A peculiar case of Paget's disease of the breast.

Mammary Paget's disease is a disorder of the nipple-areola complex of the breast that, while rare, is often associated with an underlying carcinoma. The typical aspect is usually an eczematoid change of the nipple or a red and ulcerative nipple's lesion or erythematous and crusted lesion, with or without mass-like lesion and infiltration and inversion of the nipple. It was described at first by Sir James Paget in 1874, [1] who classified the disease in mammary and extramammary type. The mammary type (Paget' s Breast Cancer: PBC) has rare frequency. PBC occurs in 0.5-5% of all cases of breast cancer, it affects the mouth of the excretory ducts of the nipple, which is characterized by lesion of nipple's large ducts. PBC can be a superficial lesion or a nodule-tumor and it can be associated with underlying carcinoma in situ (DCIS) in more than 95% of cases, especially in postmenopausal women. In a small percentage of cases, PBC can also be associated with an invasive breast cancer. Accuracy in the diagnostic phase, in order to distinguish PBC from others diseases is paramount and histological examination of lesion's biopsy has a crucial role. Prognosis and treatment depend on the type of underlying breast cancer and are based on the stage of cancer, but more importantly, on the prompt of an adequate multidisciplinary diagnostic pathway. KEY WORDS: Histopathological Report, Oncological Outcomes Paget's Breast Cancer.

Therapeutic Targets and Tumor Microenvironment in Colorectal Cancer.

Colorectal cancer (CRC) is a genetically, anatomically, and transcriptionally heterogeneous disease. The prognosis for a CRC patient depends on the stage of the tumor at diagnosis and widely differs accordingly. The tumor microenvironment (TME) in CRC is an important factor affecting targeted cancer therapy. The TME has a dynamic composition including various cell types, such as cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, as well as extracellular factors that surround cancer cells and have functional and structural roles under physiological and pathological conditions. Moreover, the TME can limit the efficacy of therapeutic agents through high interstitial pressure, fibrosis, and the degradation of the therapeutic agents by enzymatic activity. For this reason, the TME is a fertile ground for the discovery of new drugs. The aim of this narrative review is to present current knowledge and future perspectives regarding the TME composition based on strategies for patients with CRC.

Excisional Haemorrhoidectomy: Where Are We?

Haemorrhoidal disease (HD) is defined as the symptomatic enlargement and/or distal displacement of anal cushions and is one of the most frequent and ancient anorectal conditions. Bleeding, during or after defecation, is the most common symptom. The color of the blood is typically bright red covering the outer surface of the stools. The severity of HD is based on the degree of the prolapse. There are several excisional surgery treatments. In this review, we describe the most common techniques such as Milligan and Morgan, Parks, Ferguson and Whitehead technique. Despite significant improvements in conservative treatments, excisional haemorrhoidectomy techniques are the most effective treatment for III- and IV degree.

Mesenchymal Stromal Cell Therapy in the Management of Perianal Fistulas in Crohn's Disease: An Up-To-Date Review.

Crohn's Disease (CD) is a chronic inflammatory disorder that potentially involves the entire gastrointestinal tract. Perianal fistulizing CD (pCD) is a serious and frequent complication associated with significant morbidities and a heavy negative impact on quality of life. The aim of CD treatment is to induce and maintain disease remission and to promote mucosal repair. Unfortunately, even the best therapeutic regimens in pCD do not have long-term efficacy and cause a significant number of side effects. Therefore, it is mandatory to study new therapeutical options such as the use of mesenchymal stromal cells (MSCs). These cells promote tissue repair via the induction of immunomodulation. The present review aims to analyze the existing updated scientific literature on MSCs adoption in the treatment of pCD to evaluate its efficacy and safety and to compare the use of bone marrow and adipose tissue derived MSCs, type of administration, and dose required for recovery.

Mast Cells, microRNAs and Others: The Role of Translational Research on Colorectal Cancer in the Forthcoming Era of Precision Medicine.

Colorectal cancer (CRC) is a heterogeneous disease, molecularly and anatomically, that develops in a multi-step process requiring the accumulation of several genetic or epigenetic mutations that lead to the gradual transformation of normal mucosa into cancer. In fact, tumorigenesis is extremely complex, with many immunologic and non-immunologic factors present in the tumor microenvironment that can influence tumorigenesis. In the last few years, a role for mast cells (MCs), microRNAs (miRNAs), Kirsten rat sarcoma (KRAS) and v-raf murine sarcoma viral oncogene homologue B (BRAF) in cancer development and progression has been suggested, and numerous efforts have been made to thoroughly assess their correlation with CRC to improve patient survival and quality of life. The identification of easily measurable, non-invasive and cost-effective biomarkers, the so-called "ideal biomarkers", for CRC screening and treatment remains a high priority. The aim of this review is to discuss the emerging role of mast cells (MCs), microRNAs (miRNAs), KRAS and BRAF as diagnostic and prognostic biomarkers for CRC, evaluating their influence as potential therapy targets in the forthcoming era of precision medicine.

Anti-Ri-associated paraneoplastic ophthalmoplegia-ataxia syndrome in a woman with breast cancer: a case report and review of the literature.

BACKGROUND: Breast cancer is the most common cancer in women. However, in the management of breast cancer, paraneoplastic neurological syndromes represent a diagnostic and therapeutic challenge. The diagnosis of paraneoplastic neurological syndromes is difficult due to the heterogeneity of symptoms, the timing of presentation, and the absence of antibodies, and it generally occurs before the diagnosis of breast cancer in 80% of patients who develop paraneoplastic neurological syndromes. We describe a 72-year-old woman with subacute ophthalmoplegia-ataxia syndrome who was subsequently diagnosed as having breast cancer and anti-Ri antibodies. CASE PRESENTATION: A 72-year-old post-menopausal Caucasian woman, with a positive medical history for diabetes mellitus and hypertension, presented with a 3-month onset of blurred vision, diplopia, and progressive gait disturbance. Serological tests were positive for well-characterized onconeural antibodies (anti-Ri). A whole-body computed tomography scan revealed a nodular opacity under her left nipple and axillary adenopathy. A biopsy of her left breast was performed, and histological examination showed ductal carcinoma. She underwent a superoexternal quadrantectomy with left axillary dissection. The final diagnosis showed infiltrating ductal carcinoma of the breast (T1c N1 M0, stage IIA) associated with paraneoplastic ophthalmoplegia-ataxia syndrome. At a 6-month follow-up, she showed no clinical or instrumental evidence of neoplastic recurrence with partial clinical improvement of neurological symptoms, such as ataxia and diplopia. CONCLUSION: The diagnosis of paraneoplastic neurological syndromes is often late, as in this patient, but treatment at an early stage may provide a good prognosis. Furthermore, this is one of several cases of an anti-Ri paraneoplastic neurological syndrome not associated with myoclonus, which reinforces the belief that opsoclonus myoclonus syndrome is not pathognomonic of the associated anti-Ri paraneoplastic neurological syndromes.

The prognostic value of KRAS and BRAF in stage I-III colorectal cancer. A systematic review.

BACKGROUND: Colorectal cancer (CRC) is one of the leading cause of cancer deaths worldwide. The aetiology of CRC is complex and involves interaction on environmental and genetic factors. The two most important pathways are the EGFR (Epidermal Grow Factor Receptor) signaling pathway, with the involvement of KRAS and BRAF, and the DNA mismatch repair (MMR). Generally, KRAS and BRAF mutations are mutually exclusive. They are both able to cause RAS/RAF/MAPK signaling pathway upregulation and are necessary for CRC development. BRAF mutations confers a poor prognosis in Western CRC patients, particularly in metastatic CRC (mCRC) and its mutations occur in approximately 4-20% CRC, with the vast majority being the V600E hotspot mutation. KRAS mutations are observed in 30- 40% CRC patients and act as predictive markers of resistance to epidermal growth factor receptor (EGFR)-targeted antibodies in metastatic CRC. Initial patient management is defined by TNM stage at diagnosis but in patient with stage II and III CRC, TNM staging alone does not predict outcome in CRC patients who may be eligible for adjuvant chemotherapy. Furthermore, for stage II and III, non-metastatic CRC patients, the prognostic role of BRAF and KRAS mutations is still controversial, particularly comparing microsatellite-unstable (MSI) and - stable tumors (MSS). The aim of this study was to clarify the impact of KRAS/BRAF mutations on prognosis in patients with stage I-III CRC. MATERIALS AND METHODS: A systematic review of literature was undertaken to evaluate the prognostic value of KRAS and BRAF mutations in stage I-III colorectal cancer. Four major databases (PUBMED, EMBASE, WEB OF SCIENCE and COCHRANE LIBRARY) were searched. RESULTS: Ninety-two studies were identified. After screening of titles, abstract and inclusion criteria sixteen articles were included. Of the selected articles, five were prospective, ten were retrospectives studies, and one was a combined retrospective/ prospective study. CONCLUSION: In our opinion, a combination of molecular markers, tumor location with the other clinical-pathological variables and microsatellite status is essential to have a correct prognosis. Nevertheless, this combination could be useful as a predictive factor in stage I-III CRC. KEY WORDS: BRAF, Colorectal Cancer, KRAS, Stage I-III CRC, Translational research.

Tryptase mast cell density, protease-activated receptor-2 microvascular density, and classical microvascular density evaluation in gastric cancer patients undergoing surgery: possible translational relevance.

BACKGROUND: Mast cells (MCs) can stimulate angiogenesis, releasing several proangiogenic cytokines stored in their cytoplasm. In particular, MCs can release tryptase, a potent in vivo and in vitro proangiogenic factor via protease-activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase (MAPK) phosphorylation. Nevertheless, no data are available concerning the relationship among tryptase MC density (TMCD), endothelial cells (ECs) positive to PAR-2 microvascular density (PAR-2-MVD) and classical MVD (C-MVD) in gastric cancer (GC) angiogenesis. METHODS: In this study, we analyzed the correlation of TMCD, PAR-2-MVD, C-MVD with each other and with the main clinicopathological features in GC patients who underwent surgery. A series of 77 GC patients with stage T2-3N2-3M0 (classified by the American Joint Committee on Cancer for Gastric Cancer, 7th edition) were selected and then underwent surgery. RESULTS: Tumour tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of numbers of TMCD, PAR-2-MVD and C-MVD. A significant correlation between the TMCD, PAR-2-MVD and C-MVD groups with each other was found by Pearson t-test analysis (r ranged from 0.64 to 0.76; p value ranged from 0.02 to 0.03). There was no other significant correlation between the above parameters and clinicopathological features. CONCLUSIONS: Our in vivo preliminary data suggest that TMCD and PAR-2-MVD may play a role in GC angiogenesis and they could be further evaluated as a target of antiangiogenic therapy.

Multivisceral resection for occlusive colorectal cancer: Is it justified?

BACKGROUND: The only possibility of curative surgery in primary T4, locally advanced, adherent colorectal carcinoma (LAACRC) or recurrent disease with infiltration of adjacent organs is the en bloc resection of the invaded structures to achieve clear surgical margins (R0). The role of extended resections for occlusive LAACRC remains unclear. We report on our experience on Multivisceral resections (MVR) for LAACRC patients between 2003 and 2012. METHODS: Twenty-two patients, who were treated with MVR with curative purpose for non-metastatic disease were recruited. General epidemiologic data, clinical findings, surgical treatment and/or multimodal therapy, histo-pathological examination and follow-up were collected. In addition post-operative complications were classified. Patients with occlusive LAACRC (n = 6) were compared to patients with uncomplicated presentation (n = 16) defined according to the UICC classification. RESULTS: No statistically significant differences were observed between the two groups, in terms of median age, gender and localization of tumors. R0 resection was performed in 14 (87.5%) patients with uncomplicated tumors and in all patients with occlusive LAACRC. R1 resection was performed in 2/16 (12.5%) patients with uncomplicated disease. No peri-operative mortality was reported in patients of both groups. In the group of uncomplicated tumors, 11 patients (68.7%) were classified as pathological (p)T4 and 5 patients (31.2%) were classified pT3 whereas in the group of occlusive LAACRC the majority of patients were classified as pT4 (83.3%). Lymph node involvement occurred in 9 patients (56.2%) of the fist group and in two patients (33.3%) of the second group, respectively. The 3-year survival rates in all patients with both uncomplicated and occlusive diseases were 58.4% and 33.3%, respectively. The 3-years survival of patients with locally advanced adherent rectal cancer was significantly lower than the observed survival of patients with colon cancer (p < 0.0001). CONCLUSION: MVR offers cure (R0 resections) in uncomplicated and obstructive LAACRC with three years survival in 40% of patients. Patients affected by rectal cancer with occlusive disease showed significantly decreased survival in comparison with those affected by colon cancer.

PPH vs Milligan-Morgan: early and late complications in the treatment of haemorrhoidal disease with circumferential prolapse.

BACKGROUND: The aim of this study was to assess the early and late complications of haemorrhoidectomy according to Milligan-Morgan (Milligan-Morgan laser optical fibers variant) vs haemorrhoidopexy with PPH-stapler and to assess the long-term results in terms of recurrences in circumferential prolapse patients classified P4-E4 (PATE 2000). METHODS: Onehundredsixty patients, with haemorrhoidal disease classified P4-E4, who underwent surgery between 2001 and 2007, were included in an retrospective observational study. Group A (M-M laser fibre) 80 patients (50%) (50 Male, 30 Female; median age 39 years, range 23-57 years). Group B (PPH-Stapler) 80 patients (50%) (58 Male, 22 Female; median age 40 years, range 23-60 years). RESULT: Early complications were thrombosis (6 cases in M-M vs 1 in PPH) and urinary retention (13 M-M vs 5 PPH). There weren't cases of sepsis. Late complications have been: occasional bleeding 13.5 % in the M-M-group vs 10 % in the PPH-group; defecatory urgency 2.5 % (M-M-group) vs 5% (PPH-group) with p < 0.1; persistent pain 2.5 % (M-M) vs 5 % (PPH) with p < 0.1; soiling 18.75 % (M-M) vs 0 % (PPH) with p < 0.001; recurrences 5 % in PPH-group vs 0 % in M-M (p < 0.05); residual disease 7.5 % in M-M-group vs 0 % in PPH p < 0.01. CONCLUSIONS: PPH-stapler procedure for treatment of haemorrhoidal prolapse is an important improvement, but may be followed by severe complications. We think that it has a clear indication in the treatment of haemorrhoidary disease with circumferential prolapse classified P4-E4.

PPH vs Milligan-Morgan: early and late complications in the treatment of haemorrhoidal disease with circumferential prolapse.

BACKGROUND: The aim of this study was to assess the early and late complications of haemorrhoidectomy according to Milligan-Morgan (Milligan-Morgan laser optical fibers variant) vs haemorrhoidopexy with PPH-stapler and to assess the long-term results in terms of recurrences in circumferential prolapse patients classified P4-E4 (PATE 2000). METHODS: Onehundredsixty patients, with haemorrhoidal disease classified P4-E4, who underwent surgery between 2001 and 2007, were included in an retrospective observational study. Group A (M-M laser fibre) 80 patients (50%) (50 Male, 30 Female; median age 39 years, range 23-57 years). Group B (PPH-Stapler) 80 patients (50%) (58 Male, 22 Female; median age 40 years, range 23-60 years). RESULT: Early complications were thrombosis (6 cases in M-M vs 1 in PPH) and urinary retention (13 M-M vs 5 PPH). There weren't cases of sepsis. Late complications have been: occasional bleeding 13.5 % in the M-M-group vs 10 % in the PPH-group; defecatory urgency 2.5 % (M-M-group) vs 5% (PPH-group) with p < 0.1; persistent pain 2.5 % (M-M) vs 5 % (PPH) with p < 0.1; soiling 18.75 % (M-M) vs 0 % (PPH) with p < 0.001; recurrences 5 % in PPH-group vs 0 % in M-M (p < 0.05); residual disease 7.5 % in M-M-group vs 0 % in PPH p < 0.01. CONCLUSIONS: PPH-stapler procedure for treatment of haemorrhoidal prolapse is an important improvement, but may be followed by severe complications. We think that it has a clear indication in the treatment of haemorrhoidary disease with circumferential prolapse classified P4-E4.

Mast cell positivity to tryptase correlates with metastatic lymph nodes in gastrointestinal cancer patients treated surgically.

BACKGROUND: Angiogenesis has been found to be a reliable prognostic indicator for several types of malignancies. Tryptase is a serine protease stored in mast cell (MC) granules, which plays a role in tumor angiogenesis. MCs can release tryptase following c-Kit receptor activation. METHOD: In this study, immunohistochemistry, image analysis methods and clinical aspects were employed in a series of 41 gastrointestinal cancer patients with stage T3-4N2a-bM0 (by the American Joint Committee on Cancer, AJCC, for colorectal cancer, 7th edition) and T3N2-3M0 (by AJCC for gastric cancer, 7th edition) to evaluate the possible correlation between MCs positive to tryptase (MCPT) in tumor tissue and the number of metastatic lymph nodes harvested. RESULTS: Data demonstrated a positive correlation between MCPT in tumor tissue and the number of metastatic lymph nodes; the validity of these data needs confirmation in larger patient cohorts. CONCLUSION: This is the first report considering MCPT in tumor tissue as a potential tool for a valid indication of the type of surgical treatment and its radicality, and it might be considered for the prognosis of patients before radical surgical treatment. Our pilot data need confirmation in a larger patient cohort.

Tryptase-positive mast cells and angiogenesis in keloids: a new possible post-surgical target for prevention.

Literature data indicate that mast cells (MCs) are involved in angiogenesis through the release of several pro-angiogenetic factors among which tryptase, a serine protease stored in MC granules, is one of the most active. However, no data are available concerning the role of MCs during keloids' angiogenesis. In this study, we evaluated the correlations of the number of MCs positive to tryptase (MCDPT) and microvascular density (MVD) within a series of 15 keloids and 10 normotrophic scars, by means of immunohistochemistry and image analysis methods. Data demonstrated a significant difference of MVD and MCDPT between keloids and normotrophic scars and a significant correlation between MVD and MCDPT in keloids. Our results suggest that tryptase-positive MCs might play a key role in keloids' angiogenesis. In this context, several tryptase inhibitors might be clinically evaluated as a possible new anti-angiogenetic approach to prevent keloid formation after surgery.

From 3-port to new laparoendoscopic single-site (LESS) cholecystectomy: a critical analysis of available evidence.

In recent years, laparoendoscopic single-site surgery (LESS) has gained greater interest and diffusion for the treatment of gallstones. This critical review aims to evaluate the feasibility and safety of LESS cholecystectomy versus the 3-port technique (TPT) through a comparative analysis of 5 parameters: mean operative time, intraoperative and postoperative complications, conversion to open, conversion to the 4-trocar technique and postoperative hospital stay. The authors performed a systematic search of the medical literature through a search of PubMed and Ovid EMBASE. Inclusion criteria were as follows: publication date between January 1, 2005, and December 31, 2010; English or Italian language; human participants and series of 20 operations or more. There were 5 manuscripts meeting the inclusion criteria for TPT and 23 for LESS. Only one prospective randomized controlled trial comparing TPT and LESS was identified. Operative time is significantly longer in the single-incision group. Complications and conversion rates to the 4-port technique are higher in LESS. Postoperative hospital stay is similar in the 2 groups. Rate of conversion to open is higher in TPT. Despite the number of publications on LESS cholecystectomy, the vast majority of data available in the literature are from small case series without any comparative data. Although LESS cholecystectomy is a fashionable technique there are few data available for an evidence-based determination as to the real benefits of this technique. Well-designed comparative studies are suggested to validate the clinical benefits and ensure that there are no new complications or added costs associated with the new technique.

[Relief of gastric cancer with an electromagnetic interaction system (TRIMprob) in outpatients]. / Rilievo di carcinoma gastrico mediante sistema di interazioni elettromagnetiche (TRIMprob) in pazienti ambulatoriali.

Gastric cancer is currently an important clinical and social problem. TRIMprob is a portable system for the non-invasive diagnosis of gastric cancer, designed to differentiate between normal and pathological tissues on the basis of their electromagnetic characteristics. The aim of our study was to evaluate the accuracy and feasibility of use of the TRIMprob system in diagnosing gastric neoplasms. From January to September 2006 we screened 28 symptomatic patients with TRIMprob; afterwards they underwent an endoscopic and bioptic examination. On the basis of the histological diagnosis these patients were divided into 2 groups: group A (patients with a diagnosis of gastric malignancies) and group B (patients with inflammatory disease). There also was a group C, which was a control group of 15 asymptomatic volunteers. The TRIMprob system located all cases of gastric cancer (group A) with 100% sensitivity, specificity and accuracy. The TRIMprob examination seems to be extremely accurate in diagnosing gastric malignancies. If these results are confirmed, TRIMprob could be used for the early diagnosis of gastric cancer and for selecting symptomatic subjects for gastroscopy.