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Eccrine porocarcinoma (EPC) is a rare malignancy of the sweat glands. Currently, there is no standard algorithm for its presentations, diagnosis, and management. However, immunotherapy is an emerging option that may be crucial to the treatment of EPC. This report presents a case of a 79-year-old male who had a skin biopsy of an anterior scalp lesion, which revealed EPC. The patient underwent Mohs micrographic surgery to excise the tumor followed by two additional Mohs surgeries for recurrence and adjuvant radiotherapy. A follow-up positron emission tomography (PET) scan revealed yet another recurrence at the scalp as well as metastases to the left parotid gland and left submandibular lymph node. The patient was started on immunotherapy with pembrolizumab, a programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor, and later achieved remission. This report demonstrates the effective management of EPC using immunotherapy with pembrolizumab.

The aim of the present study is the modelling of the total haemoglobin mass responses in altitude environment with the dose-response model in elite endurance athletes and comparison different existing approaches in the quantification of hypoxic dose.Data from seven healthy elite endurance athletes specialised in middle distance speed skating participated in the study: six males (24±1.8 years, 182 ±0.3 cm, 84 ±1.5 kg, BMI 23.2±0.6 kg/m2, 59.3±1.5 ml/kg/min) and one female (21 years, 164 cm, 56 kg, BMI 17.1 kg/m2, 59.9 ml/kg/min). Data were collected during a 3-month training period which included two training camps (14 +14 days) at sea level and two training camps (21+21 days) at altitude of 1224 m and 1850 m above sea level. Total haemoglobin mass (tHb-mass) were measured before the start of the season (baseline) and before and after each training camp (seven measurements) using an optimized CO-rebreathing method, training loads and oxygen saturation at altitude were measured and hypoxic dose were calculated.Mean total haemoglobin mass for the male group at the base line were 1067±83 g, before the training camp 1 were 1095±82 g, after TC1 1113±105 g, before the training camp 2 (TC2) 1107±88 g, after TC2 1138±104 g. For the female athlete at the base line were 570 g, after TC1 564 g, after TC2 582 g.The increase of tHb-mass after TC2 were 3,25% and were significant (pThe relationship between hypoxic dose and haematological response was analysed with a non-linear model. The magnitude of the increase of the total haemoglobin mass were investigated using simulation procedures based upon individual responses to the hypoxic dose. We introduced a measurement error to the list square method as a way of avoiding overfitting problem. Dose-response mathematical model between hypoxic dose and total haemoglobin mass was developed. Modelled total haemoglobin mass was within measurement error range. This model is suitable for the computer simulations. The individual response to hypoxic dose due to model data was different. Maximal values in total haemoglobin mass that can be achieved by male athletes according to the model was 1321.9 ± 32 g. The model predicted that (τ) erythrocyte life span is 73.8 ± 9.0 days. Moreover, highest value of individual tHb-mass increase after returning to the sea level according to the model was16.3 ±0.7 days.The model developed in the current study describes the time course of total haemoglobin mass during altitude exposure and post-altitude decline in elite speed skaters.

Traditionally, searching the Slichter mode (the longest-period mode of the Earth's free oscillations 1S1) is based on the data of the superconducting gravimeters of the international GGP network. Currently this network is included in the International Geodynamics and Earth Tide Service (IGETS).The sensitivity limit of the best superconducting gravimeters is about 1 nGal and not sufficient for direct observation of the Slichter mode even after the significant earthquakes. To reduce the detection threshold, the researchers used the “stacking” procedure — an joint data processing of the several instruments, but the different sensitivity level of the gravimeters prevents the achievement of maximum efficiency.We have developed an asymptotically optimal algorithm based on the maximum likelihood method that takes into account the features of the Slichter mode and seismic noise. An important feature of the algorithm is its ability to evaluate the splitting parameter b which determines the distance between the side singlets of the triplet, simultaneously with the mode period T. The use of a non-linear inertial converter allows to take into account the non-Gaussian noise of real data. The use of the Neumann-Pearson criterion makes also possible to determine confidence level of detection: the false alarm probability and the correct detection probability, depending on the signal-to-noise ratio).The algorithm was tested on synthetic data. A computer experiment has shown that the algorithm can detect the Slichter mode for a signal-to-noise ratio of 10-4. The algorithm was used to search the Slichter mode after the largest earthquakes based on the data of the IGETS network.The results of the analysis are reported.This work is supported by the Russian Foundation for Basic Research under Grant No Grant No 19-05-00341.

Рассмотрены вопросы системного подхода к обеспечению технологической надежности и предложены технические решения для подсистем и узлов прецизионных автоматизированных металлорежущих станков, направленные на минимизацию влияния процессов различной скоро-сти на показатели точности прецизионной обработки. С учетом накопленного опыта исследований предлагается концепция системного подхода к организации контроля, диагностирования и испытаний прецизионных автоматизи-рованных металлорежущих станков для повышения их точности и надежности в виде много-уровневой структуры. Этапы жизненного цикла станков представлены в ней как уровни орга-низации, причем в них можно выделить подуровни, каждый из которых имеет свой конечный результат. В соответствии с мировыми тенденциями развития технологии металлообработки и организации производства основу потребности этих отраслей будут составлять высоко-точные автоматизированные виды оборудования для создания гибких быстропереналажи-ваемых производств. На базе комплексных теоретических и экспериментальных исследований обоснована необходимость повышения точности формообразующих движений рабочих органов прецизи-онного технологического оборудования за счет применения многоступенчатых фрикционных передач в силу того, что известные механические передачи приводов не удовлетворяют ряду требований для применения их в приводах подачи, обеспечивающих сверхпрецизионное фор-мообразование деталей. Анализ контактных и силовых взаимодействий в многоступенчатой фрикционной пе-редаче определяет необходимые для конструирования соотношения геометрических разме-ров роликов, что обеспечивает, в совокупности с выбором оптимального угла между векто-рами сил поджима роликов, минимальное взаимовлияние фрикционных пар при передаче момента, создающего тяговую силу многоступенчатой фрикционной передачи привода пода-чи модуля. Разработана математическая модель взаимодействия сил, возникающих при ра-боте двухступенчатой фрикционной передачи, что позволяет оптимизировать силы прижатия роликов, обеспечить повышение КПД многоступенчатых фрикционных передач. Ключевые слова

Infusional interleukin-2 (IL-2) is able to elicit lymphokine-activated killer cell (LAK) cytotoxicity against kidney cancer in vitro and in vivo. Famotidine may be able to augment LAK cytotoxicity against neoplastic cells. Fifteen (15) patients were treated with continuous-infusion IL-2 (9-18 MIU/m2/24 hours) for 72 hours and famotidine 20 mg intravenously twice per day. Cycles were repeated every 3 weeks. These patients had a median age of 60 years (range, 29-72), had a median performance status of 1 (range, 0-1), and had metastatic sites, including lung, bone, lymph node, and liver. The most common toxicities of this regimen were hypophosphatemia, fever, nausea/emesis, rigors, elevated creatinine, and hypomagnesemia. One (1) complete and 6 partial responses have been seen (47% response rate). The median duration of response is 9 months. The median survival for all patients is 20 months. Five (5) patients are alive at a median of 36+ months. This combination of infusional IL-2 with famotidine is active in metastatic kidney cancer.

The administration of high-dose continuous intravenous infusion interleukin-2 (IL-2) is able to induce the presence of lymphokine-activated killer (LAK) cells. LAK are able to nonspecifically lyse tumor cells. They are also able to lyse endothelial cells, which accounts for, at least in part, the capillary leak syndrome seen as one of the toxicities with this therapy. A pulmonary manifestation of capillary leak syndrome is the presence of pulmonary edema. We postulated that capillary leak may also be a mechanism by which LAK could conceivably reach pulmonary metastases or could be a reflection of damage of endothelial cells in vasculature supplying metastases and that capillary leak syndrome may actually correlate with the response of pulmonary metastases. We examined our database of patients with lung metastases treated with high-dose continuous infusion IL-2 (18 MIU/m(2)/day for 3 days) regimens. Eighteen patients had the following characteristics: melanoma (11), renal cancer (7), median age of 67 years (range, 28-79 years), and males (15). All patients were treated by oncology nurses on either the stem cell transplant unit or oncology ward. Pulmonary edema was defined as the presence of pleural fluid on a chest X-ray, computed tomography (CT) scan, and/or as noted on a physical examination by at least 2 observers. No patients required endotracheal intubation, mechanical ventilation, or an intensive care unit transfer. The median number of cycles received was 6 (range, 1-13). All 8 responding patients (6 patients with melanoma, 2 patients with kidney cancer) manifested pulmonary edema during interleukin-2 therapy. Four patients with pulmonary edema were nonresponders. The presence of pulmonary edema correlated with the response to therapy (p = 0.01). The median duration of response of pulmonary nodules was 5 months (range, 1-16 months). There is a correlation between the development of pulmonary edema and the response of pulmonary metastases in patients with melanoma and kidney cancer treated with high-dose continuous infusion interleukin-2.

High-dose continuous infusion interleukin-2 (IL-2) regimens generate a higher degree of lymphokine activated killer cell (LAK) cytotoxicity when tested against tumor cells in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 have increased cytotoxicity against cancer cells when they are subsequently pulsed with additional IL-2. Famotidine may enhance LAK cytolytic ability. Six patients with kidney cancer have been treated with a combination of famotidine 20 mg intravenous bid and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes. The most common metastatic sites were the lung, lymph node, and bone. Median number of cycles received = 5 (range, 3-8). The most common toxicities were fever, rigors, nausea/emesis, hypophosphatemia, hypotension, elevated creatinine, and metabolic acidosis. There were no treatment-related deaths, and no patients required intensive care admission. Two partial responses (33% response rate) have been seen. Median survival has not been reached at greater than 8 months. The combination of high-dose continuous infusion plus pulse IL-2 and famotidine is active in metastatic kidney cancer. An accrual of additional patients is needed to better assess the response rate.

High-dose, continuous infusion interleukin-2 (IL-2) regimens generate greater Lymphokine Activated Killer cell (LAK) cytotoxicity in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 then subsequently pulsed with IL-2 have increased cytotoxicity against cancer cells. Famotidine may enhance the lysis of tumors by cytotoxic lymphocytes. Fourteen patients with melanoma were treated with famotidine 20 mg intravenously twice per day and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes for 1 dose (12 patients) or daily for 3 doses (2 patients). Most common toxicities were fever, nausea/emesis, hypophosphatemia, hypomagnesemia, and rigors. Nine partial responses (64% response rate; 95% Confidence Interval: 39%-84%) have been seen. Median survival has not been reached at greater than 10 months. Two patients responding to therapy showed an increase in detectable CD 56(+) cells in serial subcutaneous or lymph node biopsies, while 1 patient undergoing progression of disease had no such infiltrate. High-dose, 72-hour continuous infusion plus pulse interleukin-2 with famotidine has activity in melanoma. CD 56(+) cells may play a role in responding patients.

While high-dose bolus inpatient interleukin-2 is generally given on 8-week cycles, continuous infusion interleukin-2 could potentially allow for more rapidly repeated cycles. Fourteen (14) patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, having either kidney cancer (6) or melanoma (8), have been treated with continuous infusion (CIV) interleukin-2 (IL-2) 18 MIU/m(2)/24 hours for 72 hours. Cycles were repeated every 3 weeks up to 4 cycles, then every 3-4 weeks for 2 cycles, then every 6-8 weeks, until progression or intolerable toxicity. All patients received famotidine 20 mg intravenously (i.v.) twice per day during the 72-hour infusions. Patient characteristics included a median ECOG performance status of 1; median age = 63 (range: 25-79); most common metastatic sites: lung (9), bone (5), lymph nodes (5), and the liver (3). No patients with metastatic kidney cancer underwent a nephrectomy prior to interleukin-2. Median number of cycles received = 5 (1-9). No patients required Intensive Care Unit (ICU) admission. There have been no treatment-related deaths. Most common toxicities have been rigors, fever, nausea/emesis, and the reversible elevation of creatinine. One complete response and three partial responses (67% response rate; 95% confidence interval: 30%-90%) have been seen in kidney cancer, and two partial responses (25% response rate; 95% confidence interval: 7%-60%) have occurred in melanoma. Median survival has not been reached at9+ months. Responding sites include the liver, bone, lung, lymph node and subcutaneous sites. Inpatient 72-hour continuous infusion interleukin-2 at this dose and schedule is well tolerated by patients with an ECOG performance status of 0 or 1 and has activity in kidney cancer and melanoma.

Lymphokine-activated killer (LAK) cells generated by high-dose continuous infusion interleukin-2 (IL-2) are able to nonspecifically lyse melanoma and kidney cancer cells. In vitro famotidine enhances cytotoxicity of LAK against tumor cells, possibly by increasing IL-2 uptake at the IL-2 receptor on lymphocytes. Outpatient IL-2 regimens typically have response rates of 15% or less, with most patients eventually experiencing progressive disease. Second-line therapy is, therefore, needed. We treated 11 patients (6 with metastatic melanoma; 5 having metastatic kidney cancer) who had previously experienced progressive disease on prior IL-2 regimens, with a combination of famotidine 20 mg intravenously (i.v.) twice per day and continuous-infusion IL-2 18 MIU/M2/24 hours x 72 hours, followed 24 hours later by a pulse IL-2 dose (18 MIU/M2 over 15 minutes). Cycles were repeated every 3 weeks. Patient characteristics were: 9 males, median age 63 years (range, 57-75), median Eastern Cooperative Oncology Group (ECOG) performance status: 1; most common metastatic sites: lungs, lymph nodes, and soft tissue/subcutaneous (s.c.); median number of cycles received: 4; most common toxicities were fever, nausea/emesis, hypophosphatemia, and hypomagnesemia. Five (5) patients (3 with melanoma, 2 with kidney cancer) have had partial responses. Two (2) patients with kidney cancer have been converted to complete responders with resection of residual disease, remaining without relapse at 5+ and 20+ months. Responding sites are lungs, lymph nodes, abdominal mass, and s.c. Median duration of response was 9.5 months. Median survival was 12 months. This combination has activity in patients with metastatic kidney cancer or melanoma who have received prior IL-2.

High-dose bolus or continuous infusion interleukin-2-based therapy can cause capillary leak syndrome. Significant cardiovascular/hemodynamic events, including myocardial infarction, hypotension, pulmonary edema, and cardiac arrhythmia, have been described with such therapy. Concern over the toxicity of highdose interleukin-2 (IL-2) therapy has led to some clinicians excluding patients 70 years of age or over. We have treated 15 patients 70 years of age or over having an Eastern Conference Oncology Group (ECOG) performance status of 0 or 1, with therapy based on continuous infusion IL-2 18 MIU/sq m/24 hours for 72 hours. All patients underwent a pretreatment evaluation of cardiac status with a low-level stress or adenosine stress test. Cycles were typically repeated every 3 weeks for 4 cycles, then every 3-4 weeks thereafter. Patients were treated by oncology nurses in either the stem cell transplant (intermediate unit) or the oncology inpatient unit. Patient characteristics were: median age, 72 years (range, 70-83 years); tumor types: melanoma (10), kidney cancer (5); most common sites of disease: lung (11), lymph nodes (6), subcutaneous (3), liver (2); prior therapy included: none (8), outpatient IL-2 (5), other immunotherapy (4). Median number of cycles received: 3 (1-10). Most common toxicities were: fever, rigors, nausea, emesis, hypophosphatemia, and hypomagnesemia. Three patients required the use of dopamine for blood pressure support. Two patients declined further therapy. There were no treatment-related deaths. No patients required endotracheal intubation or transfer to an intensive care unit. One complete and 8 partial responses (60% response rate) have been seen. Responding sites include the lung, lymph node, intact kidney primary, and liver. Median survival has not been reached at over 14 months (range 3+-26+ months). Patients who are 70 years of age and older with an ECOG performance status of 0 or 1 are able to tolerate high-dose continuous infusion IL-2-based therapy and may respond to such treatment.