Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study.

The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2±13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents.

Sentinel node biopsy in thin and thick melanoma.

BACKGROUND: Although sentinel node biopsy (SNB) has become standard of care in patients with melanoma, its use in patients with thin or thick melanomas remains a matter of debate. METHODS: This was a retrospective analysis of patients with thin (≤1 mm) or thick (≥4 mm) melanomas who underwent SNB at two Italian centers between 1998 and 2011. The associations of clinicopathologic features with sentinel lymph node positive status and overall survival (OS) were analyzed. RESULTS: In 492 patients with thin melanoma, sentinel node was positive for metastatic melanoma in 24 (4.9 %) patients. No sentinel node positivity was detected in patients with primary tumor thickness <0.3 mm. Mitotic rate was the only factor significantly associated with sentinel node positivity (p = 0.0001). Five-year OS was 81 % for patients with positive sentinel node and 93 % for negative sentinel node (p = 0.001). In 298 patients with thick melanoma, 39 % of patients had positive sentinel lymph nodes (median Breslow thickness 5 mm). In patients with positive sentinel node, 93 % had mitotic rate >1/mm(2). Five-year OS was 49 % for patients with positive sentinel lymph nodes and 56 % for patients with negative sentinel nodes (p = 0.005). CONCLUSIONS: The rate of sentinel node positivity in patients with thin melanoma was 4.9 %. The only clinicopathologic factor related to node positivity was mitotic rate. Given its prognostic importance, SNB should be considered in such patients. SNB should also be the standard method for melanoma ≥4 mm, not only for staging, but also for guiding therapeutic decisions.

Alternatives for the treatment of local advanced disease: electrochemotherapy, limb perfusion, limb infusion, intralesional IL2. What is the role?

Nowadays, melanoma is one of the most common fatal malignancy of young adults. Incidence is increasing, but mortality rates from melanoma have remained stable. In-transit metastases from extremity or trunk melanoma are subcutaneous or cutaneous deposits of melanoma distant from the primary site, but not reaching the draining nodal basin. According to American Joint Committee on Cancer classification of stages based on Tumor, Node, Metastases classification stages IIIb and IIIc are considered local advanced disease and survival outcomes is quite poor, with 5-year survival rates of 24-54%. Loco-regional recurrence is an important risk factor for distant metastatic disease, either synchrone or metachrone. Therapy for this pattern of recurrence is limited and options vary based on the volume and site of disease. Definitive surgical resection remains the preferred therapeutic approach. However, when surgery cannot be performed with a reasonable cosmetic and functional outcome, other options must be utilized. Treatment options are classified as local, regional, or systemic. The choice of therapy depends on the number of lesions, their anatomic location, whether or not they are dermal or subcutaneous, the size, and the presence or absence of extra-regional disease.

Recurrence and prognostic factors in patients with aggressive fibromatosis. The role of radical surgery and its limitations.

BACKGROUND: Surgery is still the standard treatment for aggressive fibromatosis (AF); however, local control remains a significant problem and the impact of R0 surgery on cumulative recurrence (CR) is objective of contradictory reports. METHODS: This is a single-institution study of 62 consecutive patients affected by extra-abdominal and intra-abdominal AF who received macroscopically radical surgery within a time period of 15 years. RESULTS: Definitive pathology examination confirmed an R0 situation in 49 patients and an R1 in 13 patients. Five-year CR for patients who underwent R0 vs R1 surgery was 7.1% vs 46.4% (P = 0.04) and for limbs vs other localizations 33.3% vs 9.9% (P = 0.02) respectively. In 17 patients who had intraoperative frozen section (IFS) margin evaluation R0 surgery was more common (17 of 17 vs 32 of 45, P = 0.01) and CR lower (five-year CR 0% vs 19.1%, respectively, P = 0.04). However, in multivariate analysis only limb localization showed a negative impact on CR (HR: 1.708, 95% CI 1.03 to 2.84, P = 0.04). CONCLUSIONS: IFS evaluation could help the surgeon to achieve R0 surgery in AF. Non-surgical treatment, including watchful follow-up, could be indicated for patients with limb AF localization, because of their high risk of recurrence even after R0 surgery.

Sarcoma spreads primarily through the vascular system: are there biomarkers associated with vascular spread?

Sarcomas are a heterogeneous group of tumors with specific molecular characteristics and currently classified on the basis of their tissue of origin and histologic appearance. Except for epithelioid sarcoma, clear cell sarcoma, angiosarcoma and rhabdomyosarcoma, which may spread to regional lymph nodes, the other histotypes spread via the vascular system to the lungs most of the time. A variety of molecular approaches, including gene expression profiling, have identified candidate biomarkers and generated insights into sarcoma biology. The comprehension of the pathogenesis of this malignancy according to the mesenchymal stem cell hypothesis parallels the description of several molecular pathways deregulated in sarcoma. Individuation of vascular spread biomarkers is actually focused on the study of factors involved both in hemostasis and angiogenesis. Interestingly the microenvironment of sarcomas showed the very same mesenchymal origin of the surrounding stromal cells. The presence of circulating tumor cells and miRNAs in blood samples of sarcoma patients represents the possibility not only to better stratify patients group according to the prognosis but also to tailor new individualized therapy. So, it could be predicted that some genes expressed in a specific sarcoma might have prognostic significance or therapeutic targeting potential and molecular targets can be identified in the tumor or in the tumor microenvironment. Therefore the initial evaluation of a sarcoma patient should include in-depth genetic evaluation including karyotyping and c-DNA/protein expression profiling. The chemokine signaling demonstrated to be deeply implicated in sarcoma development as well as to have a significant role in development of metastatic disease, especially in directing tumor cells towards the preferential sites of metastases in sarcoma, lung and bone. It is unsolved if the blood stream is a more favorable environment compared to lymphatic or if lymph nodes are more efficient in destroying metastatic sarcoma cells. But the comprehension of the regulatory mechanisms of the behavior of mesenchymal malignant tumors is at its dawn.

Local and intralesional therapy of in-transit melanoma metastases.

Regional relapse of melanoma may occur as satellite or in-transit metastases proximal to the primary tumor in the direction of the lymph flow. The management of in-transit metastases is challenging because the efficacy of treatment is largely dictated by the biological behavior of the patient's melanoma. This review examines local treatment modalities.

Diagnostic and therapeutic imaging for cancer: therapeutic considerations and future directions.

As cancer treatment cost soar and the mantra for "personalized medicine" grows louder, we will increasingly be searching for solutions to these diametrically opposed forces. In this review we highlight several exciting novel imaging strategies including MRI, CT, PET SPECT, sentinel node, and ultrasound imaging that hold great promise for improving outcomes through detection of lymph node involvement. We provide clinical data that demonstrate how these evolving strategies have the potential to transform treatment paradigms.

Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach.

Electroporation uses pulsed, high-intensity electric fields to temporarily increase cell membrane permeability by creation of pores, through which small molecules, such as chemotherapeutic agents, can diffuse inside cells before they reseal. The combination of electroporation with the administration of otherwise low-permeant cytotoxic drugs is known as electrochemotherapy (ECT). The two most commonly used drugs are bleomycin and cisplatin. ECT has already been proven to be effective in diverse tumor histotypes, including melanoma and basal and squamous cell carcinoma, Kaposi sarcoma, and breast cancer, also in those cases nonresponding to classical chemotherapies or other loco-regional treatment modalities, with a good safety profile. ECT can be proposed as loco-regional therapy for disseminated cutaneous and subcutaneous tumor lesions as alternative treatment modality to conventional therapies or as palliative care, in order to improve patients' quality of life.

Radio-guided ultrasound lymph node localization: feasibility of a new technique for localizing and excising nonpalpable lymph nodes ultrasound suspicious for melanoma metastases.

Identification of lymph nodes suspicious for metastases is crucial in melanoma patients during the follow-up. We propose a procedure called radio-guided ultrasound lymph node localization (RULL) for melanoma patients with ultrasound (US) suspicious, not palpable, lymph nodes. The aim of this study was to evaluate the feasibility of this technique, and to assess the efficacy of this new method. RULL was applied in 12 consecutive melanoma patients with non-palpable lymph nodes found suspicious for metastases during US follow-up. Macro-aggregates of human serum albumin labelled with diluted technetium-99m were injected into the suspected lymph node under US guidance and followed by a scintigraphy. The surgical treatment was carried out with the support of hand-held gamma-probe used for sentinel node biopsy. The tracer was correctly positioned in all 12 patients. Pathological examination revealed seven patients with metastatic lymph nodes, four with no metastatic lymph node, one patient with Hodgkin disease. No surgical complications were described. In conclusion, RULL may integrate the standard ultrasound-guided fine-needle aspiration to improve the diagnostic accuracy on US suspicious nodes and might replace the more logistically complicated wire identification or less accurate cutaneous marker identification of these nodes. Sensibility and specificity of this approach should be defined through a large multicentric study.

Pelvic sentinel lymph node biopsy in melanoma patients: is it worthwhile?

The original procedure of intraoperative lymphatic mapping by using vital blue dye initially described by Morton and colleagues in 1992 was implemented in subsequent years by the introduction of preoperative lymphoscintigraphy (LS) and intraoperative gamma detection probe to allow a better identification of sentinel nodes (SNs). However, it is common, in practice, to detect more than one radioactive node with the gamma detection probe. Whether these additional lymph nodes represent true SNs is not yet clear. The aims of this study are: to investigate the role of pelvic sentinel node biopsy in recurrent pelvic disease in those patients with negative inguinal SN, having one or more deep hot spots identified by preoperative LS (follow-up group). One hundred and four stage I/II melanoma patients with primary tumor of the lower limb and lower trunk were enrolled in a restrospective study at the European Institute of Oncology, Milan, Italy, between 2000 and 2007. All patients presented hot spots both in superficial (groin) and deep (iliac-obturator) areas during dynamic LS. The study population consisted of 35 men and 69 women with a median age of 57 years at the time of diagnosis. The median follow-up period was 49 months (SD 22.4; range, 10-98 months). Of the 104 patients, 83 had a negative SN (80%). All sentinel-lymph-node-positive patients underwent superficial and deep inguinal dissection. Two patients (2.4%; 95% confidence interval: 1.5-8.8%) with negative SNs had pelvic recurrence. Among patients who underwent ilioinguinal dissection, three (14%; 95% confidence interval: 4-35%) had positive pelvic lymph nodes. After a 60-month follow-up, 79% of patients were alive and 66% were disease free. In SN-negative patients, disease-free survival was 69% and in SN-positive patients 53%. No significant difference was found by SN status (log-rank P values 0.15). Even if the sample size of our study cannot bring to conclusive results, and further studies are needed, it might be possible that harvesting pelvic SN in those patients with pelvic hot spots at LS could modify the natural history of melanoma patients in terms of pelvic recurrence and disease free survival. We recommend to improve our knowledge in the role of pelvic sentinel node in the natural history of melanoma.

Cutaneous melanoma in the elderly.

The aim of this review was to analyze the difficulties in diagnosing and treating elderly patients with cutaneous melanoma. It focused on the main causes for late diagnosis and relatively poor prognosis in these patients. Early detection of melanoma is vital to reduce mortality in these patients and surgery is often curative. Adequate treatment of elderly patients with melanoma requires knowledge of the clinical features and histopathology of the disease, and the therapeutic options. This review also examined the main surgical procedures for primary melanoma and regional lymph node staging, and the curative and palliative procedures indicated for those elderly patients with advanced disease. It is expected that several molecular genetic factors will soon provide further prognostic information of possible benefit for elderly patients with melanoma.

Modification of lymphoscintigraphic sentinel node identification before and after excisional biopsy of primary cutaneous melanoma.

The aim of this study was to determine whether excision biopsy and primary closure of primary cutaneous melanoma modifies lymphatic drainage and accuracy of sentinel node biopsy. Thirty patients with 31 cutaneous melanomas were prospectively enrolled to undergo lymphoscintigraphy (LS) before and after excision biopsy. Tc-human serum albumin nanocolloid was first injected intradermally around the primary tumor and subsequently, after excision biopsy, adjacent to the scar. Sentinel nodes were identified by preoperative LS and the gamma-probe. Patent Blue V dye was injected intraoperatively before sentinel node biopsy. Intraoperative sentinel node identification was 100%. In 23 of 31 cases, both LSs were concordant in terms of nodal basins visualized. Two patients had a basin downstaged and six patients had a basin upstaged by the second LS. Only 50% of LS hot nodes stained blue (42 of 84). In 24 of 31 cases, the sentinel node was negative for metastases. Seven patients underwent complete lymph node dissection because of sentinel node positivity. Only one patient had metastases also to a non-sentinel node. After a median follow-up of 30 months lymph node metastases have not been observed in the eight discordant cases. This study shows that sentinel node identification and biopsy after lymphatic mapping is accurate after excision biopsy of primary cutaneous melanoma. Excision biopsy may, however, modify lymphatic drainage and a narrow excision margin should be performed if melanoma is suspected.

A report of six cases of familial papillary thyroid cancer.

AIMS: Familial occurrence of papillary thyroid cancer is uncommon. The purpose of this study was review our own experience in a series of 267 papillary thyroid cancers. METHODS: We analysed the clinical records of 267 consecutive patients operated on for papillary thyroid cancer (PTC) in our hospital between June 1980-March 2000. RESULTS: We identified a family history in three families (6 patients), which results in a 2.25% familial papillary thyroid carcinoma (FPTC) rate. Pathology findings revealed that the tumour was multifocal and bilateral in 2 patients. Lymph-node metastases were found in 4 patients. They are all alive with a mean time of follow-up of 74.3 months (range 2-120). CONCLUSIONS: We recommend that patients with familial disease should be treated according to the disease stage and other risk factors, similar to those with sporadic differentiated papillary thyroid cancer. We encourage the further reporting and pedigree analysis to identify patients affected by FPTC.