downstream high throughput drug discovery efforts on the PIK3 family of kinases.

Asunto(s)

RESUMEN

OBJECTIVES: Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain histogenesis. Most OFMTs have benign behavior, and many harbor gene fusions involving the PHD finger protein 1 (PHF1), such as EP400::PHF1, MEAF6::PHF1, EPC1::PHF1, and PHF1::TFE3. The PHF1::TFE3 fusion is unique because PHF1 is at 5' instead of residing at 3' in the other fusions. In this study, we describe 2 cases of OFMT harboring PHF1::TFE3 fusions and review 13 published cases. METHODS: Two cases of PHF1::TFE3-positive OFMT were investigated using RNA Next-Generation Sequencing and immunohistochemistry. RESULTS: Most (12/15) of the PHF1::TFE3 OFMTs we studied were located at proximal and distal extremities, with a multinodular growth pattern. Only 1 case (1/10) had a shell of bone at the periphery. Areas morphologically similar to sclerosing epithelioid fibrosarcoma or low-grade fibromyxoid sarcoma were found in 8 of 12 (66.7%) cases. Eleven cases (11/15 [73.3%]) were regarded as malignant based on more than 2/50 high-power field mitotic figures, increased cellularity, or the presence of necrosis. Among the 9 cases with follow-up data, 2 patients died of disease (with metastases), 1 patient is alive with metastases, and 1 patient had multiple local recurrences. CONCLUSIONS: Because PHF1 is located at 3' in all the PHF1 fusions in OFMTs except PHF1::TFE3, the different driver molecular alterations suggest that OFMTs with 3'-PHF1 fusions and OFMTs with PHF1::TFE3 are different tumors. Immunohistochemistry confirmed TFE3 expression in all PHF1::TFE3 OFMTs. Because PHF1::TFE3-positive OFMTs have increased mitotic figures and tumor cellularity, with a high rate of metastasis, using the name PHF1::TFE3 positive fibromyxoid sarcoma may be appropriate.

RESUMEN

With the wide use of RNA sequencing technologies, the family of FET::CREB fusion mesenchymal neoplasms has expanded rapidly to include potentially aggressive neoplasms, not fitting any well established WHO entity. Recently, a group of intra-abdominal FET(EWSR1/FUS)::CREB(CREM/ATF1) fused unclassified neoplasms has been reported followed by recent recognition of an analogous extra-abdominal category of unclassified neoplasms carrying EWSR1::ATF1 fusions. We describe 9 additional tumors (5 extra-abdominal and 4 abdominal) carrying an EWSR1::CREM (n = 8) and FUS::CREM (n = 1) fusion. Patients were 7 females and 2 males aged 10 to 75 years (median, 34). Extra-abdominal tumors originated in the head and neck (2 sinonasal, 1 orbital) and soft tissues (1 gluteal, 1 inguinal). Abdominal tumors involved stomach (2), mesentery (1), and kidney (1). Tumor size ranged from 3.5 to 11 cm (median, 6). Treatment was radical surgery with (5) or without (2) neo/adjuvant radio/chemotherapy. Extended follow-up of 5 patients (21-52 months; median, 24) showed an aggressive course in two (40%); one died of disseminated metastases 52 months after several intensified chemotherapy regimens, and one was alive with progressive abdominal disease at 21 months. The immunophenotype of the two subcohorts was significantly overlapping with variable expression of EMA (7 of 8), keratin AE1/AE3 (5 of 9), CD99 (4 of 7), MUC4 (2 of 8), ALK (3 of 8), synaptophysin (3 of 9), chromogranin (1 of 8), CD34 (3 of 6), CD30 (1 of 6), PAX8 (1 of 7), and inhibin (1 of 7), but no reactivity with desmin (0 of 8), S100 (0 of 8), and SOX10 (0 of 8). This series further solidifies the notion that FET::CREB fusions are not limited to the triad of angiomatoid fibrous histiocytoma, clear cell sarcoma, and malignant gastrointestinal neuroectodermal tumor, but characterize an emerging family of potentially aggressive neoplasms occurring at both intra- and extra-abdominal sites. These tumors underscore the promiscuity of the FET::CREB fusions and highlight the pivotal role of phenotype-oriented classification of these neoplasms that share the same genotype, still featuring significant biological and behavioral distinctness.

RESUMEN

Pleomorphic dermal sarcoma (PDS) and atypical fibroxanthoma (AFX) are rare mesenchymal tumors that share similar clinical, histological, and immunohistochemical characteristics. Careful histopathological examination of a biopsy specimen that includes subcutaneous fat remains the preferred way to differentiate between these tumors. AFX is limited to dermal invasion, whereas PDS demonstrates deeper invasion. Moreover, PDS may present with tumor necrosis and high-grade histological findings, such as lymphovascular and perineural invasion, features absent in AFX. However, like PDS, AFX is a diagnosis of exclusion, and an exhaustive immunohistochemistry panel is recommended to distinguish these tumors from other spindled cell tumors in the differential diagnosis. The authors present the case of an 86-year-old man with biopsy-suspected AFX who was referred for Mohs micrographic surgery for tumor excision. During Mohs, the tumor was observed to have invaded deeply into the subcutaneous tissue and galeal aponeurosis, aligning more closely with a PDS. The diagnosis of PDS was confirmed using en face processing during Mohs surgery, which captured the intravascular involvement of a solitary vessel. Differentiating between PDS and AFX is important because PDS is a more aggressive tumor, with a higher rate of local recurrence and metastasis, and requires closer monitoring.

RESUMEN

Sarcomas of thyroid glands represent a distinctive subset of rare and perplexing anomaly that present a challenges in the field of thyroid pathology. Thyroid sarcomas, primary or secondary, are exceptionally rare with only a handful of case reports documented so far. The challenges lie in the fact that certain primary thyroid malignancies of epithelial origin may exhibit spindle cell morphology, making them difficult to differentiate from thyroid sarcomas. Despite the morphological similarities, discerning between these entities is crucial due to their distinct treatment and management implications. This report documents a series of unusual types of sarcoma in the thyroid gland. The aim is to explore the peculiarities of these lesions, the diagnostic challenges faced as well to study the potential implications for both clinicians and patients.

RESUMEN

Sarcoma samples from 33 dogs, 25 subcutaneous and 8 articular, were submitted for cytokeratin immunohistochemistry. Eight of the 25 subcutaneous sarcomas (32%) expressed cytokeratin in 1% to 50% of the neoplastic cells. Of the 7 articular sarcomas evaluated, 1 (14%) expressed cytokeratin in 10% of neoplastic cells. The Kaplan-Meier survival analysis showed that the mean overall survival of dogs with subcutaneous sarcomas (28.1 months [confidence interval [CI]:17.8, 38.4]) did not significantly differ from those with articular sarcomas (24.8 months [CI = 0.5, 29.0]). Overall survival of dogs with sarcomas (both locations combined) immunoreactive for cytokeratin (31.2 months [CI = 17.8, 44.6]) did not differ from those not immunoreactive for cytokeratin (22.0 months [CI = 8.4, 35.6]). Therefore, cytokeratin expression does not indicate synovial origin (P = .64) and neither sarcoma location (P = .76) nor cytokeratin expression (P = .53) affects patient overall survival in this small study. The use of cytokeratin immunohistochemistry is not helpful to determine synovial origin of sarcomas in dogs.

RESUMEN

Cancer predisposition syndromes are recognized in about 10% of pediatric malignancies with several genes specifically involved in a subset of pediatric tumors such as DICER1, in pleuropulmonary blastoma, cystic nephroma, and brain sarcomas. By contrast, the role of BRCA1/2 in pediatric cancer predisposition is still under investigation. We present two cases of young first-degree cousins, both carrying a germline BRCA2 variant and developing tumors characterized by somatic DICER1 mutations. Patient 1 presented with a cystic nephroma harboring a somatic DICER1 variant (p.Asp1810Tyr), while patient 2 had a primary intracranial DICER1-mutated sarcoma showing a distinct somatic DICER1 variant (p.Asp1709Glu) as well as biallelic inactivation of TP53 (p.Val173Leu, VAF 91%) and APC (p.Ile1307Lys, VAF 95%) and a pathogenic variant in KRAS (p.Gln61His). Both patients carried the same germline BRCA2 variant (p.Arg2842Cys) of unknown significance. The same variant was found in the mother of patient 2 and in the father of patient 1, who are siblings. A homologous recombination deficiency signature was not identified in any of the two tumors, possibly suggesting a reduction of BRCA2 activity. The association of BRCA2 and DICER1 variants in our cases hints at a potential cooperative role in cancer pathogenesis. Further studies are warranted to elucidate the interplay between BRCA1/2 and DICER1 variants and their implications for cancer predisposition and treatment in pediatric patients.

Asunto(s)

RESUMEN

Melanoma is a malignant neoplasm that arises in melanocytes, pigment-producing cells present primarily in the skin. However, not all malignant melanomas originate from the skin, and the other sites of origin include the uveal (eye) or mucosa (rectal or oral); it can have different patterns of mutations. While targeted therapies and immunotherapies have transformed the treatment of this disease in the metastatic setting, resistance mechanisms can still pose challenges for patients and their healthcare providers. We present a case of a male patient with metastatic melanoma and discuss its clinical presentation, diagnostic workup, treatment options, and outcomes. By exploring the complexities of this multifaceted disease process, clinicians and researchers can gain valuable insights into potential areas for improved management strategies. Ultimately, we should aim to deepen our understanding of melanoma and work towards better patient outcomes.

RESUMEN

Mammary-type myofibroblastomas (MFBs) are benign spindle cell tumors, typically presenting in common locations such as the breast, abdomen, and inguinal region. We present a case of a 66-year-old male with a four-year history of painless scrotal swelling. The preoperative diagnosis was challenging, with an initial suspicion of soft tissue sarcoma. A complete surgical excision was performed, revealing a well-circumscribed, encapsulated mass. The tumor measured 30 x 20 x 14 cm, weighing 5.28 kg. Histopathology confirmed an MFB. This exceptionally large paratesticular MFB emphasizes the diagnostic difficulty of such tumors. Surgical resection remains the treatment of choice, with an excellent prognosis. This case highlights the importance of considering MFB in the differential diagnosis of scrotal masses, even with atypical presentations.

RESUMEN

Small bowel malignant tumors, particularly leiomyosarcomas (LMSs), are rare and challenging to diagnose due to their asymptomatic nature in the initial stages. The lack of specific symptoms makes it difficult to differentiate LMSs from other gastrointestinal tumors. This report highlights the clinical presentation, diagnostic challenges, treatment, and prognosis of small bowel LMSs, specifically focusing on a rare case of jejunal LMS presented in a 75-year-old man, initially suspected as a gastrointestinal stromal tumor (GIST). Clinical examination, laboratory investigations, imaging studies, and histopathological analysis were performed to diagnose and treat the patient. The patient underwent surgical excision of the tumor with successful recovery. The histopathological analysis confirmed a high-grade LMS, and the patient was advised on adjuvant chemotherapy for further treatment. This case report emphasizes the importance of considering small bowel LMSs in the differential diagnosis of abdominal pain and highlights the challenges in diagnosing and treating these rare tumors. Early detection and appropriate management can improve the prognosis of patients with small bowel LMSs.

RESUMEN

Introduction Detection of gynecological cancers preoperatively is imperative for practitioners for optimal patient management and outcome. This study aimed to estimate the incidence of unexpected malignancy (UM) in patients who underwent hysterectomy or myomectomy for presumed benign indications and to detect the predictive factors of UM. Methods A retrospective analytical study that included patients who underwent hysterectomy or myomectomy for benign indications from January 1st, 2016, to December 31st, 2020, was conducted at the Department of Obstetrics and Gynecology at Salmaniya Medical Complex, Bahrain. The main outcome was the overall incidence of UM and the incidence of each malignancy. Characteristics of UM were compared with benign pathologies. Fisher's exact and Pearson's chi-square tests were used to compare categorical variables and the Mann-Whitney U test or student's t-test for continuous variables. Binary logistic regression was used to identify the predictors of occurrence of UM. Confidence interval (CI) was set at 95%. A probability value (p-value) less than 0.05 was considered statistically significant. Results Out of 513 patients who underwent hysterectomy or myomectomy, 379 (73.9%) fulfilled the inclusion criteria, 314 (82.8%) hysterectomies and 65 (17.2%) myomectomies. The overall incidence of UM was 1.3% (n=5/379), 1.3% (n=4/314) among hysterectomies and 1.5% (n=1/65) among myomectomies. Three (0.8%) pre-malignant pathologies were identified: one (0.26%) smooth muscle tumor of unknown malignant potential, leiomyoma with bizarre nuclei, and mucinous borderline tumor of endocervical type of ovary each. The types of UM were sarcomas in three (0.26%) patients (two (0.5%) leiomyosarcoma and one (0.26%) endometrial stromal sarcoma) and endometrial adenocarcinoma and ovarian cancer in one (0.26%) patient each. No significant difference was found between the characteristics of UM and benign pathologies. Conclusion Although this study demonstrated a low incidence of UM among both hysterectomies and myomectomies, the age at the diagnosis of our patients with UM was as young as 34 years of age, and sarcomas were the most common type of UM. Disconcertingly, none of the studied independent variables had significantly predicted the occurrence of UM.

RESUMEN

Sarcomas present challenges in management due to their aggressive nature. Interventional radiology, utilizing ablation and embolization, offer promising alternatives for recurrent cases. In recent years, combined techniques (ablation + embolization) and the use of balloon-microcatheter have been introduced to enhance the necrotic effect in HCC treatment. This paper presents the case of a 47-year-old female with recurrent abdominal sarcoma treated with balloon-occluded microwave ablation (b-MWA) and balloon-occluded transarterial embolization (b-TAE). Post-treatment imaging revealed a significant reduction in lesion size and absence of pathological contrast enhancement. This study highlights the potential of balloon-catheter-assisted combined therapies (b-MWA + b-TAE) in managing sarcomas, expanding the applicability of interventional radiology for inoperable cases that are too large for ablative therapy alone or requiring multiple antennas. Further research is warranted to refine protocols and enhance patient outcomes in sarcoma management.

RESUMEN

Background: Ewing sarcoma is a rare malignant neoplasm that is primarily localized in bone tissues. The prognosis for patients with a newly diagnosed localized Ewing sarcoma has been greatly improved by multimodality treatment. However, treating patients with disseminated or recurrent disease is challenging, with a 5-year overall survival rate of <30%. Case Report: A 17-year-old female with an asymptomatic tumor of the left temple underwent 3 cycles of vincristine, ifosfamide, doxorubicin, and etoposide and achieved partial remission. However, the patient refused further chemotherapy and surgical intervention and was lost to follow-up. After 7 months, the patient presented again with a sizeable tumor on her left temple and worsening symptoms. Chemotherapy with alternating cycles of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide according to the EURO EWING 2012 trial was initiated. After a positive response, debulking surgery was performed, followed by postsurgical radiation, and partial remission was achieved. Conclusion: Optimal treatment protocols for recurrent Ewing sarcoma are lacking. Treatments are individualized based on the patient's response to treatment and the decisions of tumor boards. Patients with rare tumors such as Ewing sarcoma benefit from multidisciplinary collaboration, resulting in improved quality of care and treatment outcomes.

RESUMEN

Perianal alveolar rhabdomyosarcoma is a rare sarcoma that requires a high index of suspicion along with tissue biopsy for accurate diagnosis. Successful treatment, even in the setting of recurrence, requires a multidisciplinary approach.

RESUMEN

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an extremely rare and aggressive form of inflammatory myofibroblastic tumor. Clinically, it has a high risk of relapse and peripheral organ infiltration, and it responds poorly to conventional chemotherapy. Anaplastic lymphoma kinase (ALK) inhibitors are currently the most effective targeted therapy for EIMS. This report discusses a typical case of abdominal EIMS in a 43-year-old woman. The tumors recurred rapidly within one month after surgery. Alectinib was promptly administered upon diagnosis. However, the patient developed a severe allergic reaction to the medication. After a comprehensive assessment and symptomatic treatment, her condition stabilized, leading to a favorable prognosis. This study summarizes cases of abdominal EIMS, highlights the successful use of Alectinib for treatment, and discusses the management of medication-related complications.

RESUMEN

Extraskeletal Ewing's sarcoma (ES) has been reported to originate from various sites. Primary endobronchial ES is an extremely rare bronchial tumor, especially multifocal lesions. This report describes a rare presentation of primary bronchial ES in a 31-year-old female who was referred to the emergency department of our hospital due to suspicion of a foreign body in the bronchus. Computed tomography and bronchoscopy revealed multiple polypoid nodules in the middle bronchus of her right lung, thus excluding the initial diagnosis. Infection-related laboratory tests and serum tumor markers were normal. The bronchial sleeve resection was performed to remove the tumor completely and the patient's clinical symptoms obviously improved. Subsequent imaging, histopathological, immunohistochemical and genetic analyses made a conclusive diagnosis of primary endobronchial ES. To our knowledge, this is the eighth case of primary bronchial ES reported in medical literature.

RESUMEN

Background: This study aimed to develop and validate nomograms to predict overall survival (OS) for pelvic Ewing's sarcoma (EWS) and chordoma, identify prognostic factors, and compare outcomes between the two conditions. Methods: We identified patients diagnosed with pelvic EWS or chordoma from the SEER database (2001-2019). Independent risk factors were identified using univariate and multivariate Cox regression analyses, and these factors were used to construct nomograms predicting 3-, 5-, and 10-year OS. Validation methods included AUC, calibration plots, C-index, and decision curve analysis (DCA). Kaplan-Meier curves and log-rank tests compared survival differences between low- and high-risk groups. Results: The study included 1175 patients (EWS: 611, chordoma: 564). Both groups were randomly divided into training (70 %) and validation (30 %) cohorts. OS was significantly higher for chordoma. Multivariate analysis showed year of diagnosis, income, stage, and surgery were significant for EWS survival, while age, time to treatment, stage, and surgery were significant for chordoma survival. Validation showed the nomograms had strong predictive performance and clinical utility. Conclusions: The nomograms reliably predict overall survival (OS) in pelvic EWS and chordoma, helping to identify high-risk patients early and guide preventive measures. The study also found that survival rates are significantly higher for chordoma, highlighting different prognostic profiles between EWS and chordoma.

RESUMEN

Ewing sarcoma (ES) is a rare malignancy that typically occurs within the skeletal system but can also develop extraskeletally. Extraskeletal ES typically presents paraspinally, in the limbs, and retroperitoneum. Rarely, it presents as a primary gastric ES. To our knowledge, there are only 13 reports of primary gastric ES, none of which originated in the cardia of the stomach. Increased identification of how extraskeletal ES, specifically primary gastric ES, presents and characterized is crucial for future treatment development and accurate prognosis. We present the case of a 36-year-old man with hematemesis, ultimately found to have primary gastric ES in the cardia.

RESUMEN

Background: Death Receptor 5 (DR5) is expressed on the surface of primary bone and soft tissue sarcoma cells, and its activation induces cell death primarily through apoptosis. The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death. Currently, clinical trials are investigating the effectiveness of DR5 activation using new biological agents, such as bi-specific or tetravalent antibodies, in improving the survival of patients with relapsed or refractory cancers. Furthermore, investigations continue into the use of novel combination therapies to enhance DR5 response, for example, with inhibitor of apoptosis protein (IAP) antagonist agents [such as the second mitochondria-derived activator of caspase (SMAC) mimetics] and with immune checkpoint inhibitor anti-programmed death-ligand 1 (anti-PD-L1) or anti-programmed cell death-1 (anti-PD-1) antibodies. Other therapies include nanoparticle-mediated delivery of TRAIL plasmid DNA or TRAIL mRNA and stem cells as a vehicle for the targeted delivery of anti-cancer agents, such as TRAIL, to the tumor. Methods: scoping review of the literature from November 2017 to March 2024, utilizing PubMed and Google Scholar. Results: New agents under investigation include nanoTRAIL, anti-Kv10.1, multimeric IgM, and humanized tetravalent antibodies. Developments have been made to test novel agents, and imaging has been used to detect DR5 in preclinical models and patients. The models include 3D spheroids, genetically modified mouse models, a novel jaw osteosarcoma model, and patient-derived xenograft (PDX) animal models. There are currently two ongoing clinical trials focusing on the activation of DR5, namely, IGM-8444 and INBRX-109, which have progressed to phase 2. Further modifications of TRAIL delivery with fusion to single-chain variable fragments (scFv-TRAIL), directed against tumor-associated antigens (TAAs), and in the use of stem cells focus on targeted TRAIL delivery to cancer cells using bi-functional strategies. Conclusion: In vitro, in vivo, and clinical trials, as well as advances in imaging and theranostics, indicate that targeting DR5 remains a valid strategy in the treatment of some relapsed and refractory cancers.

RESUMEN

Background: Soft tissue sarcomas (STS) often occur in the peri-pelvic region (proximal thigh, groin, gluteal region). A common complication following resection of STS is surgical site infection (SSI). The peri-pelvic site appears to be particularly problematic. Surgical site infections are associated with a high proportion of gram-negative and anaerobic micro-organisms. To date, there are no published recommendations for peri-operative antibiotic prophylaxis in pelvic STS resection. Therefore, the aim of this study was to determine the rate of SSI and the spectrum of micro-organisms detected in this region. Methods: In this monocentric study, 366 patients were retrospectively evaluated. All of these patients had undergone surgery for STS in the peri-pelvic and pelvic regions. Surgical site infections were recorded, and the microbial spectrum was analyzed. Results: There were 85 (23.2%) patients with SSI, and 188 revisions were required in these patients (2.21 per case). Swabs were sterile in 20% of clinically infected cases. In total, 36.5% of infections were polymicrobial. The most common bacteria were coagulase-negative staphylococci in 31.5%, followed by Enterococcus species in 13.3% and Escherichia coli in 7.7%. In total, 30.8% of the bacteria were gram-negative and 25.9% were anaerobic. Conclusions: Our results demonstrate the uniqueness of the bacterial spectrum of SSI after STS resection in the peri-pelvic region. In the authors' opinion, recommendations regarding the peri-operative antibiotic prophylaxis need to be adapted for the typical microbial spectrum at this site.