Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

[Immunotherapy for malignant melanoma]. / Immuntherapie beim malignen Melanom.

Although cutaneous melanoma accounts for only about 4% of all skin cancers (including nonmelanocytic skin cancer), it is responsible for 80% of all deaths caused by skin cancer. The introduction of immune checkpoint inhibitors led to a significant improvement in long-term survival of patients in an advanced stage regardless of BRAF mutation status. In addition to targeted therapy for patients with BRAF-mutated melanoma, immunotherapies are the therapies of choice in advanced stages and, since 2018, also in the adjuvant setting. The effectiveness of combination therapies and sequences of targeted and immunotherapies are currently being tested.

GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma.

BACKGROUND: GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. OBJECTIVES: To characterize these tumours in terms of clinical behaviour and genetic characteristics. METHODS: Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. RESULTS: We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). CONCLUSIONS: Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807.

[Extramammary Paget's disease]. / Extramammärer Morbus Paget.

Extramammary Paget's disease (EPD) is a rare, slowly growing, cutaneous adenocarcinoma with an incidence of 0.1-2.4 per 1,000,000 inhabitants. Histologically, EPD is characterized by the presence of epidermal Paget's cells, similarly to mammary Paget's disease. The EPD is typically divided into primary EPD (type I) and secondary EPD (type II associated with colorectal carcinoma and type III associated with urogenital carcinoma). From a clinical point of view, EPD is unspecific commonly mimicking chronic inflammatory skin disorders. This unspecific clinical picture can impede and delay the diagnosis of EPD. The treatment of choice for local EPD is the micrographically controlled excision. The extent of the infiltration of adnexal structures should be histologically determined prior to topical therapies, such as imiquimod and superficial ablative therapy. The complete excision of the tumor can be challenging due to ill-defined borders. In the metastatic stage the EPD has a poor prognosis. Controlled clinical trials for systemic treatment are still lacking.

Arteriovenous fistula of superficial temporal vessels.

We present a case of patient with a rare vessel pathology - arteriovenous fistula (AVF) of superficial temporal artery and vein. The 56-year-old man was admitted to the Department of Neurology because of a headache in the right temporal region with concomitant buzzing sound in his right ear. The pain was present mainly in the evenings and was stronger when touching the temporal region. He denied having any head injury in the last few years. There were no signs of central nervous system involvement in the neurological examination. Within the right temporal area a subcutaneous mass with redness of the surrounding skin and with palpable and audible pulsatile thrill was observed. In computed tomography (CT) of the head no abnormalities were found. In duplex-Doppler ultrasound examination of carotid arteries the systolic blood velocity in the right external carotid artery was over two times higher than in the left one. Its flow profile was turbulent and low-resistant. In CT angiography (CTA) an AVF between superficial temporal artery and vein was revealed - it was located at the level of the right zygomatic arch. In both CTA and magnetic resonance angiography, no abnormal connections between extra- and intracranial vessels were found. The patient underwent surgery with good result - all the symptoms disappeared. AVFs of vessels of the scalp are rare and their aetiology is mainly traumatic or iatrogenic. By describing this case we wanted to draw attention to less frequent causes of headache.

[The patterns of oxygen metabolism in the early posthemorrhagic period]. / Zakonomirnosti obminu kysniu v rann'omu pisliahemorahichnomu periodi.

Investigated all links of oxygen homeostasis of patients in early period afterwards surgical stoppage gastro-intestinal bleeding and urgent intravascular volume replacement. Macrodelivery of oxygen (DO2) was reduced in two and more time in comparison with norm predominant in connection with anemia. In spite of the infringement of transport of oxygen through alveolar-capillary membrane (especially in patients with complications and death in early postoperative period), little affected of degree of hemoglobin saturation by oxygen. Despite decrease of erythrocyte zeta-potential, largely expressed in cases of lethal outcome, considerable infringement of passage through microcirculation vessels is fixed was not. The increase of degree of morbidity and anaerobic metabolism in early postoperative period was accompanied of hyperdynamic hemodynamic reaction. The increase of degree of morbidity was accompanied of increase oxygen deficit owing to infringement of oxidoreduction in fabries also.

[The relative critical threshold of erythrocyte hemoglobin concentration in isovolemic hemodilution]. / Vidnosnyi krytychnyi porih kontsentratsiï hemohlobinu erytrotsytiv pry izovoliumichnii hemodyliutsiï.

The purpose of our research was register the relative critical threshold of erythrocyte hemoglobin concentration: that criteria, on basis of which was possible to be determined, whether the parameters of red blood for maintenance of oxygen delivery are sufficient in each particular case. Have compared two groups patients afterwards surgical stoppage gastro-intestinal bleeding and urgent intravascular volume replacement; 1) hemotransfusion was accompanied decrease of concentration patient's lactate level; 2) hemotransfusion was not accompanied decrease of concentration patient's lactate level. Have generated the algorithm of indications for transfusion of homologous blood in kind pyramid, in basis are incorporated sensitive, but underspecifically symptoms: the decrease of hemoglobin concentration, especially less 6 g/dl; the decrease of oxygen pressure, degree of hemoglobin saturation with oxygen in venous blood; the increase of blood lactate level; the relative increase cardiac output for account frequency of stroke volume and/or value of stroke volume; positive "oxygen cost" of hemotransfusion.

[Hemostasis in patients operated for abdominal bleeding. I. Estimation of the relationship of hemostasis parameters according to data of the correlation coefficient and factor analysis]. / Gemostaz u bol'nykh, operirovannykh po povodu abdominal'nykh krovotechenii. I. Otsenka sviazi pokazatelei gemostaza po dannym koéffitsienta korreliatsii i faktornogo analiza.

The work was aimed to estimate the interrelation and indexes which define the main alterations of hemostatic deviations in the patients with abdominal bleeding. For this reason the authors have analysed interrelations between 31 hemostasis indexes in 30 patients after operations. Fourteen groups of interrelated indications have been revealed. They are as follows: 1. Prothrombin index, activated partial thromboplastin index; 2. Prothrombin's inactive forms (prethrombin-1, decarboxylated prethrombin etc.), ecamulin index; 3. Velocity bend of distraction of fibrin clot, velocity bend of forming of fibrin clot, height of clot using turbidimetric method; 4. Half-lysis time, lysis time, time of fibrin clot using turbidimetric method; 5. Velocity, Intensity, remainder of platelet aggregation induced by ADP 10 mcg/ml, 2.5 mcg/ml, 1.9 mcg/ml; 6. Thrombin time; 7. Protein C; 8. Fibrinogen; 9. Platelet count; 10. Soluble fibrin; 11. Ancystron time; 12. X factor; 13. Antithrombin-III; 14. Fibrin(ogen) degradation products. It was shown how different groups affect hemostasis. The authors have suggested to use the data of mathematical analysis and laboratory tests for the estimation of hemostatic deviations.

[Hemostasis in patients operated on for abdominal hemorrhage. 2. Characterization of the process of activation of blood coagulation system factors. Coagulation inhibitors]. / Gemostaz u bol'nykh, operirovannykh po povodu abdominal'nykh krovotechenii. 2. Kharakteristika protsessa aktivatsii faktorov sistemy svertyvaniia krovi. Ingibitory svertyvaniia.

Haemostasis indexes were estimated in four groups of patients which were isolated by the cluster analysis and operated for abdominal haemorrhages. A tendency or explicit hyperfibrinogenemia have been fixed which are connected with the syndrome of the system inflammation response of the patient in the critical state. The correlation between the indexes of the prothrombin time, activated partial prothrombin time and protein C activity is shown. An analysis of anticoagulants effect suggests it possible to consider the antithrombin III to be the main, stable blood anticoagulant, while protein C is responsible for the operational response of the organism on the part of haemostasis. The decrease of ancystron and thrombin time was recorded in 50% of patients notwithstanding the hyperfibrinogenemia and presence of fibrin fibrinogen degradation products. It is supposed that the acceleration of fibrin polymerization in the examined groups of patients is the mechanism of the organism protection from the blood loss under the given pathology.

[Hemostasis in patients operated on for abdominal hemorrhage. 3. Boundary deviations of hemostasis]. / Gemostaz u bol'nykh, operirovannykh po povodu abdominal'nykh krovotechenii. 3. Krainie varianty otkloneniia gemostaza.

The fibrinolytic process in the plasma of patients operated for abdominal haemorrhages have been investigated. The results allowed to conclude that the blockade of fibrinolysis did not effect on the course of the disease. The high level of the inhibitors and of the platelets hypoaggregation can be considered as a cause increased of the recurring gastrointestinal haemorrhages. It was demonstrated that the probability of DIC-syndrome development increased at the aggravation of the patient's state after the operation.

[Hemostasis in patients operated on for abdominal hemorrhage. 4. Conception of hemostasis changes]. / Gemostaz u bol'nykh, operirovannykh po povodu abdominal'nykh krovotechenii. 4. Kontseptsiia izmenenii gemostaza.

Studies of haemostasis changes in the dynamics of early post-operational period permitted revealing the tendency to the growth of fibrinogen concentration, decrease in the fibrinogen self-assembling rate, weakening of thrombinemia, disturbances in fibrinogen degradation products (FDP) elimination, increase of inhibitors activity and/or weakening of blood coagulation factors activity, intensification thrombocytes aggregation. Hypercoagulation has been registered under acute haemorrhage and the haemorrhage time exceeding 24 h before the operation, the weakening of hypercoagulation response was observed, notwithstanding the possibility of haemorrhage continuation. The letter is underlined by the changes in the balance between the coagulation factors and inhibitors up to the absence of typical hypercoagulation response to surgical interference.

In vitro neurogenesis by neuronal precursor cells derived from the adult songbird brain.

The vocal control nucleus of the adult songbird forebrain, HVc, exhibits de novo neurogenesis in adulthood, with the production of new neurons from precursor cells located in the overlying ventricular zone (Goldman and Nottebohm, 1983). We previously established that explants derived from neurogenic regions of the adult canary forebrain could be maintained in vitro, under conditions that permitted the migration and differentiation of those new neurons previously generated in vivo (Goldman, 1990). However, we found no evidence for continued neuronal mitogenesis in these cultures, which were raised in high concentrations of serum. In the present study, we investigated the permissive conditions for in vitro neurogenesis by these adult forebrain-derived ventricular zone explants. When HVc explants derived from adult zebra finches were maintained in low-serum medium, in vitro neurogenesis could be demonstrated by 3H-thymidine uptake as long as 5 days after explantation. Immunocytochemistry for microtubule-associated protein-2 followed by autoradiography confirmed the neuronal identity of these 3H-thymidine-incorporating cells. In vitro neuronal production occurred in an inverse relation to the serum concentration: Over the range of 2.5-25% fetal bovine serum, neuronal 3H-thymidine labeling was most frequent in those cultures exposed to the lowest serum levels. This facilitation of in vitro neuronal mitogenesis by serum depletion suggests that fetal serum may contain factors that inhibit the division of adult-derived neuronal precursor cells, either directly or by agents released by serum-stimulated glial or ependymal cells.