A New Medium (HistoCold) for Surgical Specimens Preserving to Improve the Preanalytic Issues in Histopathological Samples Handling: Morphologic and Antigenic Analysis.

Introduction: The onset of precision medicine has led to the integration of traditional morphologic tissues evaluation with biochemical and molecular data for a more appropriate pathological diagnosis. The preanalytic phase and, particularly, timing of cold ischemia are crucial to guarantee high-quality biorepositories of formalin-fixed paraffin-embedded (FFPE) tissues for patients' needs and scientific research. However, delayed fixation using the gold-standard and carcinogenic fixative neutral-buffered formalin (NBF) can be a significant limitation to diagnosis and biopathological characterization. HistoCold (patented; Bio-Optica Milano S.p.A., Milano, Italy) is a nontoxic, stable, and refrigerated preservative solution for tissue handling. This study examined HistoCold's potential role in improving the preanalytic phase of the pathological diagnostic process. Materials and Methods: Breast, lung, or colorectal cancers (20, 25, and 10 cases, respectively) that were to be surgically resected were recruited between 2019 and 2021. Once specimens were surgically removed, three residual samples for each patient were first promptly immersed into HistoCold for 24, 48, and 72 hours and then FFPE. These were compared with routine specimens regarding morphologic features (hematoxylin and eosin) and tissue antigenicity (immunohistochemical stains). Results: Good concordance regarding both the morphologic characteristics of the neoplasms and their proteins expression between the routine and HistoCold handled tissues were found. The tissue handling with the solution never affected the histopathological diagnosis. Conclusions: The use of HistoCold for samples transporting is easy, allows for improving the management of cold ischemia time, and monitoring the fixation times in NBF, resulting in good quality tissue blocks for biobanking. Moreover, it could be a candidate to eliminate formalin from operating theaters. HistoCold looks very promising for the preanalytic phase of human tissues handling in the era of precision medicine, to provide the best service to patients, and to scientific research.

Accuracy and feasibility of SentiMag technique for localization of non-palpable breast lesions.

BACKGROUND: Non-palpable breast lesions are more frequent now than in the past due to the attention toward the mammary pathology and the screening diffusion; the marking of such lesions is very important for a successful surgery. The SentiMag System uses a magnetic marker that is inoculated transdermal in the breast through an 18-gauge needle. METHODS: Between April 1st and June 30th, 2018, 16 patients with non-palpable breast lesions were selected and subjected to surgery using the SentiMag System in our Unit. They were women with a mean age of 52 years (range 30-84 years). Seven of 16 (43.7%) had a borderline preoperative histological or cytological diagnosis (C3/B3), and nine (56.3%) a diagnosis of carcinoma (C5/B5). Six (37.5%) were marked on ultrasound guidance and 10 (62.5%) on a mammography stereotaxic guide. RESULTS: The time for the marker positioning ranged from 2 to 10 minutes. The radiological control of the surgical specimen always showed the presence of both the lesion and the marker, both centered within the specimen and intact. The pathology revealed seven benign lesions, one in-situ, and eight infiltrating carcinomas. CONCLUSIONS: The SentiMag represents a fast and safe preoperative marking system of non-palpable breast lesions, cutting the radio exposure for personnel and patients. The marker is not displaced over time and it is rapid to place and easy to locate intraoperatively, allowing a clear dissection plane around the lesion. Thus, this reduces the amount of gland removed, improving the aesthetic result mostly in small breasts.

Reduction of postoperative lymphorrhoea in patients undergoing radical lymphadenectomy for stage III melanoma: prospective study using collagen-fibrin patches.

BACKGROUND: Radical lymph nodes dissection (RLND) is the standard procedure for regional control of disease in patients with metastatic melanoma (stage III). Because of its aggressiveness, lymphorrhoea is a constant problem in postoperative. METHODS: In this prospective nonrandomized study with a retrospective analysis of data, patients undergoing surgical treatment of axillary or iliac-inguinal RLND received standard treatment plus a collagen-fibrin sealant patch (TachoSil) (N.=50) or standard treatment alone (N.=50). The first endpoint was the comparison between the treated population and the control group, in terms of persistence of drainage and average daily volume of lymphorrhoea. The second aim was to relate patients' BMI, volume of lymphorrhoea and time of drainage in the two groups. RESULTS: In the comparison between the two groups receiving or not the treatment with collagen-fibrin patch, we found an average difference both in the volume of daily lymphorrhoea (42.91±6.61 cc) and in the persistence of drainage (9.292±1.644 days) with P value <0.0001. Besides, the collagen-fibrin patch was actually effective in reducing lymphorrhoea and time of drainage, regardless of patients' BMI. CONCLUSIONS: The results of this study confirm and support the starting thesis: TachoSil is an effective tissue sealant able to reduce lymphorrhoea and drainage removal times following a radical lymphadenectomy, independently from the BMI.

Influence of chemotherapeutic drug-related gene polymorphisms on toxicity and survival of early breast cancer patients receiving adjuvant chemotherapy.

BACKGROUND: We investigated whether GSTT1 ("null" allele), GSTM1 ("null"allele), GSTP1 (A313G), RFC1 (G80A), MTHFR (C677T), TS (2R/3R) polymorphisms were associated with toxicity and survival in patients with early breast cancer (EBC) treated with adjuvant chemotherapy (CT). METHODS: This prospective trial included patients with stage I-III BC subjected to CT with CMF or FEC regimens. PCR-RFLP was performed for MTHFR, RFC1 and GSTP1, while PCR for TS, GSTT1 and GSTM1 genes. RESULTS: Among the 244 patients consecutively enrolled, 48.7% were treated with FEC and 51.3% with CMF. Patients with TS2R/3R genotype showed less frequently severe neutropenia (G3/G4) than those with TS2R/2R and 3R/3R genotype (p = 0.038). Patients with MTHFRCT genotype had a higher probability of developing severe neutropenia than those with MTHFR CC genotype (p = 0.043). Patients with RFC1GG or GSTT1-null genotype or their combination (GSTT1-null/RFC1GG) were significantly associated with a shorter disease free survival (DFS) (p = 0.009, p = 0.053, p = 0.003, respectively) and overall survival (OS) (p = 0.036, p = 0.015, p = 0.005, respectively). Multivariate analysis confirmed the association of RFC1GG genotype with a shorter DFS (p = 0.018) and of GSTT1-null genotype of a worse OS (p = 0.003), as well as for the combined genotypes GSTT1-null/RFC1GG, (DFS: p = 0.004 and OS: p = 0.003). CONCLUSIONS: Our data suggest that TS2R/2R and 3R/3R or MTHFR CT genotypes have a potential role in identifying patients with greater risk of toxicity to CMF/FEC and that RFC1 GG and GSTT1-null genotypes alone or in combination could be important markers in predicting clinical outcome in EBC patients.

Elaboration of a nomogram to predict nonsentinel node status in breast cancer patients with positive sentinel node, intraoperatively assessed with one step nucleic amplification: Retrospective and validation phase.

BACKGROUND: Tumor-positive sentinel lymph node (SLN) biopsy results in a risk of non sentinel node metastases in micro- and macro-metastases ranging from 20 to 50%, respectively. Therefore, most patients underwent unnecessary axillary lymph node dissections. We have previously developed a mathematical model for predicting patient-specific risk of non sentinel node (NSN) metastases based on 2460 patients. The study reports the results of the validation phase where a total of 1945 patients were enrolled, aimed at identifying a tool that gives the possibility to the surgeon to choose intraoperatively whether to perform or not axillary lymph node dissection (ALND). METHODS: The following parameters were recorded: Clinical: hospital, age, medical record number; Bio pathological: Tumor (T) size stratified in quartiles, grading (G), histologic type, lymphatic/vascular invasion (LVI), ER-PR status, Ki 67, molecular classification (Luminal A, Luminal B, HER-2 Like, Triple negative); Sentinel and non-sentinel node related: Number of NSNs removed, number of positive NSNs, cytokeratin 19 (CK19) mRNA copy number of positive sentinel nodes stratified in quartiles. A total of 1945 patients were included in the database. All patient data were provided by the authors of this paper. RESULTS: The discrimination of the model quantified with the area under the receiver operating characteristics (ROC) curve (AUC), was 0.65 and 0.71 in the validation and retrospective phase, respectively. The calibration determines the distance between predicted outcome and actual outcome. The mean difference between predicted/observed was 2.3 and 6.3% in the retrospective and in the validation phase, respectively. The two values are quite similar and as a result we can conclude that the nomogram effectiveness was validated. Moreover, the ROC curve identified in the risk category of 31% of positive NSNs, the best compromise between false negative and positive rates i.e. when ALND is unnecessary (<31%) or recommended (>31%). CONCLUSIONS: The results of the study confirm that OSNA nomogram may help surgeons make an intraoperative decision on whether to perform ALND or not in case of positive sentinel nodes, and the patient to accept this decision based on a reliable estimation on the true percentage of NSN involvement. The use of this nomogram achieves two main gools: 1) the choice of the right treatment during the operation, 2) to avoid for the patient a second surgery procedure.

Axillary Lymph Node Metastases of Melanoma: Management of Third-level Nodes.

AIM: To state the limits of axillary lymphadenectomy in patients with metastatic melanoma. PATIENTS AND METHODS: We performed a prospective study on patients submitted to axillary dissection for stage III melanoma. At surgery, the third-level nodes were separately dissected to be examined by the pathologist. RESULTS: We analyzed 86 patients. In 93%, the third-level nodes were disease-free; none of the patients with previous positive sentinel nodes (SN) showed nodal metastases at level III. Patients (7%) found to have positive level III nodes had undergone therapeutic lymphadenectomy for bulky nodal disease. CONCLUSION: Our data show that axillary non-sentinel nodes of level III are usually disease-free in cases of previously positive SN, while they can be involved in the presence of bulky disease. A prerequisite allowing sparing of level III nodes after a positive SN biopsy is the meticulous research of all level I and II lymph nodes.

IMP3 Is Strongly Expressed in Malignant Phyllodes Tumors of the Breast: An Immunohistochemical Study.

BACKGROUND: Phyllodes tumors (PTs) of the breast are rare biphasic neoplasms and are classified as benign, borderline, or malignant. Many biological markers have been studied to discriminate between different grades of PTs. IMP3 is a member of the insulin-like growth factor II mRNA binding protein (IMP) family and is expressed in developing tissues during embryogenesis, whereas in adult tissues it is found only at low or undetectable levels. IMP3 is considered a marker of biological aggressiveness in many cancers, including breast and lung. The aim of this study was to evaluate the immunohistochemical expression of IMP3 in a series of PTs and to determine its association with histological grade and clinical outcome. MATERIALS AND METHODS: We reviewed retrospectively 62 cases of PTs including their recurrences and 20 cases of fibroadenoma. PTs have been classified as benign in 40 cases, borderline in 13 cases, and malignant in 9 cases. RESULTS: There were significant differences in IMP3 expression: in malignant PTs IMP3 expression was higher (56% of cases) than in borderline (15%) and benign cases (5%), (P = .001). Fibroadenoma showed no expression for IMP3. IMP3 expression was different in cases with recurrence than cases without recurrence. Furthermore, 3 of the recurrences had a higher histological grade with a positive IMP3 expression compared with the primary tumor. CONCLUSIONS: This is the first study evaluating the IMP3 immunohistochemical expression in PTs. Its expression correlates with histological grade and could be used in the differential diagnosis of fibroepithelial tumors and in predicting a more aggressive behavior.

Therapeutic options for body packers: surgical or conservative treatment? A single center experience and review of literature.

UNLABELLED: Body packing is a way to deliver packages of drugs hidden in body cavities. In Europe, as noted the latest report coming from the Brussels observatory, there are 74 million drugs consumers. Italy is in pole position and Perugia was considered as a "capital city" in the drug market. Body packers usually swallow the drug packets, although their insertion into the rectum and vagina has also been reported. The management depends on whether or not the patient becomes symptomatic. Surgery is indicated in presence of repeated bouts of drug toxicity not controlled by medical treatment, radiological evidence of packet retention in the stomach, intestinal obstruction or perforation. It is also important to emphasize that, in a multidisciplinary context, the patient's management before reaching the operating theater if symptomatic, is aimed to stabilization and is usually demanded to Intensive Care Unit (ICU) physicians. We present our center recent experience with body packers, managed both with surgical and conservative treatments. KEY WORDS: Body packers, Drugs, Emergency surgery, Foreign bodies.

The integrated role of ultrasonography in the diagnosis of soft tissue metastases from melanoma: preliminary report of a single-center experience and literature review.

Currently melanoma has the fastest growing incidence of all cancers in men and the second in women (after lung cancer) in Western countries. Since prognosis of skin melanoma is excellent in early stages but dramatically worsens in advanced stages, an early diagnosis is fundamental in granting patients a favorable outcome. Sentinel node (SN) biopsy represents the gold standard for accurately staging melanoma, but other tests are commonly endorsed both in the initial staging work-up and in the follow-up, such as ultrasonography, computed tomography (CT)-scan and positron emission tomography (PET)-CT. PET-CT, among others, has high sensitivity and specificity for the study of distant metastases, the assessment of soft tissues and lymph node involvement, and for the guidance of surgical biopsies. Ultrasonography (US) is a non-invasive procedure whose use has recently expanded in our service, both preoperatively, intraoperatively and postoperatively, thanks to its wide availability, low costs and easy and fast reproducibility; ultrasonography even surpassed the reliability of PET-CT or CT-scan in the seven cases presented herein. US is operator-dependent, and this is probably the major limitation of the procedure, together with lack of prospective studies validating its strength, but our preliminary study demonstrates that ultrasound can assume an important role in melanoma, both for staging and the follow-up of patients, especially with lymph nodal or subcutaneous involvement.

Optimizing therapeutic timing in patients undergoing mastectomy through use of the Tiloop® synthetic mesh: single-step surgery.

Patients undergoing mastectomy for breast cancer have to face a long and elaborated therapeutic path, very often burdened by reoperation to replace the temporary expander, used to enlarge the submuscular pouch, with a definitive implant. Postoperative planning represents a critical moment of care, as it requires the integration of multiple treatments (chemotherapy, radiotherapy, hormonotherapy) each with a specific deadline. We believe that in such a complex multidisciplinary approach, coordination among the different therapeutic phases should be the key to success. The aim of the Breast Unit is to manage rapidly the ad hoc paths set out for each patient in order to guarantee compliance with adequate therapeutic timing. With this purpose in mind we tested the advantage of immediate reconstruction with definitive implants, by using a polypropylene mesh which, prolonging the inferolateral profile of the pectoralis major muscle (PMM), allows for direct accommodation of the desired implant volume. This leads to a single-step surgical approach, guaranteeing at the same time reduced interference with adjuvant therapies and good aesthetic results. We applied this technique to 4 patients, one of which was bilateral and, in spite of the restricted number of cases, our results seem to be promising.

Oncologic reliability of nipple-sparing mastectomy for selected patients with breast cancer.

BACKGROUND: Nipple sparing mastectomy (NSM) is the current surgical alternative to conventional techniques, when mastectomy is required. This less invasive procedure safeguards the integrity of the nipple areola complex (NAC), whose removal is recognized as a factor that exacerbates the patient's feeling of mutilation, however ensuring oncological radicality for women with breast cancer. PATIENTS AND METHODS: From January 2003 to January 2011, 77 patients underwent Nipple Sparing Mastectomy (NSM). Patients were carefully selected according to specific criteria. When requested, postoperative radiotherapy on the residual glandular tissue was performed within 6 months of surgery. Patients were on close clinical and instrumental follow-up every 4 months for 2 years and every 6 months for the remaining 3 years. RESULTS: Of the 77 patients who underwent NSM, 10 suffering from bilateral cancer were subjected to bilateral procedure, for a total of 87 performed procedures. Furthermore, in the same group, 13 NSMs were carried out for preventive purposes. The average diameter of resected tumors was 13.5 mm, with a range of 2 to 25 mm. During the follow-up (range 23-115 months, mean 50.33 months) 2 locoregional recurrences in the NAC were observed, identified through instrumental check, and surgically treated by NAC removal after 33 and 37 months respectively. CONCLUSION: According to the litterature data and confirmed by our experience, we consider NSM as an oncologically safe technique that, in the respect of inclusion criteria may be performed in any patient with indication to mastectomy. A careful selection of patients by a multidisciplinary team according to strict criteria is the key in determining feasibility as well as oncological safety and should lead the general acceptance and widespread use of such surgical technique.

Synchronous primary lung cancer. Critical review of diagnostic criteria.

QUESTION OF THE STUDY: Synchronous primary lung cancers (SPLCs) may pose a radiologic-pathologic and therapeutic dilemma in according to recent WHO classification. PATIENTS AND METHODS: Two cases of surgically treated SPLCs are reported. RESULTS: In the first case two nodules were detected by Computed Tomography (CT) in the upper right lobe. The patient underwent lobectomy and histological diagnosis was adenocarcinoma and squamous cell carcinoma. The second patient presented at CT one nodule in the upper left lobe and another nodule in the upper right lobe. Sternotomic access was chosen for bilateral removal of the lesions. The diagnosis was sarcomatoid carcinoma and large cell neuroendocrine adenocarcinoma. DISCUSSION: The criteria of Martini and Melamed are inadequate for the diagnosis of SPLCs. The use of TTF-1 (thyroid transcription factor-1) is necessary to establish the diagnosis of SPLC in patients with adenocarcinoma of other sites. Bronchioloalveolar carcinomas must be excluded because of their multicentricity. When histology of two tumors found in the same lobe is identical and histotype is adenocarcinoma, large cell carcinoma or sarcomatoid carcinoma, the diagnosis of SPLCs must be excluded and those lesions must be considered as metastatic disease. The prognosis and treatment of SPLCs are discussed after critical review of the literature.

Surgical solutions for the reconstruction of the lower eyelid: canthotomy and lateral cantholisis for full-thickness reconstruction of the lower eyelid.

The lower eyelid is the most common site of tumors of the orbital region, usually of basocellular skin carcinoma, whose incidence is increasing with population aging in Western countries. The treatment must achieve the complete removal of the neoplasm in order to prevent recurrences, thus requiring eyelid and periocular reconstruction. Several techniques are described for eyelid defect reconstruction, aiming for direct suture eased by flaps, or considering the use of grafts. We report our experience with 22 patients operated on for basocellular carcinoma of the lower eyelid, for wich defects were repaired by means of a full-thickness reconstruction using a canthotomy and lateral cantholisis; in 13 patients the canthotomy was combined with a lateral-canthal flap. We achieved good results in terms of orbital function and aesthetic outcome, as long as radical removal of the tumor without local recurrences was attainable.

Spontaneous splenic rupture in patient with metastatic melanoma treated with vemurafenib.

BACKGROUND: BRAF inhibitors such as vemurafenib are a new family of biological drugs, recently available to treat metastatic malignant melanoma. METHODS: We present the case of a 38-year-old man affected by metastatic melanoma who had been under treatment with vemurafenib for a few days. The patient suffered from sudden onset of abdominal pain due to intra-abdominal hemorrhage with profuse hemoperitoneum. An emergency abdominal sonography confirmed the clinical suspicion of a splenic rupture. RESULTS: The intraoperative finding was hemoperitoneum due to splenic two-step rupture and splenectomy was therefore performed. Histopathology confirmed splenic hematoma and capsule laceration, in the absence of metastasis. CONCLUSIONS: This report describes the occurrence of a previously unreported adverse event in a patient with stage IV melanoma receiving vemurafenib.

Surgical treatment of primitive gastro-intestinal lymphomas: a systematic review.

Primitive Gastrointestinal Lymphomas (PGIL) are uncommon tumours, although time-trend analyses have demonstrated an increase. The role of surgery in the management of lymphoproliferative diseases has changed over the past 40 years. Nowadays their management is centred on systemic treatments as chemo-/radiotherapy. Surgery is restricted to very selected indications, always discussed in a multidisciplinary setting. The aim of this systematic review is to evaluate the actual role of surgery in the treatment of PGIL. A systematic review of literature was conducted according to the recommendations of The Cochrane Collaboration. Main outcomes analysed were overall survival (OS) and disease free survival (DFS). There are currently 1 RCT and 4 non-randomised prospective controlled studies comparing surgical versus medical treatment for PGIL. Seven hundred and one patients were analysed, divided into two groups: 318 who underwent to surgery alone or associated with chemotherapy and/or radiotherapy (surgical group) versus 383 who were treated with chemotherapy and/or radiotherapy (medical group). Despite the OS at 10 years between surgical and medical groups did not show relevant differences, the DFS was significantly better in the medical group (P=0.00001). Accordingly a trend was noticed in the recurrence rate, which was lower in the medical group (6.06 vs. 8.57%); and an higher mortality was revealed in the surgical group (4.51% vs. 1.50%).The chemotherapy confirms its primary role in the management of PGIL as part of systemic treatment in the medical group. Surgery remains the treatment of choice in case of PGIL acutely complicated, although there is no evidence in literature regarding the utility of preventive surgery.

High tie versus low tie of the inferior mesenteric artery: a protocol for a systematic review.

In anterior resection of rectum, the section level of inferior mesenteric artery is still subject of controversy between the advocates of high and low tie. The low tie is the division and ligation to the branching of the left colic artery and the high tie is the division and ligation at its origin at the aorta. We intend to assess current scientific evidence in literature and to establish the differences comparing technique, anatomy and physiology. The aim of this protocol is to achieve a meta-analysis that tests safety and feasibility of the two procedures with several types of outcome measures.

Interstitial high-dose-rate brachytherapy after breast conserving surgery.

We evaluated local recurrence, toxicity rate and cosmetic outcome in 72 patients treated with high-dose-rate (HDR) brachytherapy after breast conserving surgery. HDR brachytherapy was administered: i) as partial breast irradiation (PBI) in 64 patients with low-risk early stage breast cancer, enrolled in a phase II prospective study; ii) as PBI after a second conservative surgery as treatment of local relapse in 3 patients; iii) for delivering a boost after whole breast external beam radiotherapy in 5 patients. Implantation was done during surgery (breast conserving or re-excision to achieve adequate surgical margins), with the wound open, or postoperatively. The implant was well tolerated in all patients, so no premature catheter removal was required. At a median follow-up of 32 months (range 5-52) no local recurrence has been observed. Toxicity was very low. Cosmetic outcome was excellent/good in a high percentage of patients. Our results suggest that PBI administered with HDR brachytherapy is feasible in selected patients with low risk early stage breast carcinoma. PBI seems feasible to repeat radiotherapy after a salvage breast conserving surgery for local relapse in a second attempt to preserve the breast.