Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer.

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 ß-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of ß-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/ß-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.

Levels of miR-126 and miR-218 are elevated in ductal carcinoma in situ (DCIS) and inhibit malignant potential of DCIS derived cells.

A substantial number of ductal carcinoma in situ (DCIS) detected by mammography never progress to invasive ductal carcinoma (IDC) and current approaches fail to identify low-risk patients not at need of adjuvant therapies. We aimed to identify the key miRNAs protecting DCIS from malignant evolution, that may constitute markers for non-invasive lesions. We studied 100 archived DCIS samples, including pure DCIS, DCIS with adjacent IDC and pure DCIS from patients with subsequent IDC in contralateral breast or no recurrence. A DCIS derived cell line was used for molecular and cellular studies. A genome wide study revealed that pure DCIS has higher miR-126 and miR-218 expression than DCIS with adjacent IDC lesions or than IDC. The down-regulation of miR-126 and miR-218 promoted invasiveness in vitro and, in patients with pure DCIS, was associated with later onset of IDC. Survival studies of independent cohorts indicated that both miRNAs play a protective role in IDC. The clinical findings are in agreement with the miRNAs' roles in cell adhesion, differentiation and proliferation. We propose that miR-126 and miR-218 have a protective role in DCIS and represent novel biomarkers for the risk assessment in women with early detection of breast cancer.

Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus.

IMPORTANCE: The molecular mechanism leading to the development of vulvar squamous cell carcinoma (VSCC) from vulvar lichen sclerosus (VLS) is unknown. OBJECTIVE: To assess the possible involvement of the IRF6 tumor-suppressor gene in the development of VSCC from VLS. DESIGN: In laboratories at the University of Ferrara, Ferrara, Italy, IRF6 gene expression and promoter methylation were investigated in paraffin-embedded VSCC and adjacent vulvar intraepithelial neoplasia (VIN) and VLS specimens, in cancer-free VLS (cfVLS) specimens, and in healthy skin specimens by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) analysis and by sequencing of PCR-amplified bisulfite-treated DNA. Methylation-induced dysregulation was assessed by expression of p63, the IRF6-transactivator gene. MAIN OUTCOMES AND MEASURES: IRF6 expression, correlation with promoter methylation and p63 expression, and association with development of VSCC from VLS. RESULTS: Specimens from 60 participating women (1 specimen from each) were analyzed for the study (mean [SD] age, 66.3 [12.1] years): 20 paraffin-embedded specimens of VSCC (patient age, 75.3 [8.3] years) with adjacent VLS lesions, in 5 of which VIN preneoplastic tissue was also present (patient age, 64.3 [15.3] years); 20 cfVLS specimens (patient age, 62.1 [11.4] years) obtained from diagnostic biopsies; and 20 normal skin specimens from noncancer surgical patients (patient age, 61.4 [9.1] years). IRF6 messenger RNA was found to be reduced 4.5-, 2.9-, 6.6-, and 2.2-fold in VLS, VIN, VSCC, and cfVLS specimens, respectively, compared with controls, although p63 was still expressed in all specimens. IRF6 promoter was hypermethylated in 9 (45%) of 20 VLS specimens, 1 (20%) of 5 VIN specimens, 16 (80%) of 20 VSCC specimens, 2 (10%) of 20 cfVLS specimens, and 0 normal skin specimens. CONCLUSIONS AND RELEVANCE: IRF6 dysregulation may be involved in the development of VSCC from VLS. Methylation of the IRF6 promoter may be a marker of cancer risk in patients with VLS.

Dermoscopic Features of Vulvar Lichen Sclerosus in the Setting of a Prospective Cohort of Patients: New Observations.

OBJECTIVE: Dermoscopic features of vulvar lichen sclerosus (VLS) were investigated in order to determine both vascular and non-vascular features of this disease. MATERIALS AND METHODS: Dermoscopic images of 35 patients affected with histopathologically confirmed VLS were evaluated for the presence of predefined morphological criteria. RESULTS: On dermoscopy, VLS lesions exhibited very sparse vessels, mainly linear, without a specific arrangement. Dotted vessels were observed mostly in the early stage of the disease. Patchy, structureless areas, whitish to white-yellowish to pink-whitish in colour over a diffuse whitish background, were a distinctive and constant dermoscopic feature. Grey-blue dots, usually with a characteristic peppered arrangement, corresponding to dermal melanophages, were also frequently seen. Comedo-like openings and scales were observed, as well as peculiar structures like ice slivers, not identified by histological examination. CONCLUSION: Our findings show that VLS exhibits characteristic dermoscopic patterns that can aid in its clinical diagnosis.

Endoscopic CO(2) Laser Horizontal Partial Laryngectomy in Larynx Carcinosarcoma.

Background. Carcinosarcoma is an extremely rare malignant neoplasm, with both a malignant epithelial and mesenchymal component, that rarely affects the larynx. Aim. Aim of this paper is to describe the case of a patient affected by a larynx carcinosarcoma treated by endoscopic horizontal partial laryngectomy with CO(2) laser and particularly discuss the histogenetic hypothesis as well as the possible treatment modalities of this rare lesion. Methods. Case report and literature review. Discussion and Conclusion. Still little is known about the biology of carcinosarcoma and there is still no consensus in the literature on the treatment of these tumors. Endoscopic horizontal partial laryngectomy could represent another treatment option in selected cases.

A new case of syringocystadenocarcinoma papilliferum: a rare pathology for a wide-ranging comprehension.

We report a new case of p63/cytokeratin 7 (CK7) positive syringocystadenocarcinoma papilliferum (SCACP), on the shoulder of an 88-year-old man, with superficial dermal infiltration and squamoid differentiation. We describe the 24th case of SCACP, the malignant counterpart of syringocystadenoma papilliferum (SCAP). At the present, we do not know whether SCACP arises from eccrine or apocrine glands because of the contrasting opinions in the literature. Only few histochemical and ultrastructural studies have previously advised that SCACP could arise from pluripotent stem cells. Through our case, we wish to suggest the stem cell-like properties of the syringocystadenocarcinoma papilliferum. This rare neoplasm shows two different patterns of stem cell marker expression in the glandular and squamous components, respectively. For the double phenotype of SCACP, we propose it like an intriguing model to study histogenesis and stem cell properties for more wide-ranging epithelial tumors.

The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery.

PURPOSE: In patients with locally advanced rectal cancer (LARC) staging and, after preoperative chemo-radiation therapy (CRT), restaging workup could be useful to tailor therapeutic approaches. Fluorine-18-fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) is a promising tool for monitoring the effect of antitumor therapy. This study was aimed to evaluate the possible role of dual time sequential FDG-PET scans in the staging and restaging workup of LARC. METHODS AND MATERIALS: Eighty-seven consecutive patients with LARC were enrolled. CRT consisted of external-beam intensified radiotherapy (concurrent boost), with concomitant chemotherapy PVI 5-FU (300 mg/m(2)/day) followed 8-10 weeks later by surgery. All patients underwent [(18)F]FDG-PET/CT before and 5-6 weeks later after the completion of CRT. Measurements of FDG uptake (SUV(max)), and percentage of SUV(max) difference (Response Index = RI) between pre- and post-CRT [(18)F]FDG-PET scans were evaluated. RESULTS: Six of 87 patients were excluded due to protocol deviation. Following CRT, 40/81 patients (49%) were classified as responders according to Mandard's criteria (TRG1-2). The mean pre-CRT SUV(max) was significantly higher than post-CRT (15.8, vs 5.9; p < 0.001). The mean RI was significantly higher in responders than in nonresponder patients (71.3% vs 38%; p = 0.0038). Using a RI cut-off of 65% for defining response to therapy, the following parameters have been obtained: 84.5% sensitivity, 80% specificity, 81.4% positive predictive value, 84.2% negative predictive value, and 81% overall accuracy. CONCLUSION: These results suggest the potential role of [(18)F]FDG-PET in the restaging workup after preoperative CRT in LARC. RI seems the best predictor to identify CRT response.

Consolidation treatment with rituximab induces complete and persistent remission of mixed type Evans syndrome.

We describe a 58-year-old woman affected by immune thrombocytopenic purpura (ITP) since 1999, well controlled by low doses of steroid for 4 years, who experienced a relapse with severe mixed type Evans syndrome in March 2006. After an initial response to high doses of steroid, severe anaemia recurred 2 months later, this time resistant to second-line therapy with intravenous immunoglobulins (IVIG) and cyclophosphamide. So in May, we started the treatment with anti-CD20 monoclonal antibody rituximab with the dose of 375 mg/m2 once weekly for a total of four doses. We obtained a full normalization of haemoglobin concentration, but the disease haemolytic parameters persisted. Therefore, we decided to treat the patient with two monthly courses of rituximab, and a gradual normalization of haptoglobin and lactate dehydrogenase (LDH) plasma levels was finally achieved, with a sustained response up to date, lasting more than 12 months. We conclude that rituximab treatment is effective in refractory patients with mixed type Evans syndrome, and consolidation therapy should be considered to prolong beneficial effects achieved during the induction.

FDG-PET detection of primary bone marrow large B-cell lymphoma in a patient with hairy cell leukemia.

We describe a case of hairy cell leukaemia (HCL) coexistent with non-Hodgkin's lymphoma (NHD). This combination is reported to be extremely rare with no clear demonstration of the clonal relationship between the two conditions. After a previous failure of purine analogue therapy, our patient was successfully treated with rituximab resulting in normalisation of blood cell count cessation of blood transfusion and negative iliac crest biopsy. Unfortunately, the patient developed intense and persistent bone pain during the 1(st) line treatment for HCL. Skeletal X-rays, neck-thorax-abdomen CT scan and repeated bone MRI were unremarkable and bone scintigraphy showed non-specific changes. Laboratory examinations were normal. To better evaluate bone scintigraphy results, we finally performed FDG-PET/CT, which showed multiple foci of intense abnormal radiotracer uptake involving the bone marrow. An FDG-PET/CT guided bone marrow biopsy showed primary bone marrow diffuse large B-cell lymphoma (LBCL). Despite 2(nd) and 3(rd) line treatment, the patient died shortly after for central nervous system involvement by NHD. The role of FDG-PET/CT in identifying bone and bone marrow localization of NHD is reviewed and an earlier use is suggested in poorly understood bone pain.

Effective prevention of massive periprocedural embolism during renal artery stenting.

We report the case of a massive embolism of atheromatous material during stenting of a tight renal artery stenosis, which was prevented by using a distal embolic protection device and aggressive aspiration of the blood through a guiding catheter. A 72-year-old man who was referred to our institution for coronary artery disease treated with coronary angioplasty underwent renal angiography which revealed a tight stenosis (99%) located at the ostium of the right renal artery extending for 15 mm into the main tract. The diameter of the artery was estimated to be 5.5 cm in the main tract, and the plaque had a soft appearance complicated by the presence of a thrombus (persistence of contrast agent in the plaque on selective renal angiography). Renal artery Doppler ultrasound and renal scintigraphy confirmed the need for renal revascularization. An embolus protection device (FilterWire EZ, Boston Scientific, Natick, MA, USA) was successfully opened distally to the stenosis after gentle predilation. After stent deployment (Genesis 5.5x18 mm, Cordis, J&J Medical, Miami Lakes, FL, USA), aggressive aspiration of the blood through the guiding catheter was performed. A large amount of embolic material with macroscopic particles was retrieved into the basket of the embolic protection device and in the blood aspirated with the guiding catheter. Good functional results were obtained on Doppler analysis of intrarenal blood flow, with a resistive index of 70. Despite the fact that the extensive use of embolic protection devices in renal artery stenting is still under discussion, this technique may be advisable in selected cases with favorable anatomy and high embolic risk, especially in patients with complex and hazy lesions.

Spontaneous evolution of essential thrombocythaemia into acute megakaryoblastic leukaemia with trisomy 8, trisomy 21 and cutaneous involvement.

Spontaneous transformation of essential thrombocythaemia (ET) into acute leukaemia is rare. We describe a case of ET that spontaneously transformed after 19 yrs uneventful follow-up into acute megakaryoblastic leukaemia. Cytogenetic analysis of bone marrow nucleated cells showed trisomy 8 and trisomy 21 at time of leukaemic transformation supporting the hypothesis that chromosomal abnormalities are part of the mechanism that drives the leukaemic progression independently of drug cytotoxicity. In addition, the very rare and intriguing finding of M7 FAB subtype evolution of ET was complicated by cutaneous involvement in the leukaemic process.

Hashimoto's thyroiditis and Graves' disease associated with retroperitoneal fibrosis.

Retroperitoneal fibrosis is a rare disease of uncertain pathogenesis. However, its possible association with several immunopathologic conditions, the possibility of systemic involvement by the fibrous process, the presence of various autoantibodies, and the frequent response to immunosuppressive treatment all support an autoimmune pathogenesis. Riedel's thyroiditis is a rare disease the pathogenesis of which is also thought to be immune-mediated based on its optimal response to steroids; Riedel's thyroiditis is also frequently reported in association with retroperitoneal fibrosis. We describe here two cases of autoimmune thyroid disease associated with retroperitoneal fibrosis, the first with features of primary myxedema, the second of primary thyrotoxicosis. Histology of retroperitoneal fibrosis is documented and it is compatible with an immunopathologic condition. Thus, these two cases add further support to the hypothesis of an autoimmune pathogenesis of retroperitoneal fibrosis and indicate the importance of carefully monitoring for the development of other autoimmune disorders, i.e., of the thyroid gland, in patients with retroperitoneal fibrosis.