MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Superhydrophobic lab-on-chip measures secretome protonation state and provides a personalized risk assessment of sporadic tumour.

Secretome of primary cultures is an accessible source of biological markers compared to more complex and less decipherable mixtures such as serum or plasma. The protonation state (PS) of secretome reflects the metabolism of cells and can be used for cancer early detection. Here, we demonstrate a superhydrophobic organic electrochemical device that measures PS in a drop of secretome derived from liquid biopsies. Using data from the sensor and principal component analysis (PCA), we developed algorithms able to efficiently discriminate tumour patients from non-tumour patients. We then validated the results using mass spectrometry and biochemical analysis of samples. For the 36 patients across three independent cohorts, the method identified tumour patients with high sensitivity and identification as high as 100% (no false positives) with declared subjects at-risk, for sporadic cancer onset, by intermediate values of PS. This assay could impact on cancer risk management, individual's diagnosis and/or help clarify risk in healthy populations.

MiR-29b antagonizes the pro-inflammatory tumor-promoting activity of multiple myeloma-educated dendritic cells.

Dendritic cells (DCs) have a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their microRNA (miRNA) network. By analyzing six different miRNA-profiling data sets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor-associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients. In DCs co-cultured with MM cells, enforced expression of miR-29b counteracted pro-inflammatory pathways, including signal transducer and activator of transcription 3 and nuclear factor-κB, and cytokine/chemokine signaling networks, which correlated with patients' adverse prognosis and development of bone disease. Moreover, miR-29b downregulated interleukin-23 in vitro and in the SCID-synth-hu in vivo model, and antagonized a Th17 inflammatory response. All together, these effects translated into strong anti-proliferative activity and reduction of genomic instability of MM cells. Our study demonstrates that MM reprograms the DCs functional phenotype by downregulating miR-29b whose reconstitution impairs DCs ability to sustain MM cell growth and survival. These results underscore miR-29b as an innovative and attractive candidate for miRNA-based immune therapy of MM.

Innate immunity in cutaneous melanoma.

The skin immune system is composed of a vast network of immune cells, including lymphocytes, macrophages, neutrophils, dendritic cells and Langerhans cells, which not only are involved in inflammatory responses but also contribute to homeostatic function and may participate in the various steps of carcinogenesis. Many studies support the notion that innate immunity has a key role in the development, growth and prognosis of cutaneous malignant melanoma (MM), through the release of pro- and/or anti-inflammatory cytokines and tumour growth factors. The tumour environment in a major subset of cutaneous MM shows evidence of a T cell-infiltrated phenotype, but there is less known about the presence and the phenotype of other immune system cells. Response to immunotherapy is largely correlated with the presence of T cells in the tumour microenvironment, while the regulation exerted by stromal components such as macrophages and mast cells has been less investigated. In the current report, we review the recent literature, focusing our attention on the role of macrophages, dendritic cells, mast cells and natural killer cells in orchestrating MM progression, to better understand tumour immunobiology. The identification of new therapeutic targets and the application of approaches aimed at modulating crosstalk between immune and tumour cells, could have a crucial impact on immunotherapy and result in better clinical outcome. We hope this review will be helpful in cutaneous MM research.

Non-invasive real-time biopsy of intracranial lesions using short time expanded circulating tumor cells on glass slide: report of two cases.

BACKGROUND: Circulating Tumor Cells (CTCs) are promising biomarkers for monitoring solid cancer and were used to monitor brain tumors. Here we report two cases in which, for the first time, CTCs were used in cytological diagnostic evaluation to discriminate a space-occupying lesion of the brain. CASE PRESENTATION: Two cases of focal intracranial lesions, unclassified for diagnosis, untreated and apparently symptomatic, were examined after high-contrast resolution Magnetic Resonance Imaging and/or Computed Tomography scans. CTCs were seeded on chamber slides and short-time expanded under the optimized conditions as we previously reported. The first case was a focal lesion localized in the parietal-occipital area in a 67-year-old woman. The second case was a 31-year-old man with an expansive intracerebral lesion localized in the left peri-trigonal area. Both patients underwent excisional biopsy. Histopathological evaluation of the biopsy confirmed the previous cytological diagnoses, and the analysis of the clinical outcomes retrospectively validated both diagnoses. CONCLUSIONS: The cases here reported illustrate the potential for using expanded CTCs as non-invasive, real-time biopsy. Moreover, non-invasive real-time biopsy can represent an alternative diagnostic tool to be used when a functional area of the brain is at risk of injury from excisional biopsy procedures.

Elastofibroma dorsi: a histochemical and immunohistochemical study.

Elastofibroma dorsi (ED) is considered a member of a heterogeneous group of benign fibrous (fibroblastic or myofibroblastic) soft-tissue tumors, frequently localized in the periscapular region in middle aged or older individuals. However, the pathogenesis of ED is still unclear and many authors believe that ED results from a reactive hyperproliferation of fibroblastic tissue, while others suggest that it may be a consequence of a mechanical friction. In our study, we examined 11 cases of ED using histochemical and immunohistochemical methods, in order to extend the knowledge about extracellular matrix composition and histopathogenesis of ED. From the results it appeared that stroma and interspersed spindle cells of ED were positive for both periostin and tenascin-C. Mast cells tryptase-positive were also abundant throughout the lesion. The perivascular distribution of periostin and tenascin-C, associated with the CD34 positivity, suggest that endothelial-mesenchymal transition events can account for neovascularization and production of fibroelastic tissue characteristic of elastofibroma. Our data obtained in endothelial cells cultures demonstrated that elastin production is higher when the status of confluence of the cells is low. So, we can assume that such a phenomenon is a characteristic of mesenchymal/endothelial cells CD34 positive, in which elastin production results to be inversely proportional to the vascular differentiation of cellular elements. In the light of these considerations, we think that a cancerous nature of ED is unlikely. Overall, our study report, for the first time, a detailed description of extracellular matrix composition in ED, suggesting that a mechanical strain-dependent reactivation of periostin and tenascin-C expression, as well as of elastin deposition, could be responsible for development of ED.

Squamous metaplasia of the breast simulating a malignant neoplasm: a case.

Squamous metaplasia of the breast ductal epithelium is a well-documented lesion; however, it represents a very uncommon histopathologic finding. We present a case of primary florid squamous metaplasia of the mammary ducts closely simulating a breast carcinoma in a 67-year-old woman. Patient after ultrasound examination and mammography, was submitted to a fine-needle aspiration biopsy (FNAB) that was considered inconclusive, and, in order to suspicious clinic and mammographic findings, a frozen evaluation during the surgical excision was performed. Primary squamous cell metaplasia is rarely observed in the breast. This condition closely mimics a malignant lesion at US-scan, X-ray evaluation and even at FNAB. Frozen examination, in this case, is considered decisive, preserving the patient from an unnecessary aggressive surgical approach.

Huge primary retroperitoneal mucinous cystadenoma of borderline malignancy mimicking an ovarian mass: case report and review.

BACKGROUND: Primary retroperitoneal mucinous cystadenoma is a rare tumor only 48 cases have been reported in international literature. Patients affected by primary retroperitoneal mucinous cystadenoma/cystadenocarcinoma ranged in age from 17 to 86 years (median, 42.3 years) and the size of the cystis ranged from 5 to 35 cm (median, 16.1 cm). There is no unanimous opinion on the genesis of these tumors and, due to their extreme rarity, its histogenesis, biological behavior and the optimal management strategy remain at a speculative level. CASE REPORT: We report the case of a huge borderline primary retroperitoneal mucinous cystadenoma (24 x 25 cm) in a 35-year-old woman and the strategies adopted for the diagnosis and surgical management. CONCLUSION: Primary mucinous cystic tumor of the retroperitoneum was correctly diagnosed only at the time of surgery. As well as in the majority of cases reported in the literature, preoperative investigations were not able to give information about the tumor site. In spite of the short follow-up (two years), the patient's favorable course supports the hypothesis that primary retroperitoneal mucinous cystadenoma may be treated in the same manner as a primary ovarian tumor of the same grade and comparable stage.

A case of mesonephric adenocarcinoma of the vagina with a 1-year follow-up.

Mesonephric adenocarcinoma deriving from remnants of vaginal mesonephric ducts is one of the rarest tumors of the female genital tract with only three cases reported till date in international literature. Differential diagnosis from other aggressive tumors is complex and controversies exist in the literature regarding the biological behavior, prognosis, and optimal management strategies of these tumors. A 58-year-old woman presented with a large mass extending from the right adnexal region to the perineum and labia majora. CA125 was increased. A radical excision of the lesion with pelvic and para-aortic lymphadenectomy was performed. A well-capsulated mesonephric adenocarcinoma in a background of vaginal mesonephric remnants was diagnosed. Tumor cells showed immunoreactivity for pancytokeratin, cytokeratin (CK), CD 10, epithelial membrane antigen, vimentin, and calretinin; indeed they were negative for carcinoembryonic antigen, CK 20, estrogen receptor, and progesterone receptor. No evidence of lymph node involvement or metastatic disease was observed. The patient did not receive any adjuvant therapy and is alive and clinically free of disease at 1-year follow-up. In spite of the aggressive biological behavior attributed in literature to mesonephric carcinomas, which is probably due to the complex differential diagnosis with other müllerian tumors, the favorable course of our patient further supports the hypothesis that malignant mesonephric carcinomas may not behave aggressively and that radical surgery alone may be curative.

Macroscopic classification of superficial neoplastic lesions of the oral mucosa: a preliminary study.

BACKGROUND: Careful endoscopic classification of macroscopic appearance of superficial neoplasias of the gastrointestinal tract is essential in the early detection and appropriate treatment of cancer. It has contributed to introduce minimally invasive endoscopic surgery and has significantly improved survival of patients with colon and gastric cancers. Squamous cell carcinoma of the oral cavity has been characterized, in past and present times, by poor prognosis and lack of progress in treatment outcome. Failure in diagnosing oral malignancy at an early stage is a major culprit, and the lack of a worldwide adopted classification of its macroscopic appearance, similar to that of gastrointestinal neoplasias, may have contributed to it. AIM: To test the hypothesis that is possible to extend the diagnostic benefit of a classification based upon the macroscopic appearance of superficial tumours of the digestive tract to superficial carcinoma of the oral mucosa. METHODS: We retrospectively examined a group of patients who developed multiple intraepithelial and early invasive malignant oral neoplasias, applying a modified version of the Paris classification of superficial GI neoplastic lesions. RESULTS: One hundred and ten out of 116 (94.9%) of the study lesions had morphological features that accorded with the prepared classification. CONCLUSIONS: These preliminary data suggest that most superficial early neoplastic lesions of the oral cavity can be easily detected using a well-defined classification system similar to that employed in the diagnosis of early gastrointestinal malignancy.

The histopathology of psoriasis.

Psoriasis is a common, chronic, relapsing, papulo-squamous dermatitis, with overlying silvery scales. The scalp, sacral region, and extensor surfaces of extremity are commonly involved, even if flexural and intertriginous areas may be affected in the so-called "inverse psoriasis". Involvement of nails is frequent. Oral lesions (geographic stomatitis and/or glossitis) are commonly described. 5-8% of psoriatic patients develop arthritis. Interphalangeal joints are characteristically involved, but large joints are also affected. From a histological point of view, psoriasis is a dynamic dermatosis that changes during the evolution of an individual lesion; we can classify it in an early stage, advanced stage, and later lesions. Lesions are usually diagnostic only in early stages or near the margin of advancing plaques. Munro microabscesses and Kogoj micropustoles are diagnostic clues of psoriasis, but they aren't always present. All other features can be found in numerous eczematous dermatitis.

Oncocytic cyst of the larynx: an unusual occurrence.

Oncocytic cysts of the larynx are rare benign, slow growing lesions that are lined predominantly or exclusively by oncocytes, the cytoplasm of which contains a considerable number of hypertrophied mitochondria, which accounts for their eosinophilia and swollen appearance. The oncocytic change is a phenomenon of metaplasia which occurs frequently in epithelial endocrine cells with high metabolic activity and it is also associated with inflammation, degenerative process or cellular ageing. In the larynx, oncocytic metaplasia is very uncommon, but it is occasionally seen in the lining of laryngeal cysts, which are found most commonly in the ventricles or in the false vocal cords, where seromucinous glands are more abundant. Oncocytic cysts typically occur in the elderly and are usually solitary, with involvement of an isolated site, whereas diffuse involvement with multiple cysts is extremely rare. Hoarseness is the most common presenting symptom, while pain, stridor or laryngeal obstruction are unusual complaints. Management of these lesions is conservative and consists of local excision, endoscopic removal being the treatment of choice. Although oncocytic cysts are benign lesions, follow-up is recommended, as recurrence is possible, especially in the case of patients with multiple involvement, since they may show a tendency to develop new cysts. To date, approximately 150 cases of laryngeal oncocytic cysts have been published. Herein, a very unusual case is presented occurring in a 43-year-old male patient, therefore, "epidemiologically" atypical for developing oncocytic lesions. Causes of oncocytic changes and pathogenesis of laryngeal cysts are discussed.

Chromatin assembly factor-1 (CAF-1)-mediated regulation of cell proliferation and DNA repair: a link with the biological behaviour of squamous cell carcinoma of the tongue?

AIMS: Squamous cell carcinoma (SCC) of the tongue shows aggressive behaviour and a poor prognosis. Clinicopathological parameters fail to provide reliable prognostic information, so the search continues for new molecular markers for this tumour. Chromatin assembly factor-1 (CAF-1) plays a major role in chromatin assembly during cell replication and DNA repair and has been proposed as a new proliferation marker. The aim of this study was to investigate its expression in SCC of the tongue. METHODS AND RESULTS: The immunohistochemical expression of the p60 and p150 subunits of CAF-1 were evaluated in a series of SCCs of the tongue. The findings were correlated with the expression of proliferation cell nuclear antigen (PCNA) and patients' clinicopathological and follow-up data. CAF-1/p60 was expressed in all the tumours, whereas CAF-1/p150 was down-regulated in a number of cases. Overexpression of CAF-1/p60 and down-regulation of CAF-1/p150 identified SCCs with poor outcome, in addition to the classical prognostic parameters. CONCLUSIONS: Simultaneous CAF-1-mediated deregulation of cell proliferation and DNA repair takes place in aggressive SCC of the tongue. Therefore, the evaluation of CAF-1 expression may be a valuable tool for evaluation of the biological behaviour of these tumours. This may be relevant to the introduction of improved follow-up protocols and/or alternative therapeutic regimens.

Technical aspects in endoscopic biopsy of lesions in esophageal pemphigus vulgaris.

BACKGROUND AND AIMS: Aim of this study is to compare a specific kind of biopsy forceps to a traditional one in providing an adequate specimen of esophageal pemphigus vulgaris lesions that includes the basement membrane for definitive diagnosis. PATIENTS AND METHODS: Prospective, randomized, blind, single-center study. We performed upper endoscopy with biopsy in 32 patients divided into two groups of 16 each: in group A with a commercially available standard biopsy forceps while in group B with a commercially available rocking biopsy forceps. Hundred-ninety-six biopsy specimens from both groups were blindly evaluated by the same pathologist. RESULTS: In group A 18.8% of biopsy specimens were adequate (basement membrane included). In group B 87.5% of biopsy specimens were adequate. The presence of the entire thickness of the mucosa was significantly higher in group B compared to group A. All parameters typically taken into account by pathologist for diagnosis of esophageal pemphigus vulgaris were significantly improved in group B. CONCLUSIONS: The biopsy forceps used in group B permits a rocking motion of the tip on contact with the mucosa, produces a deeper full-thickness mucosal sample up to the basement membrane and assists in the evaluation of histologic features of esophageal pemphigus vulgaris.

Hemosiderotic dermatofibroma: report of one case.

Dermatofibroma (DF) is a common benign fibrohistiocytic lesion which presents with a wide variety of clinicopathological features. Generally, the clinical diagnosis is easy, but differentiating it from other cutaneous tumors could be difficult in atypical cases and rare variants. We may find at least four different histopathological variants of DF; more than one of which may be present in a single tumor. Hemosiderotic DF is a variant composed of numerous small vessels, extravasated erythrocytes, and intra- and extracellular hemosiderotic deposits. The differential diagnosis may comprise melanoma as well as other melanocytic and nonmelanocytic tumors. We report the case of a 38-year-old man who presented with a hemosiderotic DF on the abdomen.

Field cancerization in oral lichen planus.

BACKGROUND: The concept of field cancerization describes the tendency of patients with premalignant and malignant lesions of head and neck mucosal sites to develop multiple carcinomas of the upper aerodigestive tract. Here we address whether this concept should be extended also to patients affected by oral lichen planus (OLP), an inflammatory disorder associated with an increased risk of cancer development. METHODS: Data from a cohort of 45 patients with OLP who subsequently developed severe dysplastic changes and/or oral squamous cell carcinoma were retrospectively reviewed. Patients who presented more than one oral neoplastic event were considered for further data analysis as regards incidence, localization, management and prognosis. RESULTS: Twenty (44.4%) patients were affected by one single neoplastic event while 25 (55.6%) developed multiple and often multifocal oral dysplastic and/or malignant events. In most cases, a careful surveillance programme led to diagnosis and effective treatment of oral neoplasias at an early intraepithelial and microinvasive stage, leading to long-term survival. In some patients, however, additional primary tumours occurred suddenly with rapid invasion, leading to advanced stage diagnosis and poor prognosis. Overall, three patients (12%) died due to malignant oral disease. CONCLUSIONS: Patients with OLP and subsequent development of dysplasia/ oral squamous cell carcinoma are at risk of having multiple and multifocal neoplastic events of the oral cavity, a phenomenon which parallels the concept of field cancerization of traditional head and neck cancers. If detected at an early stage, these neoplasias can be managed with superficial and complete resection. However a small number of patients have loco-regional tumour spread despite a standard surveillance protocol.

Tumor infiltrating lymphocytes in uveal melanoma: a link with clinical behavior?

Experimental and clinical evidence indicate that immunological mechanisms might be important in the clinical course of uveal malignant melanoma (UMM). We analyzed the amount and phenotype of tumor infiltrating lymphocytes (TIL) and the expression of the apoptosis-inducing molecule Fas and its ligand, FasL, on tumor cells and TIL in a selected series of UMM with the aim to establish if a correlation between their expression and the clinical behavior of UMM exists. TIL phenotype and Fas/FasL expression were evaluated by immunohistochemistry in 61 cases of formalin-fixed, paraffin-embedded UMM. Results were compared with the follow-up data of patients. Most of the UMM showed a prevalence of CD8+ CD3+ T lymphocytes, or CD4+ and CD8+ cells in equal amounts. UMM showed a variable expression of FasL, ranging from 0 to > 40% of neoplastic cells. Fas was always expressed in TIL, although with a variable extent. A subgroup of UMM showed in TIL a strongly reduced or even absent expression of TCR zeta-chain, involved in activation of T-lymphocytes. This subgroup was characterized by a worse outcome. We hypothesized that an impaired cytotoxic immune response due to the loss of the zeta-chain expression plays a primary role in the biological course of UMM. Our results indicate that the overcoming of the impairment of TCR function may represent a prerequisite for the development of new therapeutic strategies for managing UMM, suggesting that elimination of tumor cells may be possible by activation of cytotoxic cells present within ocular melanomas.

Neuroendocrine differentiation after neoadjuvant hormonal treatment in prostate cancer.

AIM: Neuroendocrine (NE) differentiation occurs in various degree in the majority of prostatic adenocarcinomas and it has been correlated with tumor progression and poor prognosis. There is little knowledge about the impact of NE differentiation on tumor response to neoadjuvant hormonal treatment (NHT). The role of NE differentiation as a marker of recurrence after radical prostatectomy (RP) is also unclear. We evaluated whether there is an increase in NE differentiation during the course of NHT and whether the tumor relapse after radical surgery correlates with the extent of NE differentiation. METHODS: RP specimens from 44 patients submitted to 3 months of NHT and RP specimens from 40 nonpretreated patients were histologically assessed. Staining for NE differentiated prostate tumor cells was carried out using a specific monoclonal antibody against chromogranin A (CgA). RESULTS: CgA positive cells were found in 4 of 40 patients (10%) in the RP group and in 4 of 44 patients (9%) of the NHT+RP group. At follow-up, we had 21 biochemically relapsed patients. Among them, 6 were CgA positive (75% of 8 patients), whereas is were CgA negative (20% of 76 patients). CONCLUSIONS: The NE differentiation doesn't increase after NHT. Although not statistically significant a trend to higher risk of relapse among the chromogranin positive samples was observed. The significance of NE differentiation in the progression of the disease and its relation to other known prognostic factors remains unclear.

Carotid endarterectomy in heart transplant patients.

AIM: The aim of this study was to determine the clinical outcome of carotid endarterectomy in heart transplant recipients and morphologic features of atherosclerotic plaques removed during operation. METHODS: Between April 1993 and October 2001 5 heart transplant patients with symptomatic carotid stenosis >70% underwent carotid endarterectomy with regional anesthesia, including a staged bilateral procedure in one patient. Cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol were evaluated in each patient. The plaques ( n=6) underwent histologic analysis after carotid endarterectomy. Carotid artery duplex imaging was added to the routine postoperative evaluation. RESULTS: Carotid plaques resulted to be echolucent on B-mode ultrasound examination. Cholesterol, triglycerides and LDL-cholesterol levels were found to be increased, while HDL-cholesterol were decreased. All patients underwent successful carotid endarterectomy; there were no perioperative deaths, major neurologic or cardiac events. The mean length of stay was 2.2 days. The mean follow-up was 44 months. In 1 case, an asymptomatic restenosis >50% occurred 9 months later and, in 2 other cases, a contralateral mild stenosis was found 12 and 36 months later. One patient had a progressive contralateral stenosis, requiring operation 18 months later. High lipid content and heterogeneous cellular infiltration were observed, including macrophages, T-lymphocytes, neutrophils, and also eosinophils in the rapidly progressing plaque. CONCLUSIONS: Heart transplant patients receiving immunosuppression may successfully undergo carotid endarterectomy, without increased risk, but progression of atherosclerotic disease in the carotid arteries seems to continue, despite lipid-lowering regimen and antiplatelet therapy.