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.

Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study.

BACKGROUND: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. PATIENTS AND METHODS: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. RESULTS: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. CONCLUSION: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.

Warfarin elimination and responsiveness in patients with renal dysfunction.

Plasma warfarin half-life was estimated in four patients with renal dysfunction and five normal control subjects. Hypoprothrombinemic responsiveness to a single oral dose of warfarin (0.75 mg/kg) was also evaluated for both groups. The mean warfarin half-life of 29.9+/-5.0 (S.E.M.) hours for renal patients was significantly shorter than the 44.8+/-6.0 hours half-life for normal controls (P less than 0.05). Additionally, a positive correlation was found between warfarin half-life and creatinine clearance. Pharmacologic responsiveness to warfarin was comparable for both groups. It therefore appears that patients with renal dysfunction do not possess an increased susceptibility, either pharmacokinetic or pharmacologic, to the hypoprothrombinemic effect of warfarin.

Influence of renal dysfunction on warfarin plasma protein binding.

The in vitro plasma protein binding of warfarin was evaluated by ultrafiltration in plasma from seven normal subjects and seven patients with varying degrees of renal dysfunction. The unbound, or free, warfarin fraction was twice as high in the plasma samples withdrawn from patients with renal impairment than in the samples obtained from normal volunteers. Furthermore, there was a positive correlation between the extent of renal dysfunction and the magnitude of the free warfarin fraction when either creatinine clearance, plasma creatinine, or BUN was used to estimate renal function.

Cestode transmission patterns.

The paradox of high prevalence but low probability of having an egg develop to an adult has been resolved by the evolution of 3 major and basic strategies involving transmission: evolution of life cycles interpolated into host biology; presentation of infective stages that increase probability of contact between host and parasite; and increase in reproductive potential. The rarity of direct cycles confirms that cycles in themselves, with at least 2 hosts, are a key element of cestode success because they provide a vehicle for dispersal and transmission of infective stages. Transmission is primarily by passive stages that become incorporated through intermediate hosts or accidentally in the food chain. High host specificity results from efficient transmission pathways but may represent a fragile system for the evolution of the species. Probability of transmission is increased through diversity of intermediate hosts, making eggs more susceptible to ingestion and by behavioral manipulation of hosts by parasite stages. Spatial and temporal aspects of transmission may be increased through paratenesis. Asexual proliferation of immature stages is uncommon and is favored where there is selective predation; such proliferation may be part of a transmission strategy of colonial cestodes that require high infrapopulations in order to survive. Hyperapolysis may be part of a transmission strategy used by the Tetraphyllidea, Trypanorhyncha, and Lecanicephalidea to increase proglottid production. The dynamics of transmission for cestodes of humans and domestic animals require a different perspective than those of wild hosts. All strategies are reviewed within the framework of certain cestode morphological and ecological constraints. A total of 11 figures and 48 references complements the text.

Etiology of uveitis in rural and urban areas of mid-eastern Poland.

The aim of this study was to assess and compare the frequencies of uveitis etiology in inhabitants of rural and urban areas of mid-eastern Poland. We reviewed the cases of 563 patients (263 males, 300 females; aged 2-87) with uveitis, treated at the 1st Department of Ophthalmology at the Medical Academy in Lublin and at the District Ophthalmic Hospital in Kielce, Poland, from January 1996-December 2000. Anatomical classification of uveitis was used according to the International Uveitis Study Group and etiological classification including uveitis associated with trauma, infection, systemic disease, non-associated with a systemic disease and masquerade syndromes. Data regarding age, gender, place of residence, anatomical location and etiology of uveitis were obtained. Statistical analyses were performed using Pearson's chi-square test, Spearman's rank correlation test and logistic regression. Etiology of uveitis was established in 70.0% of cases. The most common cause of uveitis was infection. Patients from rural areas were significantly more likely to have uveitis of infectious origin whereas patients from urban areas significantly more likely to have uveitis associated with a systemic disease. In conclusion, the pattern of uveitis in mid-eastern Poland confirms the influence of environmental factors on the etiology of this heterogenous disease.

[Case of subacute myelo-optico-neuropathy]. / Przypadek neuropatii rdzeniowo-ocznej.

A 52-year-old female patient is reported in whom after taking of about 20 g Clioquinol blindness and paralysis of extremities with urinary incontinence developed. Complete cure ensued.

[Vitrectomy in the treatment of endophthalmitis]. / Witrektomia w leczeniu zapalen wnetrza galki ocznej.

PURPOSE: To present our experience with the surgical management of endophthalmitis. MATERIAL AND METHODS: The results of 27 pars plana vitrectomies in 19 patients with clinical evidence of endophthalmitis were analysed. The endophthalmitis was considered as endogenous in 4 cases and exogenous in 15 cases. RESULTS: With the use of vitrectomy good anatomical and functional results were obtained. Pre-operative visual acuity was worse than 1/50 in 16 patients and ranged from 1/50 to 4/50 in 3 patients. Postoperative visual acuity was worse than 1/50 in 7 patients, ranged from 1/50 to 4/50 in 3 patients and was better than 5/50 in 9 patients. CONCLUSIONS: Pars plana vitrectomy in the management of endophthalmitis makes it possible to collect material for culture, removal of viable organisms and inflammatory products. In cases of posttraumatic endophthalmitis vitrectomy allows to prevent future complications.

[Retinitis due to cytomegalovirus in AIDS]. / Zapalenie siatkówki wywolane wirusem cytomegalii w przebiegu AIDS.

Clinical course of 4 AIDS patients suffering from CMV retinitis is presented. Two patients were treated with ganciclovir, one died before starting the treatment and one was vitrectomized with silicone oil injection. Of the two patients treated with ganciclovir one improved significantly when the other continued to deteriorate and died after 8 months of follow-up. Early diagnosis and treatment of patients with zone I involvement gives the best chances for improvement. Mean life expectancy in aids patients after diagnosis of CMV retinitis is 7-10 months.

[Histopathologic studies of the rabbit retina after use of perfluorodecalin]. / Badania histopatologiczne siatkówki królika po zastosowaniu perfluorodekaliny.

PURPOSE: To investigate the retinal toxicity of a vitreous substitute perfluorodecalin (PFD) in the rabbit eye up to 2 weeks after injection. MATERIAL AND METHODS: A space was created in the vitreous cavity by injecting 0.4 cc of perfluoropropane gas. After 3 days gas-fluid exchange was performed. Experimental eyes were injected with 1 cc of PFD and control eyes with 1 cc of Ringer solution. The eyes were enucleated 1, 3, 6 and 14 days after the procedure and histological studies were conducted. RESULTS: Control samples showed almost normal histology. One day after PFD injection photoreceptor nuclei dropout and migration below the outer limiting membrane, pyknosis and occasional densification of cell bodies were observed. After 3 days glial cell hypertrophy and accumulation of macrophages above the inner limiting membrane was also noted. After 6 days necrosis was observed in the outer and inner retinal layers. Foci of cell death in the retina were also observed 14 days after PFD injection. CONCLUSION: PFD induced degenerative changes in the rabbit retina within the first 24 hours after administration. Structural alterations in the inner and outer retina persisted within the two weeks of observation. Our results support the removal of PFD at the end of the primary surgical procedure.

[Diode laser trans-scleral cyclo-photo-coagulation]. / Przeztwardówkowa cyklofotokoagulacja laserem diodowym.

The purpose of this study is to present the results of treatment of refractory glaucoma with diode laser transscleral cyclophotocoagulation (DLCT). 88 patients (from 10 to 91 years old) were treated with diode laser. The follow up was 6 months. Mean intraocular pressure (IOP) before treatment was 38.2 mm Hg, 1 week after treatment--23.8 mm Hg, 1 month after treatment--21.3 mm Hg, after 6 months--19.0 mm Hg. We repeated treatment in 5 patients (5.6%). In 2 patients we observed hypotony--about 2 mm Hg. Diode laser cycloablation is a relatively safe and effective method in treatment of advanced refractory glaucoma.

[Localization of intraocular foreign bodies using computed tomography]. / Zastosowanie tomografii komputerowej (TK) w lokalizacji cial obcych wewnatrzgalkowych.

PURPOSE: To present the evaluation of computed tomography (CT) application for detecting the intraocular foreign bodies. MATERIAL AND METHODS: Sixteen computed tomographies of orbit to localise a foreign body were performed in the 2nd Radiology Department at Lublin University School of Medicine from May 1995 to October 1998. During examination 2 mm computed tomography cuts were taken. In almost all cases fundus examination was not possible because of hazy media (cataract, vitreous haemorrhage, endophthalmitis). Pars plana vitrectomy was applied to remove foreign body in all cases. RESULTS: In 14 cases a foreign body was localised inside the eye (3 of them were embedded in the wall of the eye) and in 2 cases a double perforation was noticed. With pars plana vitrectomy 12 of 14 intraocular foreign bodies were removed. Two foreign bodies deeply embedded in the wall of the eye were left. One of the two foreign bodies after double perforation was removed from the orbit and the second, which was localized deeply in the orbit, was left. CONCLUSION: The localisation of the foreign bodies using the computed tomography is a very accurate and sensitive method, facilitating further surgery.

[Intraretinal foreign bodies]. / Wewnatrzsiatkówkowe ciala obce.

PURPOSE: To present our experience with the removal of intraretinal foreign bodies. MATERIAL AND METHODS: 9 intraretinal foreign bodies were removed by pars plana vitrectomy. Laser photocoagulation of the retina surrounding the foreign body was performed either before surgery or intraoperatively (endolaser). Pars plana vitrectomy with foreign body removal through the sclerotomy site with endomagnet and/or forceps was performed. In some cases fluid-gas exchange was done. RESULTS: The average follow-up period was 6.2 months. Seven of nine foreign bodies were magnetic and two were nonmagnetic. Five of seven magnetic foreign bodies had negative magnetic traction as the first surgical procedure. In these 9 eyes, final visual acuity was below 1/50 in 2 eyes and over 5/50 in 7 eyes. CONCLUSION: Pars plana vitrectomy should be the method of choice in removal of intraretinal foreign bodies.

[Secondary glaucoma in the course of arterio-cavernous fistula: a case report]. / Jaskra wtórna w przebiegu przetoki tetniczo-jamistej--opis przypadku.

PURPOSE: To present a case of 59-year-old woman with the symptoms of redness, proptosis of her left eye and temporary bruit in her head. METHODS: Basic ophthalmological examination, measurement of proptosis, tonometry, visual field examination (Humphrey 30-2 threshold) CT, MRI and carotid angiography were performed. CLINICAL SIGNS: Proptosis of the left eye, dilatation of the episcleral vessels, fundus examination--optic disc normal, enlarged and engorged venous vessels, intraretinal haemorrhages in posterior pole. Tonometry--13 mm Hg--right eye, 24 mm Hg--left eye. Perimetry--general reduction of sensitivity. CT scan--abnormal structure (0.9 x 0.4 cm) in the medial part of the left orbit, without enhancement after applying contrast. MRI examination--enlargement of extraocular muscles of the left eye. Carotid artery angiography revealed indirect carotid--cavernous fistula. CONCLUSION: Special investigations like CT and MRI showed different picture, final diagnosis could be based upon the clinical picture and confirmed by angiography.

[Solar retinopathy]. / Retinopatia sloneczna.

The purpose of this study is the present clinical evaluation of 21 patients (number of affected eyes--33), who watched eclipse of the sun on 12 October 1996. All patients had general ophthalmic examination with emphasis on visual acuity, visual field, Amsler test, fluorescein angiography and fundus appearance. Eleven out of 21 patients had at least one follow up examination (number of affected eyes--17). None of the patient received any treatment. All patients revealed tiny, central scotomata--positive Amsler test and decreased visual acuity on the first visit; reading Snellen chart could be improved in all patients by adequate head tilt or eye movement (improvement up to 3 Snellen chart lines). No signs of retinopathy were observed in two eyes with uncorrected refractive error and one amblyopic eye. After 7-8 weeks the visual acuity was decreased to 5/30 in two eyes and to 5/10 in ten eyes. In all those eyes persisted a tiny, central scotoma. Looking at the eclipse of the sun in spite of using primitive eye protection may cause irreversible retinal damage. Return of visual acuity to 5/5 does not always imply complete recovery because of persistent central scotoma.

Vitellogenesis in Archigetes sieboldi Leuckart, 1878 (Cestoda, Caryophyllidea, Caryophyllaeidae), an intestinal parasite of carp (Cyprinus carpio L.).

Vitellogenesis in the caryophyllidean tapeworm Archigetes sieboldi Leuckart, 1878, from carp Cyprinus carpio L. in Slovakia, has been examined using transmission electron microscopy and cytochemical staining with periodic acid-thiosemicarbazide-silver proteinate (PA-TSC-SP) for glycogen. Vitelline follicles extend in two lateral bands in the medullary parenchyma along both sides of the monozoic body. They are surrounded by an external basal lamina and contain vitellocytes and an interstitial tissue. The general pattern of vitellogenesis is essentially like that of other caryophyllideans. It involves four stages: immature, early maturing, advanced maturing cells and mature vitellocytes. During vitellogenesis, a continuous increase in cell volume is accompanied by an extensive development of cell components engaged in shell globule formation, e.g. granular endoplasmic reticulum and Golgi. Shell globule clusters are membrane-bound. Nuclear and nucleolar transformation are associated with formation and storage of large amounts of intranuclear glycogen, a very specific feature of the Caryophyllidea. For the first time, (a) additional vitelline material in Archigetes is represented by lamellar bodies and (b) lipid droplets are described in the mature vitellocytes from vitelline follicles and vitelloduct of the Caryophyllidea. Our results indicate that there may be a double origin of lamellar bodies: either from the endoplasmic reticulum or through transformation of shell globule/shell globule clusters. Lamellar body clusters and some single lamellar bodies appear to have a membrane. Other ultrastructural features of vitellogenesis and/or vitellocyte in A. sieboldi from its vertebrate (fish) and invertebrate (oligochaete) hosts are briefly compared and contrasted with those in other caryophyllideans and/or Neodermata.

Gene-modified cellular vaccines: technologic aspects and clinical problems.

Activity in the cancer vaccine sector has quadrupled in the last decade. A number of therapeutic cancer vaccines are reaching the market. The huge number of clinical trials in progress is expected to undergo evaluation shortly. Whole cell tumor vaccines or gene-modified whole cells are being intensively tested in clinical trials. However, the specificity of the product makes the drug development process, including clinical trials, a considerable challenge. Their complex nature, standardization of manufacturing, and characterization often pose problems. Accordingly, to develop a well characterized controlled vaccine, more than a few factors need to be established. The final cell vaccine formulation must be characterized for product identity, purity, impurities, sterility, potency, cell viability, and total cell number. Therapeutic cancer vaccines show different clinical characteristics than cytotoxic anticancer agents. Unfortunately, the rules of clinical trial design for active immunotherapy have been adapted from the designs for examination of cancer chemotherapy. Accordingly, many research groups and clinical consortia have postulated modifications and unifications of existing clinical trial designs. A clinical development model has suggested that cancer vaccines be investigated in 2 categories of clinical trials: proof-of- principle and efficacy. Moreover, it is becoming clear that no drug demonstrates anticancer activity in all patients. Thus, intensive studies have been performed to seek specific biomarkers which could help stratify patients who are likely to respond to a particular treatment. This presents a big challenge beyond the analysis of the immune system status necessary to assess the effects of active immunotherapy.