Current and developing therapies for the treatment of non-small cell lung cancer with ALK abnormalities: update and perspectives for clinical practice.

INTRODUCTION: The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies. In addition, early clinical data demonstrated that 3rd generation ALK-inhibitors Lorlatinib (PF-06463922), Entrectinib (RxDx-101) and Ensartinib (X-398) provided promising advantages in terms of both clinical activity and safety. Areas covered: In this review, the efficacy and tolerability of Crizotinib for 1st and 2nd-line treatment, and the clinical and preclinical data that led to the development of innovative second and third generation ALK-inhibitors are described. Expert opinion: The better characterization of the mechanisms of resistance to Crizotinib led to the development of newest drugs, which are active both after Crizotinib failure and in patients naïve from ALK-inhibitors. Tumor characterization at disease progression will allow to further personalize the treatment by establishing optimal sequences, which represent tough challenges for the future research in this field of cancer treatment.

Postsurgical adjuvant therapy for melanoma. Evaluation of a 3-year randomized trial with recombinant interferon-alpha after 3 and 5 years of follow-up.

BACKGROUND: Early surgical intervention is still the most successful therapy for patients with melanoma. The results obtained with medical therapies are still quite disappointing, with better results observed in soft tissue and lymph node metastasis. There currently is no standardized adjuvant therapy for primary melanoma. On the basis of the activity demonstrated in vitro against melanoma cell lines and the results obtained in many clinical trials in patients with advanced melanoma, the authors chose to study the use of recombinant interferon-alpha (IFN-alpha) as adjuvant therapy for patients with Stage I and Stage II melanoma. METHODS: A randomized multicenter trial based on the use of recombinant IFN-alpha-2b for 3 years at the dose of 3 MU given intramuscularly 3 times a week for a period of 6 months with a 1-month interval between cycles was conducted in Stage I and Stage II melanoma patients (using the American Joint Committee on Cancer classification). The efficacy of this treatment was evaluated calculating the incidence of recurrence after 3 and 5 years. RESULTS: Results were collected at the end of the treatment period and after 5 years of follow-up for a smaller number of patients. Statistical evaluation showed a significant difference between treated patients and untreated controls with regard to progression of the disease. In particular, IFN-alpha appears to be more effective in patients with worse prognosis lesions. CONCLUSIONS: IFN-alpha appears to be effective as adjuvant therapy for high risk melanoma patients and the risk/benefit ratio appears to be very favorable. The authors' next goal is to separate those patients who might benefit from adjuvant therapy from those who are cured after the surgical intervention only.

Giant molluscum contagiosum in AIDS.

A 31-year-old man, an intravenous drug user and in an advanced stage of acquired immune deficiency syndrome (AIDS), was admitted in our Department for the treatment of skin lesions that had been diagnosed as molluscum contagiosum (MC). The clinical examination revealed the presence of multiple nodular lesions, some of which were notably large and whose color resembled that of normal skin. These lesions were localized mainly to the face, and in particular on the forehead, glabellar, malar, beard, submandibular, and neck regions (Fig. 1). Smaller, crateriform lesions were detected on the hands and the upper limbs. The lymphocyte subsets ratio was 0.02, with a CD4+ T cell count of 13 cells per mm3 (1%) and a CD8+ T cell count of 624 per mm3 (48%). The patient also had leukopenia (1690 WBC per mm3), moderate macrocytic anemia, elevation of transaminases (SGOT 105 U/L, SGPT 114 U/L) and of immunoglobulins (IgG 2660 mg/dL), and a decrease of C3 (44.2 mg/dL) and C4 (16.6 mg/dL). Histologic examination revealed the presence of typical MC lesions. In addition to an important acanthosis, it was possible to detect pyriform lobules of perfectly delineated epidermal cells, radially separated by fibrous septa that merge towards the central crater. The characteristic MC eosinophil bodies were observed in infected cells (Fig. 2). The lesions were treated with cryosurgery by spray. Many courses of therapy were given with intervals of 2-3 weeks. Every session consisted of two cycles of rapid freezing followed by a slow thaw. Many lesions disappeared with this treatment, and others were reduced in size, but total destruction of all lesions was not achieved (Fig. 3).