Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial.

AIM: ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAFV600-mutated melanoma. METHODS: In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed. RESULTS: Of 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37-0.84; PStratified=0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; PStratified=0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53-78 versus 58%; 95%CI, 45-70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively. CONCLUSION: In patients with BRAFV600-mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT.

Morphological features of naevoid melanoma: results of a multicentre study of the International Dermoscopy Society.

BACKGROUND: Naevoid melanoma (NeM), a rare variant of melanoma, can be difficult to detect as its clinical and histopathological morphology can simulate a naevus. OBJECTIVES: To describe the clinical and dermoscopic features associated with NeM. METHODS: Lesions with a histopathological diagnosis of NeM were collected via an e-mail request sent to all members of the International Dermoscopy Society. All lesions were histopathologically reviewed and only lesions fulfilling a set of predefined histopathological criteria were included in the study and analysed for their clinical and dermoscopic features. RESULTS: Twenty-seven of 58 cases (47%) fulfilled the predefined histopathological criteria for NeM and were included in the study. Clinically, 16 of the 27 NeMs presented as a nodular lesion (59%), eight (30%) as plaque type and three (11%) as papular. Analysis of the global dermoscopic pattern identified three types of NeM. The first were naevus-like tumours (n = 13, 48%), typified by a papillomatous surface resembling a dermal naevus. In these lesions local dermoscopic features included irregular dots/globules (46%), multiple milia-like cysts (38%) and atypical vascular structures (46%). The second type were amelanotic tumours (n = 8, 30%), typified by an atypical vascular pattern (75%). The third type consisted of tumours displaying a multicomponent pattern (n = 4, 15%), characterized by classical local melanoma-specific criteria. Two lesions (7%) were classified as mixed-pattern tumours as they did not manifest any of the aforementioned patterns. CONCLUSIONS: While NeMs may be clinically difficult to differentiate from naevi, any papillomatous lesion displaying dermoscopically atypical vessels and/or irregular dots/globules should prompt consideration for the possible diagnosis of NeM.

Free light chains ratio as a marker to estimate prognosis and survival in patients with multiple myeloma and primary amyloidosis.

PURPOSE: The aim of this study was to evaluate the significance of free light chains ratio (FLC ratio) as a prognostic factor for remission, progression and survival in patients with multiple myeloma (MM) and primary amyloidosis. METHODS: The concentrations of immunoglobulins and FLC ratio were measured using immunonephelometry. A total of 101 patients from 3 different disease groups were investigated during a 7-year period: 1) MM (n=95); 2) nonsecretory multiple myeloma (NSMM) (n=3); and 3) primary amyloidosis (n=3). Reference range for FLC ratio was 0.26-1.65. RESULTS: According to the International Staging System (ISS) for MM, abnormal serum FLC ratio was < 0.03 or > 32. Patients with MM and highly or intermediately abnormal FLC ratio and a combination of adverse risk factors (56.9%) had median survival of 26 months (range 16-38), as opposed to patients with normal or slightly changed values of FLC ratio without adverse risk factors (43.1%) with median survival of 45 months (range 27-69). Also, all of the patients with NSMM had slightly changed values of FLC ratio corresponding to low risk of disease progression. In patients with primary amyloidosis, 33.3% had slightly changed values of FLC ratio corresponding to low risk of disease progression, as opposed to 66.7% with abnormal FLC ratio, corresponding to high risk. CONCLUSION: Abnormal FLC ratio in the examined groups could be an independent risk factor of disease progression and worse prognosis.

Adamantiades-Behçet's disease, deep venous thrombosis and anticardiolipin antibodies: report of two cases.

Vascular thrombosis was found in different proportions of patients with Adamantiades-Behçet's disease (ABD), depending on the ethnicity of the population under study. Various thrombophilic factors, including the levels of anticardiolipin antibodies (ACA), were investigated for their role in the thrombotic process with conflicting results. The prevalence of ACA varies considerably in different studies, but their presence has not been associated with increased risk for vascular thrombosis. We present two cases with ABD, deep venous thrombosis (DVT) and elevated levels of ACA that fulfil the criteria for both ABD and antiphospholipid syndrome (APS).

Pyoderma gangrenosum with spleen involvement and monoclonal IgA gammopathy.

A 46-year-old man with a 3-year history of pyoderma gangrenosum was admitted with ulceration (6 x 5 cm), on the right leg. Previously he had been treated with tapering doses of prednisone (maximum dose 1 mg/kg per day); however, he had had a few exacerbations following each taper of prednisone dose. Immunoelectrophoresis demonstrated monoclonal IgA gammopathy of lambda light chains. Abdominal echography and abdominal computed tomographic scan revealed multiple splenic abscesses. Treatment was started with oral prednisone (1 mg/kg per day) and cyclosporin (5 mg/kg per day) and 6 weeks later complete remission was achieved. Systemic involvement in pyoderma gangrenosum is very rare, and according to our knowledge there are only a few cases with spleen involvement.

Persistent erythema multiforme: a report of three cases.

Three cases of persistent erythema multiforme, two of unknown aetiology and one precipitated by influenza are reported. Lesions were widespread, mostly atypical in appearance and regressed in response to immunosuppressants (systemic steroids and/or azathioprine) or, in one case, to dapsone. One patient developed erythroderma responding eventually to etretinate. Histology in all patients was consistent with the mixed, epidermodermal pattern of erythema multiforme. There were no significant laboratory abnormalities nor marked symptomatology apart from itching. The persistent form appears to belong to the spectrum of erythema multiforme being heterogeneous with respect to inducing stimuli, including viral antigens, neoplastic or inflammatory disease or unknown causes. Whenever it is possible, treatment should be adjusted depending on the causative agent.

[Endemic nephropathy in the region of Bela Crkva in Banat]. / Endemska nefropatija u podrucju Bele Crkve u Banatu.

The village of Kusic is situated 8 km southwestern of Bela Crkva, at the very border, separated from Romania by the river Nera. Due to frequent disease occurrence in the village Kusic, the pelustration of population was done in 1978 and 1989, and during the later follow-up, many patients were examined either in hospital or in outpatient clinics. The aim was to confirm a suspicion on the existence of the focus of endemic nephropathy in the village of Kusic. In 1978 and 1989 abnormal proteinuria was found in 17.7% and 16.7% examines from the village of Kusic, respectively-significantly higher than in surrounding villages: Grebenac, Vracev Gaj, Banatska Palanka and Kruscica (p < 0.01). Slow progression to the lasser degree of anemia was found in the patients with proteinuria, compared to the control group. Eight of 10 regularly dialyzed patients died, and in 4 patients urothelial carcinoma was diagnosed. In all of them nephroureterectomy was performed, and one patient with advanced disease died 6 months after surgery. On the basis of cited data, by their comparison and further prospective observation of the patients from the village of Kusic, it was concluded that the new focus of endemic nephropathy existed in southeastern Banat.

[IgA nephropathy--IgA1 disease]. / IgA nefropatija--bolest IgA1.

The aim of this study was to prove the increased IgA1 production in patients with IgA nephropathy compared to the control group of healthy subjects, by determination of serum subclasses IgA, IgA1 and IgA2 levels. That with the exclusive presence of IgA1 in kidney tissue, justified the assertion that IgAN was IgA1 disease. Eighteen patients with IgA nephropathy, 15 male and 3 female, average age 17-54 (mean +/- SD = 34.1 +/- 5.18) were included in the prospective study. The diagnosis was proved by immunofluorescent assay of bioptic kidney material obtained by ultrasonically guided biopsy. The total serum IgA and IgA1 and IgA2 subclasses levels were determined in the patients and healthy conscripts from the control group. The methods of immunonephelometry and radial immunodiffusion were used. Increased IgA values were found in 22.75% and of IgA1 subclass in 38.85% patients. Patients with IgA nephropathy had significantly higher IgA1 values (p < 0.01), compared to the control group. There was no significant difference in IgA2 subclass levels. Renal function did not significantly affect IgA1 and IgA2 subclasses values.

[Contamination of IgG preparation for intravenous use with IgA. I. Development of ELISA tests for determination of low concentrations of IgAc, IgA1, IgA2, IgG and IgM]. / Kontaminacija imunoglobulinima A preparata imunoglobulina G3A intravensku upotrebu. I) Razvoj postupaka enzimskog imunoeseja za merenje niskih koncentracija imunoglobulina A1, A2, G i M.

Very low amounts of immunoglobulin contaminants present in preparations of immunoglobulin G for intravenous use (IVIG) require sophysticated procedures for detection of such low concentrations in milieu of comparatively very high level of IgG. Standard RID and nephelometry procedures are not adequate for these purposes. In process of removal of IgA contamination from IVIG, which is currently under development in Blood Transfusion Institute, Belgrade, it is necessary to have senzitive and very specific procedures for determination of and follow up of very low concentrations of IgA remauning in IVIG. We have established a highly senzitive and specific ELISA precedures for determination of very low concentrations of total IgA (IgAc), IgA1, IgA2, IgG and IgM. Commercial standards of IgAc, IgA1, IgA2, IgG and IgM were bound to PVC plates coated with corresponding monoclonal antibodies anti IgAc-IgA1, anti-IgG and anti-IgM. Resulting standard curves have shown high correlation coeficients with limited range of detection (two orders of magnitude in nanogram range). Very high specificity of ELISA tests were obtained due to the highly specific monoclonal antibodies used. Very high specificity and very low detection level of developed tests are advantageous compared to standard procedures for Ig concentration determination.

[Contamination of IgG preparation for intravenous use with IgA. II. Removal of IgA1 from IgG preparation using affinity chomatography on lectin jacalin columns]. / Kontaminacija imunoglobulinima A preparata imunoglobulina G3A intravensku upotrebu. II) Uklanjenje imunoglobulina A1 iz preparata imunoglobulina G pomocu afinitetne hromatografije na koloni lektina zakalina.

Administration of preparations of IgG for intravenous use (IVIG) in individuals with high anti-IgA antibody levels in circulation is frequently accompained with anafilactoid reactions. Thus, there is a requirement for preparations of IVIG with very low levels of IgA. Reduction of IgA concentration in IgG preparations is generally difficult to achieve, since physical and chemical characteristics, on which proceses for Ig purification are based on, are similar for these two Igs. In this work the ability of lectin jacalin to selectively bind IgA1 subclass was exploited for removal of IgA1 from IVIG currently under development in Blood Transfusion Institute of Republic Serbia, Belgrade. Concentrations of Igs in this preparation of IVIG were measured by ELISA tests developed for these purposes. The results have shown 280 times decrease of IgA1 content without changes of IgG concentration. Therefore, affinity chomatography on jacalin column is a suitable method for removal of IgA1 subclass from IVIG. Because of a favourable pH and ionic strength conditions used in process, this procedure has no effect on native state of IgG.

[Immunochemical findings in the cerebrospinal fluid in patients with inflammatory demyelinating polyradiculoneuropathy]. / Imunohemijski nalaz u likvoru bolesnika sa inflamatornom demijelinizacionom poliradikuloneuropatijom.

The aim of the study was to check the hypothesis of involvement of the structure of the central nervous system on the basis of the analysis of the integrity of blood-brain barrier and the degree of IgG synthesis in the intrathecal space of patients with inflammatory demyelinization polyradiculoneuropathy. The study involved 27 patients with acute and 14 patients with chronic inflammatory demyelinization polyradiculoneuropathy. The analysis of liquor was performed in different stages of the disease. The results have shown that in the acute phase, in the phase of the maximal functional deficit there are signs of damaged integrity of the blood-brain barrier but without signs of increased intrathecal IgG synthesis. It has been concluded that there are no reliable signs of increased immunologic activity in the intrathecal space of patients with inflammatory demyelinization polyradiculoneuropathy.

[The importance of using various methods in the determination of serum immune complex levels]. / Znacaj primene razlicitih metoda za odredivanje koncentracije imunih kompleksa u serumu.

Concentration of immune complexes (IC) in the serum of patients with various diseases (glomerulonephritis systemic lupus erythematosus--SLE, rheumatoid arthritis--RA and with positive antibodies to human immunodeficiency virus--HIV+) has been determined using two methods: PEG precipitation and laser nephelometry (NL) of binding to Latex = C1 12q complement components in aqueous media. The presence of antiimmunoglobulin antibodies, that is, rheumatoid factor (RF) and its eventual effect on the precision of measurement of IC using LN C1q method has been determined by LN-Latex RF method. The results have shown that the increased IC values obtained by one method can be within physiological levels if the other method was applied and vice versa. Depending on the group of examinees such negative correlation ranged from 33% to 64%. This is the result of already known limitations of the studied methods and confirms the necessity of simultaneous application of different methods for determination of IC concentration. Regardless of anticomplementary activity of serum rheumatoid factor its presence in the serum has not shown to have any effect on the precision of determination of IC concentration using IC by LN- C1q method.