Preoperative-postoperative immunotherapy as treatment of borderline resectable and oligoprogressive stage III B-D and IV melanoma.

INTRODUCTION: Perioperative therapy has gained significant importance in patients with advanced melanoma. Currently, there is little data on the routine use of preoperative immunotherapy in metastatic melanoma outside clinical trials. This study aimed to evaluate the effectiveness of preoperative treatment in patients with borderline resectable stage III or IV melanoma as well as in oligoprogressing stage IV cases; the secondary aim is to describe the safety of surgery after immunotherapy. MATERIALS AND METHODS: Since 1/Jan/2016 seventeen patients were treated with curative intent neoadjuvant immunotherapy, surgery, and adjuvant immunotherapy, while nineteen patients were operated due to oligoprogression while treted with immunotherapy. Survival was analyzed using the Kaplan-Meier method and association between variables was tested using the chi-squared test. RESULTS: R0 resection was achieved in 76.5 % of cases after neoadjuvant immunotherapy. 24 % of patients achieved objective RECIST response and 35 % complete or major pathological response. At the median follow-up time of 51.4 months, 64.7 % of patients were free of PD after perioperative treatment, while 3-year RFS and OS rates were 68 % and 80.9 %, respectively. R0 resection was achieved in 73.7 % of oligo-progressing nodules. The median time to PD on immunotherapy after the first oligoprogression was 10.3 months. Immunotherapy did not result in any unexpected surgical complications. No patient died during preoperative treatment due to immunotherapy toxicity or disease progression. CONCLUSIONS: We confirmed treatment safety and long-term disease control after perioperative immunotherapy. Patients with borderline resectable melanoma should be referred to reference centers using neoadjuvant immunotherapy.

Diagnostics and Treatment of Extrameningeal Solitary Fibrous Tumors.

Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms that account for less than 2% of all soft tissue masses. In the latest WHO 2020 Classification of Soft Tissue Tumors, extrameningeal SFT was listed as intermediate (rarely metastasizing) or malignant neoplasms. Due to the lack of characteristic clinical features, their diagnosis and treatment remain challenging. The pathogenesis of SFT is often associated with the presence of fusions of the NAB2-STAT6 gene on the 12q13 chromosome. Cytoplasmic CD34 positive staining is considerably characteristic for most SFTs; less frequently, factor XII, vimentin, bcl-2, and CD99 are present. A key factor in the diagnosis is the prevalent nuclear location of STAT6 expression. Radical resection is the mainstay of localized SFTs. In the case of unresectable disease, only radiotherapy or radio-chemotherapy may significantly ensure long-term local control of primary and metastatic lesions. To date, no practical guidelines have been published for the treatment of advanced or metastatic disease. Classical anthracycline-based chemotherapy is applicable. The latest studies suggest that antiangiogenic therapies should be considered after first-line treatment. Other drugs, such as imatinib, figitumumab, axitinib, and eribulin, are also being tested. Definitive radiotherapy appears to be a promising therapeutic modality. Since standards for the treatment of advanced and metastatic diseases are not available, further investigation of novel agents is necessary.

Conjunction of semi-mechanistic in vitro-in vivo modeling and population pharmacokinetics as a tool for virtual bioequivalence analysis - a case study for a BCS class II drug.

Virtual bioequivalence trial (VBE) simulations based on (semi)mechanistic in vitro-in vivo (IVIV) modeling have gained a huge interest in the pharmaceutical industry. Sophisticated commercially available software allows modeling variable drug fates in the gastrointestinal tract (GIT). Surprisingly, the between-subject and inter-occasion variability (IOV) of the distribution volumes and clearances are ignored or simplified, despite substantially contributing to varied plasma drug concentrations. The paper describes a novel approach for IVIV-based VBE by using population pharmacokinetics (popPK). The data from two bioequivalence trials with a poorly soluble BCS class II drug were analyzed retrospectively. In the first trial, the test drug product (biobatch 1) did not meet the bioequivalence criteria, but after a reformulation, the second trial succeeded (biobatch 2). The popPK model was developed in the Monolix software (Lixoft SAS, Simulation Plus) based on the originator's plasma concentrations. The modified Noyes-Whitney model was fitted to the results of discriminative biorelevant dissolution tests of the two biobatches and seven other reformulations. Then, the IVIV model was constructed by joining the popPK model with fixed drug disposition parameters, the drug dissolution model, and mechanistic approximation of the GIT transit. It was used to simulate the drug concentrations at different IOV levels of the primary pharmacokinetic parameters and perform the VBE. Estimated VBE success rates for both biobatches well reflected the outcomes of the bioequivalence trials. The predicted 90% confidence intervals for the area under the time-concentration curves were comparable with the observed values, and the 10% IOV allowed the closest approximation to the clinical results. Simulations confirmed that a significantly lower maximum drug concentration for biobatch 1 was responsible for the first clinical trial's failure. In conclusion, the proposed workflow might aid formulation screening in generic drug development.

Exploiting synergistic effects of brittle and plastic excipients in directly compressible formulations of sitagliptin phosphate and sitagliptin hydrochloride.

Direct compression (DC) is the simplest and most economical way to produce pharmaceutical tablets. Ideally, it consists of only two steps: dry blending of a drug substance(s) with excipients followed by compressing the powder mixture into tablets. In this study, immediate-release film-coated tablets containing either Sitagliptin phosphate or Sitagliptin hydrochloride were developed using DC technique. After establishing the optimum ratio of ductile and brittle excipients, five formulations were compressed into tablets using a rotary press and finally film coated. Both powders and tablets were examined by standard pharmacopoeial methods. It has been shown that the simultaneous use of excipients with different physical properties, i.e. ductile microcrystalline cellulose and brittle anhydrous dibasic calcium phosphate, produces a synergistic effect, allowing preparation of Sitagliptin DC tablets with good mechanical strength (tensile strength over 2 N/mm2), rapid disintegration (shorter than 2 min), and fast release of the drug substance (85% of the drug is dissolved within 15 min). It was found that the type of calcium phosphate excipient used had a large effect on the properties of the sitagliptin tablets. All formulations developed showed good chemical stability, even when stored under stress conditions (50 °C/80% RH).