Analysis of efficacy and safety of vismodegib therapy in patients with advanced basal cell carcinoma - real world multicenter cohort study.

BACKGROUND: Basal cell carcinoma (BCC) is the most frequent non-melanoma skin cancer. The basis of treatment is surgical resection. The treatment of locally advanced and metastatic disease is currently based on sonidegb or vismodegib, small molecule inhibitors of the hedgehog signalling pathway. OBJECTIVES: The study aimed to retrospectively analyse the efficacy and safety of treatment with vismodegib in 108 patients with locally advanced or metastatic disease treated from August 1st, 2017 to December 31st, 2020. The primary objective was to evaluate the objective response rate (ORR), overall survival (OS) and progression-free survival rates. The secondary aims of the study were the disease control rate, the incidence of adverse events (AEs) and the estimation of the factors that potentially impact the treatment outcome and patient survival. METHODS: Patients treated in national drug programme were enrolled into this retrospective cohort study. Evaluation of the treatment efficacy was performed according to CT/MRI scans and by the response evaluation criteria in solid tumours (RECIST) 1.1. The safety evaluation was performed according to the Common Terminology Criteria for Adverse Events v. 5.0 (CTCAE) classification and severity assessment. RESULTS: The median duration of treatment was 14 months (range 1-94 months). The median progression-free survival reached 30.5 months (95% CI; 24.8-36.3), and the progression-free survival rate after 6, 12 and 24-months were 92%, 78% and 61%, respectively. The median overall survival was 41.5 months (95% CI; 31.6-51.3), and the overall survival rate after 1, 2 and 3 years accordingly 86%, 73% and 60%. The univariant and multivariant analysis indicated that the female gender is an independent positive prognostic factor of progression-free survival. CONCLUSIONS: The response to treatment is the prognostic factor for response maintenance and better overall survival. The therapy was well tolerated with the safety profile consistent in general with known from previous studies.

Long-term results of treatment of advanced dermatofibrosarcoma protuberans (DFSP) with imatinib mesylate - The impact of fibrosarcomatous transformation.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is rare, infiltrating dermal neoplasm, characterized by indolent growth and low probability of metastases. The first effective systemic therapy in DFSP introduced into clinical practice was imatinib, demonstrating high activity in advanced cases. The aim of the study was to perform an analysis of patients with advanced DFSP treated with imatinib, with or without surgery, in routine clinical practice with long-term follow-up. PATIENTS AND METHODS: We analyzed the data of 31 Caucasian patients (14 male, 17 female; median age 56 years) with locally advanced/initially inoperable and/or metastatic DFSP who started therapy with imatinib at initial dose 800 mg daily between 12/2004 and 07/2014. All diagnoses were confirmed cytogenetically for the presence of specific COL1A1-PDGFB fusion. Median follow-up time was 5.3 years. RESULTS: Metastases were present in 15 cases (8 - lungs, 5 - soft tissue, 2 - lymph nodes). Fibrosarcomatous transformation (FS-DFSP) was confirmed in 16 patients (52%). 5-year progression-free survival (PFS) rate was 58% (median 6.8 years), 5-year overall survival (OS) rate was 64% (median time for OS was not reached). The shorter PFS and OS correlated with FS-DFSP and presence of metastatic disease. 5-year PFS rate was 93% for classic DFSP and 33% for FS-DFSP. The best overall responses were: 21 partial responses (68%, including 8 FS-DFSP, but the responses were shorter than for classic DFSP), 6 stable disease (19%) and 4 progressive diseases (13%). Thirteen patients (47%) underwent resection of residual disease and nine of them remained free of disease, although imatinib was discontinued. Median survival after progression on imatinib was 19 months, and longer survival were observed only in cases were rescue surgery/radiotherapy was possible. CONCLUSIONS: Our results indicate the long-term activity of imatinib in therapy of inoperable and/or metastatic cases of DFSP, including FS-DFSP. Some DFSP patients initially evaluated as unresectable/metastatic or necessitating mutilating surgery turned resectable after imatinib therapy and this rational approach leading to complete remission maybe potentially curative.

Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas.

BACKGROUND: The primary treatment of soft tissue sarcomas (STS) is a radical resection of the tumor with adjuvant radiotherapy. Conventional fractionation of preoperative radiotherapy is 50 Gy in fraction of 2 Gy a day. The purpose of the conducted study was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in STS patients. METHODS: 272 patients participated in this prospective study conducted from 2006 till 2011. Tumors were localized on the extremities or trunk wall. Median tumor size was 8.5 cm, 42% of the patients had tumor larger than 10 cm, whereas 170 patients (64.6%) had high grade (G3) tumors. 167 patients (61.4%) had primary tumors. Patients were treated with preoperative radiotherapy for five consecutive days in 5 Gy per fraction, with an immediate surgery. Median follow up is 35 months. RESULTS: 79 patients died at the time of the analysis, the 3-year overall survival was 72%. Local recurrences were observed in 19.1 % of the patients. Factors that had a significant adverse impact on local recurrence were tumor size of 10 cm or more and G3 grade. 114 patients (42%) had any kind of treatment toxicity, vast majority with tumors located on lower limbs. 7% (21) of the patients required surgery for treatment of the complications. CONCLUSION: In this non-selected group of locally advanced STS use of hypofractionated preoperative radiotherapy was associated with similar local control (81%) when compared to previously published studies. The early toxicity is tolerable, with small rate of late complications. Presented results warrant further evaluation.

The analysis of the outcomes and factors related to iliac-obturator involvement in cutaneous melanoma patients after lymph node dissection due to positive sentinel lymph node biopsy or clinically detected inguinal metastases.

BACKGROUND: We assessed clinical-pathological features and outcomes of cutaneous melanoma patients after ilio-inguinal lymph node dissection (LND) in relation to the presence of metastases in iliac-obturator nodes. METHODS: We analyzed 390 consecutive patients who underwent ilio-inguinal therapeutic LND [TLND] (237) due to clinical/cytologically detected metastases or after completion LND [CLND] (153) due to positive SLN biopsy (in one cancer centre 1994-2009). Median follow-up time was 60 months. RESULTS: The 5-year overall survival (OS) rate was 49% and median OS - 52 months in the entire group of patients. According to univariate analysis following factors had significant negative influence on OS: presence of metastases to iliac-obturator nodes (5-year OS for positive versus negative: 54.5% and 32%, respectively), macrometastases, higher Breslow thickness, ulceration, higher Clark level, male gender, number of metastatic lymph nodes, extracapsular extension, and, additionally in the CLND group - micrometastases size ≥ 0.1 mm according to the Rotterdam criteria and non-subcapsular location of micrometastases. Iliac-obturator involvement was also negative factor for OS in multivariate analysis. The presence of iliac-obturator nodal metastases correlated with the following factors: type of LND-CLND versus TLND (15% versus 27.5%) of iliac-obturator involvement, respectively), higher Breslow thickness, extracapsular extension of nodal metastases, male gender. We have not identified any metastases in iliac-obturator nodes in group of patients with micrometastases size ≤1.0 mm and primary tumour Breslow thickness <4.0 mm or no ulcerated primary tumours. CONCLUSIONS: Metastases to iliac-obturator nodes have additional negative prognostic value for melanoma patients with inguinal basin involvement. We are able to identify the subgroup of patients after positive SLN biopsy without metastases to iliac-obturator nodes, probably requiring only inguinal LND.

Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour - the impact of tumour rupture on patient outcomes.

BACKGROUND: Approval of imatinib for adjuvant treatment of gastrointestinal stromal tumours (GIST) raised discussion about accuracy of prognostic factors in GIST and the clinical significance of the available risk stratification criteria. METHODS: We studied the influence of a new modification of the NIH Consensus Criteria (the Joensuu risk criteria), NCCN-AFIP criteria, and several clinicopathological factors, including tumour rupture, on relapse-free survival (RFS) in a prospectively collected tumour registry series consisting of 640 consecutive patients with primary, resectable, CD117-immunopositive GIST. The median follow-up time after tumour resection was 39 months. None of the patients received adjuvant imatinib. RESULTS: The median RFS time after surgery was 50 months. In univariable analyses, high Joensuu risk group, tumour mitotic count >5/50 HPF, size >5 cm, non-gastric location, tumour rupture (7% of cases; P = 0.0014) and male gender had adverse influence on RFS. In a multivariable analysis mitotic count >5/50HPF, tumour size >5 cm and non-gastric location were independent adverse prognostic factors. Forty, 151, 86 and 348 patients were assigned according to the Joensuu criteria to very low, low, intermediate and high risk groups and had 5-year RFS of 94%, 94%, 86% and 29%, respectively. CONCLUSION: The Joensuu criteria, which include 4 prognostic factors (tumour size, site, mitotic count and rupture) and 3 categories for the mitotic count, were found to be a reliable tool for assessing prognosis of operable GIST. The Joensuu criteria identified particularly well high risk patients, who are likely the proper candidates for adjuvant therapy.

In transit/local recurrences in melanoma patients after sentinel node biopsy and therapeutic lymph node dissection.

This study has analyzed the incidence of in transit/local recurrences (IT/LR) in melanoma patients after sentinel node (SLN) biopsy; completion lymph node dissection (CLND) that was performed due to positive node; and therapeutic LND (TLND) due to clinically detected node metastases and factors influencing IT/LR. Between May 1995 and May 2004, 1187 consecutive patients underwent SLN biopsy (median Breslow thickness 2.5 mm) and 224 of them had subsequent CLND. During the same time period, 306 patients had TLND (median Breslow 3.9 mm). The excision margin of primaries was > or =1cm. At median follow-up time of 37.5 months, we analyzed the incidence of IT/LR as the first site of relapse and clinicopathological parameters affecting these recurrences. In SLN-negative cases, IT/LR as the site of the first recurrence were rare (46/963; 4.8%) and; in SLN+/-CLND IT/LR were detected in 45/224 cases (20.1%). IT/LR in SLNB group correlated with presence of SLN metastases (P<0.0001), higher Breslow thickness (P<0.001) and lower extremity localization (P=0.03). In TLND group, IT/LR were observed in 52/306 patients (17%), which is similar to all CLND patients (P=0.3), but less common when analyzing only patients who relapsed (TLND: 52/209 (24.9%) vs. CLND: 45/121 (37.2%); P=0.02). Estimated 3-year overall survival (from the date of relapse) in IT/LR only patients was better than in other types of relapses after LND (29% vs. 8%; P<0.0001). IT/LR incidence in the entire group of SLN+/-CLND patients was similar to that observed in TLND patients and it was affected by presence of nodal metastases, Breslow thickness and lower extremity location.

Adamantylaminopyrimidines and -pyridines are potent inducers of tumor necrosis factor-alpha.

A series of (1-adamantyl)aminopyrimidine and -pyridine derivatives was prepared by adamantyl cation attack on amino heterocycles. The adamantylated compounds, particularly 2-(1-adamantyl)amino-6-methylpyridine, were found to be potent TNF-alpha inducers in murine melanoma cells transduced with gene for human TNF-alpha.

Synthesis, structure and tumour necrosis factor-alpha production-enhancing properties of novel adamantylamino heterocyclic derivatives.

The synthesis of several adamantylated aminoheterocycles is reported. The attack of the adamantyl cation formed from 1-adamantanol in refluxing trifluoroacetic acid or induced by microwave irradiation provides adamantylamino-derivatives of respective heterocycles. Adamantylated heterocycles enhance the induction of tumour necrosis factor alpha (TNF-alpha) in genetically modified murine melanoma cells transduced with the gene for human TNF-alpha. Of the studied collection of adamantylated compounds, the most biologically active are 2-adamantylamino-6-methylpyridine and 2-adamantylamino4-methylpyrimidine. The crystal structure of 2-adamantylamino-6-methylpyridine is reported.

Lovastatin potentiates antitumor activity and attenuates cardiotoxicity of doxorubicin in three tumor models in mice.

Lovastatin, a drug commonly used in the clinic to treat hypercholesterolemia, has previously been reported to exert antitumor effects in rodent tumor models and to strengthen the antitumor effects of immune response modifiers (tumor necrosis factor alpha and IFN-gamma) or chemotherapeutic drugs (cisplatin). In the present report, we show in three murine tumor cell lines (Colon-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) that lovastatin can also effectively potentiate the cytostatic/cytotoxic activity of doxorubicin. In three tumor models (Co-ion-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (15 mg/kg for 10 days) and doxorubicin (3 x 2.5 mg/kg; cumulative dose, 7.5 mg/kg) as compared with either agent acting alone. Lovastatin treatment also resulted in a significant reduction of troponin T release by cardiomyocytes in doxorubicin-treated mice. This observation is particularly interesting because lovastatin is known to reduce doxorubicin-induced cardiac injury.

Interleukin 12 and indomethacin exert a synergistic, angiogenesis-dependent antitumor activity in mice.

Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence and mortality from colorectal cancer. It has recently been demonstrated that these drugs are capable of suppressing the production of pro-angiogenic factors from tumor cells. The mechanisms of antitumor action of interleukin 12 include the enforced secretion of anti-angiogenic factors and stimulation of antitumor immunity. Therefore, we hypothesized that the combination of a model nonsteroidal anti-inflammatory drug--indomethacin and interleukin 12--would result in enhanced angiogenesis-dependent antitumor effects against a colon-26 carcinoma cells transplanted into syngeneic mice. As expected the combined administration of both agents simultaneously resulted in a strengthened antitumor activity that was manifested as a retardation of tumor growth and prolongation of mouse survival. Importantly some mice were completely cured after the combined treatment. As administration of interleukin 12 and indomethacin resulted in enhanced inhibition of angiogenesis it seems possible that prevention of new blood vessel formation is one of the mechanisms responsible for the observed antitumor effects.

Antitumor effects of the combination therapy with TNF-alpha gene-modified tumor cells and interleukin 12 in a melanoma model in mice.

In the present study, TNF-alpha gene-transduced B78 melanoma cells (B78/TNF) were used as a vaccine and combined with interleukin (IL)-12 in the treatment of B78 melanoma-bearing mice. The combined administration of genetically modified melanoma cells and IL-12 induced specific protective antitumor immunity resulting in a decreased rate of the tumor take following a rechallenge with parental B78 cells. When used therapeutically, intratumoral injections of irradiated B78/TNF melanoma cells and IL-12 exerted strong antitumor effects and led to complete regression of established tumors in 50% of mice. Injections of irradiated B78/TNF cells alone did not influence tumor development and IL-12 itself significantly delayed tumor growth but without curative effect. FACS analysis of parental B78 melanoma cells and its B78/TNF genetically modified variant showed that a proportion of cells of both cell lines expressed 87-1 (CD80) costimulatory molecule and that the expression of this molecule was increased during incubation with IFN-gamma. Moreover, IFN-gamma markedly augmented expression of major histocompatibility class (MHC) class I and II molecules on B78/TNF cells that were primarily MHC class I and II negative with no substantial effect on MHC-negative parental B78 melanoma. IFN-gamma also synergized in cytostatic/cytotoxic effects with TNF-alpha against B78 melanoma in vitro. Lymphocyte depletion studies in vivo showed reduction of the antitumor response in mice treated with anti - NK monoclonal antibodies (mAbs) as well as in mice treated with anti-CD4+ anti-CD8 mAbs. The results suggest that, when used therapeutically, IL-12 and a vaccine containing TNF-alpha gene-transduced tumor cells may reciprocally augment their overall antitumor effectiveness by facilitating development of systemic antitumor immunity and by stimulating local effector mechanisms of the tumor destruction.

Subtherapeutic doses of interleukin-15 augment the antitumor effect of interleukin-12 in a B16F10 melanoma model in mice.

Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that exhibits antitumor activity in many experimental tumor models. In the present study, we investigated the ability of IL-15, a cytokine sharing many functions of IL-2, to modulate antitumor effectiveness of IL-12 against B16F10 melanoma in mice. In a model of locally growing tumor, intratumoral (i.t.) administration of IL-12, in three cycles of five consecutive daily injections (0.1 mug) followed by 2 days of rest, led to considerable delay of tumor development but no curative response was achieved. When combined with IL-12, subtherapeutic doses of IL-15 (0.4 mug) pontentiated the antitumor effects of IL-12 and induced complete tumor regressions in 50% of mice. Similar results were obtained in a model in which tumor-bearing mice were intravenously co-injected with melanoma cells to induce metastases. Combined administration of IL-12 and IL-15 yielded greater antitumor activity than injections of either cytokine alone and resulted in prolonged survival of mice bearing locally growing tumor and metastases. Studies of immunological parameters in mice treated with both IL-12 and IL-15 have shown enhanced NK activity (against YAC-1 cells) in the spleen and stimulation of both NK activity and specific anti-B16F10 cytotoxic effector cells in tumor-draining lymph nodes (LN). The strong antitumor effect of the IL-12 + IL-15 combination correlated with a high serum level of IFN-gamma in the treated mice. Moreover, increased expression of IL-15Ralpha was demonstrated in LN lymphocytes isolated from mice injected with IL-12. This result together with findings of other authors showing enhanced expression of IL-12 receptor by IL-15 [1] suggests that the augmentation of the antitumor effect during the course of IL-12/IL-15-based therapy could result from reciprocal upregulation of receptors by both cytokines and synergistic effects on IFN-gamma induction.