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Pierluigi Ballardini,1 Guido Margutti,1 Massimo Pedriali,2 Patrizia Querzoli21Department of Internal Medicine, Hospital of the Delta, Lagosanto, 2Institute of Pathology, S Anna Hospital, Ferrara, ItalyAbstract: Syringoid eccrine carcinoma is a very rare skin tumor. Herein we describe a 72-year-old male patient presenting with a syringoid eccrine carcinoma of the nipple with associated axillary lymph node metastases. Surgery associated with adjuvant radiotherapy was performed. To the best of our knowledge, this is the first case of syringoid eccrine carcinoma of the nipple ever reported.Keywords: syringoid carcinoma, nipple, axillary metastases, radiotherapy

Anaplastic thyroid carcinoma (ATC) is a very rare disease accounting for less than 2% of all thyroid malignancies and associated to a dismal prognosis. The median survival is between 3 to 9 months with less than 10% of patients alive at 3 years after the time of diagnosis. This low cure rate is due to the late clinical presentation as a bulky unresectable tumour mass often associated with synchronous lung metastases (20-50%). A multimodality treatment consisting in a radical surgery followed by radiotherapy and chemotherapy is reported to be associated with better clinical outcomes while young age (< 65 years), tumour size (< 6.5 cm) and absence of distant metastases at time of diagnosis are recognized as strong prognostic factors of survival. We report the case of a 65 year-old man who was referred to our hospital for an ATC which extended to the external right tracheal wall and muscolar layer of esophagus. The patient underwent radical thyroidectomy with bilateral neck dissection followed by 3 cycles of adjuvant chemotherapy (Cisplatin /Epirubicin) and subsequent radiochemotherapy with Cisplatin as radiosensitizer. At more than 6 years since diagnosis the patient is still alive without evidence of local recurrence or distant metastases. Therefore, aggressive multimodality treatment after radical surgery might improve clinical outcomes and perhaps should be tested in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Next-generation Trop-2-targeted therapy against advanced cancers is hampered by expression of Trop-2 in normal tissues. We discovered that Trop-2 undergoes proteolytic activation by ADAM10 in cancer cells, leading to the exposure of a previously inaccessible protein groove flanked by two N-glycosylation sites. We designed a recognition strategy for this region, to drive selective cancer vulnerability in patients. Most undiscriminating anti-Trop-2 mAbs recognize a single immunodominant epitope. Hence, we removed it by deletion mutagenesis. Cancer-specific, glycosylation-prone mAbs were selected by ELISA, bio-layer interferometry, flow cytometry, confocal microscopy for differential binding to cleaved/activated, wild-type and glycosylation site-mutagenized Trop-2. The resulting 2G10 mAb family binds Trop-2-expressing cancer cells, but not Trop-2 on normal cells. We humanized 2G10 by state-of-the-art complementarity determining region grafting/re-modeling, yielding Hu2G10. This antibody binds cancer-specific, cleaved/activated Trop-2 with Kd < 10-12 mol/L, and uncleaved/wtTrop-2 in normal cells with Kd 3.16×10-8 mol/L, thus promising an unprecedented therapeutic index in patients. In vivo, Hu2G10 ablates growth of Trop-2-expressing breast, colon, prostate cancers, but shows no evidence of systemic toxicity, paving the way for a paradigm shift in Trop-2-targeted therapy., (©2023 American Association for Cancer Research.)

When in critical limb ischemia (CLI) the healing process aborts or does not follow an orderly and timely sequence, a chronic vascular wound develops. The latter is major problem today, as their epidemiology is continuously increasing due to the aging population and a growth in the incidence of the underlying diseases. In the US, the mean annualized prevalence of necrotic wounds due to the fact of CLI is 1.33% (95% CI, 1.32-1.34%), and the cost of dressings alone has been estimated at USD 5 billion per year from healthcare budgets. A promising cell treatment in wound healing is the local injection of peripheral blood mononuclear cells (PBMNCs). The treatment is aimed to induce angiogenesis as well to switch inflammatory macrophages, called the M1 phenotype, into anti-inflammatory macrophages, called M2, a phenotype devoted to tissue repair. This mechanism is called polarization and is a critical step for the healing of all human tissues. Regarding the clinical efficacy of PBMNCs, the level of evidence is still low, and a considerable effort is necessary for completing the translational process toward the patient bed site. From this point of view, it is crucial to identify some candidate biomarkers to detect the switching process from M1 to M2 in response to the cell treatment.

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from β-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of β-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/β-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2-centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer., (Copyright © 2021. Published by Elsevier Inc.)

Background: GATA binding protein 3 ( GATA3 ) expression is positively correlated with estrogen receptor (ER) expression, but its prognostic value as an independent factor remains unclear. Thus, we undertook the current study to evaluate the expression of GATA3 and its prognostic value in a large series of breast carcinomas (BCs) with long-term follow-up., Methods: A total of 702 consecutive primary invasive BCs resected between 1989 and 1993 in our institution were arranged in tissue microarrays, immunostained for ER, progesterone receptor (PR), ki-67, HER2, p53, and GATA3 , and scored. Clinico-pathological data were retrospectively collected., Results: GATA3 was evaluable in 608 (87%) of the 702 cases; it was positive in 413 (68%) cases and negative in 195 (32%) cases. GATA3 positivity was significantly associated with lower grade ( p < 0.0001), size ( p = 0.0463), stage ( p = 0.0049), ER+ ( p < 0.0001), PR+ ( p < 0.0001), HER2- ( p = 0.0175), and p53 wild-type pattern ( p < 0.0001). The median follow-up was 183 months, GATA3 positivity was associated with better overall survival (HR 0.70, p = 0.001), and its prognostic value was retained in a multivariate analysis. The association with better overall survival was stronger in patients with grade 1-2, pT1-2, pN0, stage I-II, ER+, PR+, ki-67 < 20%, HER2-, a wild-type p53 immunohistochemical pattern, and in luminal B BC., Conclusions: Our findings indicate that GATA3 is a positive prognostic marker in BC patients, especially in patients with biologically less aggressive BC. Incorporating GATA3 immunohistochemistry into routine practice could help further stratify BC patients for their risk.

Objective: To investigate the biological effects of a novel endovenous scaffold in a porcine model., Methods: Petalo is a compliant venous scaffold implanted into the internal jugular veins of 12 healthy pigs. The pigs were sacrificed at one, two, three, and six months, respectively. Microscopic investigations were performed at two blinded laboratories., Results: Neo-intima formation progressively covering up the stent metallic bars was observed. The inflammatory response of the venous wall showed a peak after three months by the implant, followed by marked reduction after six months. The device induced a significant ( p < 0.01) increase of the thickness respect to the control regions, but was comparable in sections obtained after three and six months., Conclusions: The implant of Petalo compliant venous scaffold in the venous wall of this porcine model is characterized by neointima formation and by an inflammatory reaction which tends to decrease after six months. Our data point against the induction of smooth muscle cells proliferation and migration as confirmed by electronic transmission microscopy analyses.

Background: Adrenal cavernous hemangiomas are very rare benign tumors that usually present as incidental findings on abdominal imaging. Preoperative differential diagnosis from other benign or malignant adrenal neoplasms may be challenging., Case Presentation: A 70-year old man was referred for an 8-cm abdominal mass incidentally discovered on a contrast-enhanced computed tomography (CT) performed to investigate a pulmonary nodule. Biochemical tests ruled out any endocrine dysfunction and iodine 123 metaiodobenzylguanidine whole body scintiscan single-photon emission CT excluded a pheocromocitoma. Findings on magnetic resonance imaging were non-specific and the patient was elected for a left adrenalectomy. Histopathological diagnosis revealed a cavernous hemangioma. A portion of the resected tissue was tested for drug sensitivity to mitotane, doxorubicin, and sunitinib., Conclusions: Adrenal hemangioma is a rare disease but should be included in the differential diagnosis of adrenal tumors. The surgical resection is generally required to exclude malignant disease, resolve pressure-related symptoms, and prevent retroperitoneal hemorrhage. Although specific features in diagnostic imaging are often lacking, if the diagnosis is established preoperatively a laparoscopic adrenalectomy can be performed due to the benign nature of the lesion. Doxorubicin and sunitinib were both capable of reducing primary culture cell viability, this suggest that similar drugs may be useful in the medical treatment of adrenal hemangiomas.