Stefano Mori

Assessing a novel immuno-oncology-based combination therapy: Ipilimumab plus electrochemotherapy

Melanoma is responsible for most skin cancer-related deaths and is one of the most common cancers diagnosed in young adults. In melanoma, tumors can become established by activation of the negative regulator of cytotoxic T lymphocytes (CTLs), CTL antigen-4 (CTLA-4). Ipilimumab blocks the interaction of CTLA-4 with CD80/CD86 and augments T-cell activation and proliferation. In electrochemotherapy (ECT), local application of short high-voltage pulses renders cell membranes transiently permeable to chemotherapeutic drugs. The combination of ipilimumab and ECT may be beneficial for the treatment of metastatic melanoma; however, no prospective data are available to date. Here, we report the retrospective analysis of patients treated with ipilimumab in an expanded access program (EAP) who also received ECT. Fifteen patients with previously treated metastatic melanoma who received ipilimumab 3 mg/kg every three weeks for four cycles and underwent ECT for local disease control and/or palliation of cutaneous lesions with bleomycin 15 mg/m2 after the first ipilimumab infusion were included in the analysis. Over the study period, a local objective response was observed in 67% of patients (27% complete response [CR] and 40% partial response [PR]). According to immune-related response criteria, a systemic response was observed in nine patients (five PR and four stable disease [SD]), resulting in a disease control rate of 60%. Evaluation of circulating T-regulatory (T-reg) cells demonstrated significant differences between responders and non-responders. Overall, treatment was well-tolerated and without notable toxicity. In conclusion, the combination of ipilimumab and ECT appears to be beneficial to patients with advanced melanoma, warranting further investigation in prospective trials.

Laparoscopic cholecystectomy for melanoma metastatic to the gallbladder: is it an adequate surgical procedure? Report of a case and review of the literature

BackgroundOnly 2% to 4% of patients with melanoma will be diagnosed with gastrointestinal metastasis during the course of their disease. The most common sites of gastrointestinal metastases from melanoma include the small bowel (35%–67%), colon (9%–15%) and stomach (5%–7%), with a median survival of 6–10 months after surgery, and 18% survival at five years. Metastatic melanoma to the gallbladder is extremely rare and it is associated with a very poor prognosis.Case presentationWe report a case of a 54-year old man presented to observation with diagnosis of 6.1 mm thick, Clarks level IV, ulcerated melanoma of the trunk, developing in the course of the disease metastatic involvement of the gallbladder as first site of recurrence, treated by laparoscopic cholecystectomy. To date only few cases of patients with metastatic melanoma of the gallbladder treated by this surgical procedure have been reported in literature.ConclusionGallbladder metastasis represents a rare event as a first site of recurrence. It must be considered a possible expression of systemic disease also despite radiological absence of other metastatic lesions. Laparoscopic approach has a possible therapeutic role, but open surgery has also a concomitant diagnostic purpose because gives the possibility of manual exploration of abdominal cavity, useful particularly to reveal bowel metastatic lesions, not easily identifiable by preoperative imaging examinations.

Use of neoadjuvant electrochemotherapy to treat a large metastatic lesion of the cheek in a patient with melanoma

BackgroundApproximately 200,000 new cases of melanoma are diagnosed worldwide each year. Skin metastases are a frequent event, occurring in 18.2% of cases. This can be distressing for the patient, as the number and size of cutaneous lesions increases, often worsened by ulceration, bleeding and pain. Electrochemotherapy (ECT) is a local modality for the treatment of cutaneous or subcutaneous tumors that allows delivery of low- and non-permeant drugs into cells. ECT has been used in palliative management of metastatic melanoma to improve patients’ quality of life. This is, to our knowledge, the first application of ECT as neoadjuvant treatment of metastatic subcutaneous melanoma.Methods and resultsA 44-year-old Caucasian woman underwent extensive surgical resection of a melanoma, with a Breslow thickness of 1.5 mm, located on the right side of her scalp. No further treatment was given and the woman remained well until she came to our attention with a large nodule in her right cheek. Whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) was performed for staging and treatment monitoring. Baseline FDG PET/CT showed the lesion in the cheek to have a maximal standardized uptake value (SUVmax) of 19.5 with no evidence of further disease spread. Fine needle aspiration cytology confirmed the presence of metastatic melanoma. The patient underwent two sessions of ECT with intravenous injections of bleomycin using a CliniporatorTM as neoadjuvant treatment permitting conservative surgery three months later.Follow-up PET/CT three months after the first ECT treatment showed a marked decrease in SUVmax to 5. Further monitoring was performed through monthly PET/CT studies. Multiple cytology examinations showed necrotic tissue. Conservative surgery was carried out three months after the second ECT. Reconstruction was easily achieved through a rotation flap. Pathological examination of the specimen showed necrotic tissue without residual melanoma. One year after the last ECT treatment, the patient was disease-free as determined by contrast-enhanced CT and PET/-CT scans with a good functional and aesthetic result.ConclusionsECT represents a safe and effective therapeutic approach that is associated with clear benefits in terms of quality of life (minimal discomfort, mild post-treatment pain and short duration of hospital stay) and may, in the neoadjuvant setting as reported here, offer the option of more conservative surgery and an improved cosmetic effect with complete local tumor control.

Omental Flap and Titanium Plates Provide Structural Stability and Protection of the Mediastinum After Extensive Sternocostal Resection

Major tenets in the reconstruction of the anterolateral chest wall include preservation of structural stability and function and coverage of the mediastinal contents. To reach these goals, a rigid support has been advocated by several authors. We describe a patient with extensive anterolateral defect after sternocostal resection of chondrosarcoma. Successful reconstruction was performed by using three metallic transverse plates and an omental flap wrapped onto the plates. This method simplifies reconstruction in comparison with previously described techniques concerning complete solid coverage and leaves several options intact in the event of future recurrences.

Malignant glomus tumour: a case report and review of the literature*

Purpose: Glomus tumours are characteristically benign solitary tumours. At our knowledge, about 23 reports are present in literature regarding the malignant counterpart, but only a minority developed metastases. We describe a locally aggressive glomus tumour with lymphnode metastasis. Patient: The patient was a 40 year-old man presenting a 1.5-cm lesion on the right wrist incompletely excised and a recurrent tumour, 4 × 2 cm in size, removed after 9 months, for which he received radiotherapy. After 2 years he developed an axillary lymphnode metastasis. Results: Histologically, both tumours (primary and metastasis) were similar. There were sheets and nests of uniform small cells with scant eosinophilic cytoplasm and round to polygonal nuclei; there was some degree of pleomorphism and the mitotic index was high (up to 18 m/10 HPF). The tumour cells were positive for vimentin and smooth muscle actin, but negative for desmin, NSE, Factor VIII, chromogranin, cytokeratin. Remarkably, in the primary, the cells strongly expressed p53 (70%) and MIB-1 (35%). Discussions: In many reported malignant cases, the histology of the tumour cells suggested that they were malignant, yet the clinical course has been benign. Carefully reviewing the literature, it seems that actually we have enough histological criteria to identify the cases with biological adverse outcome. Those unfortunate cases behave as high grade sarcomas and therefore may deserve an aggressive therapeutic treatment.

The Use of Biomaterials for Chest Wall Reconstruction 30 Years After Radical Surgery and Radiation

The combination of titanium plates and acellular collagen matrix was used to restore anterior chest wall integrity in a 68-year-old woman more than 30 years after a Halsted mastectomy and radiation treatment. A vertical rectus abdominis muscle flap was used for myocutaneous coverage of the reconstructed chest wall. Partial necrosis of the flap caused prolonged exposure of the collagen matrix and the titanium plates, which were then covered with a free skin graft. Long-term results were satisfactory despite continued infection treated with vacuum-assisted closure and surgical debridement. Recently introduced materials for chest wall reconstruction may offer resilience to infection, tolerability, and stability, and their use may be contemplated when the potential for local morbidity is high.

The Use of Veritas Collagen Matrix to Reconstruct the Posterior Chest Wall After Costovertebrectomy

Among the new materials introduced for chest wall reconstruction, the use of collagen matrix is gaining increasing favor for its biomechanical properties. We describe the reconstruction of the chest wall with Veritas (Synovis, St Paul, MN) collagen matrix of a posterior chest wall defect after costovertebrectomy for Ewings sarcoma. En bloc resection was performed, including partial D7 through D9 vertebrectomy along with the posterolateral segments of corresponding ribs. The collagen matrix patch was sutured to the spine stabilizer and the surrounding rib segments and was covered by previously raised latissimus dorsi and trapezius muscle flaps. Excellent stabilization was obtained.

Can High-Resolution Ultrasound Avoid the Sentinel Lymph-node Biopsy Procedure in the Staging Process of Patients with Stage I–II Cutaneous Melanoma?

PURPOSE The objective of our study was to define the diagnostic accuracy of high-resolution ultrasound (US) in detecting nodal involvement before sentinel lymph node biopsy (SLNB) in patients with cutaneous melanoma, to define the sonographic criteria used to assess nodal metastases, and to establish if high-resolution US can directly select patients to radical lymphadenectomy, sparing selective lymphadenectomy. MATERIALS AND METHODS 623 patients underwent high-resolution US of the regional lymph nodes, 24 hours prior being submitted to the sentinel lymph node biopsy procedure. The US findings were compared with histological findings. RESULTS In 14.7 % out of 122 excised lymph nodes, high-resolution US showed sonographic features consistent with malignant involvement before the surgical step. US scan sensitivity and specificity were 15 and 100 %, respectively, since positive and negative predictive values were 100 and 87 % respectively. CONCLUSION US is an effective modality in the presurgical detection of subclinical deposits within sentinel lymph nodes. However, preoperative staging work-up with high-resolution US cannot substitute the SLNB, mainly because of low sensitivity due to missing many micrometastases.

Combination therapy with ipilimumab and electrochemotherapy: preliminary efficacy results and correlation with immunological parameters

Background Ipilimumab is the first agent approved for the treatment of advanced melanoma that showed a survival benefit in randomized phase 3 trials. Despite the survival benefit, due to its mechanism of action it is associated with a slow onset and low rate of responses and, in many cases, responses occur after other therapies, like chemotherapy, targeted therapy and radiotherapy. Electrochemotherapy (ECT) has been shown to be effective and well tolerated for local control of metastatic melanoma with superficial lesions. The current challenge is to improve ipilimumab efficacy by combination/sequence with other therapies. We performed a pilot study of combination with ipilimumab and ECT in order to verify the possible increase of response rate. Furthermore, due to the lack of predictive markers, we evaluated the possible predictive role of circulating T-regulatory cells (T-Reg) variations in peripheral blood mononuclear cells (PBMC) of treated patients. Methods

Postoperative local morbidity and the use of vacuum-assisted closure after complex chest wall reconstructions with new and conventional materials

BACKGROUND New materials (NM) such as titanium plates, cryopreserved grafts, and acellular collagen matrices are being increasingly used for chest wall reconstruction as a result of improved incorporation while maintaining structural stability and reduced need for removal from infected areas. Direct comparisons between NM and conventional materials (CM) in terms of local morbidity and need for prosthesis removal are lacking. METHODS Between January 2005 and July 2013, 109 procedures were performed to remove chest wall tumors in 86 patients. Of these, 32 underwent complex chest wall reconstructions owing to either recurrence, defect extension (greater than 3 ribs or >100 cm2) or local conditions (ie, previous irradiation or infection). New materials and CM (ie, polytetrafluoroethylene and methyl methacrylate) were used in 17 (53%) and 15 (47%) patients, respectively. Of the 32 patients included in the high complexity group, 23 patients did not exhibit any postoperative complications (72%). However, 9 patients (28%) underwent both a first and a second reoperation after a median interval of 4 months from the first procedure (range, 7 days to 60 months). Vacuum-assisted closure (VAC) was instituted in all patients as a means to control sepsis and facilitate space obliteration with healthy tissue. RESULTS In 7 patients the reason for reintervention was local wound complications. In 4 of 7 patients, the prosthesis had to be removed (3 CM and 1 NM, 4.6% of the whole series; 12.5% in the high complexity group, 5.9% for NM and 20% for CM). The median time to complete chest wall healing after VAC in patients with local sepsis was 14 months (range, 5 to 60 months). All patients are currently alive and well except for 1 who died 11 months after complete chest wall healing as a result of dissemination of metastatic chondrosarcoma. At univariate analysis, predictors of overall and grade 2 or less morbidity according to the Common Terminology Criteria for Adverse Events version 4.0 were first (p=0.038) and second (p=0.015) redo operations. Conversely, patients with a body mass index of less than 25 kg/m2 (p=0.049) undergoing one (p=0.032) or two reconstructions (p=0.00047) with combined materials (p=0.00029) were more likely to experience local wound complications and require VAC. On multiple regression analysis, redo operations (first, p=0.032; second, p=0.00047) and the use of combined (synthetic and biologic) materials (p=0.0029) were confirmed to be related to an increased incidence of wound complications. CONCLUSIONS Multiple redo operations after complex chest wall reconstruction performed with a combination of NM and CM may be associated with an increased incidence of local wound complications. Nevertheless, in these cases, the use of NM and VAC yielded a low rate (5.8% versus 20% with CM) of prosthesis removal while achieving complete wound healing.