Vol 24, No 4 (2022)

CLINICAL ONCOLOGY

Place of durvalumab in the treatment of biliary tract cancer: A review

Breder V.V., Ledin E.V., Chubenko V.A., Orlova R.V., Petkau V.V., Pokataev I.A.

Abstract

Biliary tract cancer (BTC) is a group of rare and aggressive types of malignancies that arise from the epithelium of the intra- and extrahepatic bile ducts (cholangiocarcinoma) and gallbladder. The prognosis of unresectable BTC is poor, and less than 5% of patients are alive at 5 years after diagnosis. Radical surgical resection remains the only potentially curative treatment for early stage BTC, and antitumor chemotherapy extends survival rates in patients with unresectable or metastatic BTC. With the emerging of monoclonal antibodies targeting immune checkpoints, the possibility of such therapy in first- and subsequent-line treatment of advanced BTC has been actively studied. The positive high-level results from the TOPAZ-1 Phase III trial showed durvalumab, in combination with standard-of-care chemotherapy (gemcitabine plus cisplatin), statistically improved overall survival versus chemotherapy alone and showed improvements versus chemotherapy alone in prespecified secondary endpoints including progression-free survival and objective response rate. Durvalumab plus chemotherapy was well tolerated, had a similar safety profile versus the comparator arm and did not increase the discontinuation rate due to adverse events compared to chemotherapy alone. The U.S. Food and Drug Administration approved the combination of durvalumab and chemotherapy (gemcitabine plus cisplatin) as the first immunotherapy regimen for patients with locally advanced or metastatic BTC. In July 2022, durvalumab plus chemotherapy (gemcitabine plus cisplatin) was added to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) as a preferred regimen category 1 in first-line therapy for Unresectable or metastatic BTC based on the data from TOPAZ-1. In addition, the durvalumab plus gemcitabine and cisplatin was recently added to the practical recommendations of the Russian Society of Clinical Oncology (RUSSCO) for the treatment of hepatobiliary cancers as an alternative to standard first-line treatment of BTC.

Journal of Modern Oncology. 2022;24(4):407-412
pages 407-412 views

Real-world efficacy of the first line therapy with prolgolimab in patients with metastatic melanoma: interim results of the FORA (FOrteca Real practice Assessment) observational study

Orlova K.V., Fedyanin M.Y., Simanenkov K.E., Dergunov A.S., Goldshmidt P.R., Saydullaeva A.F., Bogacheva D.V., Yavorskaya M.A., Azanov A.Z., Fedenko A.A., Bolotina L.V., Deshkina T.I., Babina K.G., Kuzevanova E.A., Zhukova L.G., Feoktistova P.S., Polshina N.I., Peganova E.V., Shikina V.E., Sobolev M.M., Mironov O.V., Vaschenko V.A., Ershova M.M., Mezhueva A.O., Orlova S.A., Tantsyrev D.A., Taskina D.K., Teterich A.A., Karabina E.V., Kostalanova Y.V., Bogacheva M.V., Zhukova N.V., Orlova R.V., Zinkevich M.V., Kazmin A.I., Volkonskiy M.V., Voronkova L.M., Karpova A.S., Maleyko M.L., Gorshenina M.N., Kryuchkova E.I., Moiseenko F.V., Murzina Y.I., Musin S.I., Ogloblin A.N., Perminova M.S., Dumbrava R.A., Emelyanov S.A., Protsenko S.A., Sultanbaev A.V., Tarasova A.V., Shakhnovich E.B., Demchenkova M.V., Lozovskaya Y.A., Musaeva K.S., Pavlova E.M., Skotnikov R.A., Chernova V.V., Chichkanova A.S., Akhmatova A.M., Zafirova M.A., Mischenko A.A., Ovsienko E.N., Petrukhnenko V.A., Syusyukaylova O.A., Tyugina Y.A., Shumilkina E.A., Stroyakovskiy D.L., Yurchenkov A.N., Baldin P.L., Belova A.S., Diduk O.V., Konovalova E.A., Lebedeva L.N., Li Y.A., Mashtapa V.V., Mironenkova Y.A., Narovenkova K.V., Pavlikova O.A., Parsadanova E.L., Pimonova I.S., Ruzhnikova A.A., Sivunova I.D., Soloveva E.P., Sosnin M.I., Temirsultanova T.K., Tyulegenova M.Z., Khodkevich A.V., Shakurova N.R., Efendieva S.N., Avagimyan K.L., Anokhina E.P., Antoshkina M.I., Borzyanitsa S.M., Dzhentemirov S.K., Dmitrochenko M.V., Zheleznyak A.V., Komoza Y.V., Kopanev A.S., Kornienko T.I., Krasilnikova M.A., Lukhmanova D.A., Mazur N.S., Markina P.M., Mitapov Z.S., Osodoeva S.N., Prokopenko I.A., Radyukova I.M., Ramazanova M.S., Safarova A.R., Safronova M.A., Khabrieva K.M., Tsygankova N.S., Chermakova K.V., Chirkova T.A., Samoylenko I.V., Nazarova V.V., Akhmetyanova A.E., Demidov L.V.

Abstract

Background. Novel agents – immune checkpoint inhibitors – fundamentally changed the prognosis for life in patients with metastatic and/or inoperable melanoma. The development, studies, and approval of a new original PD1 inhibitor in Russia in 2020 prompted the professional community to conduct a prospective observational study in the Russian Federation to assess the real-world efficacy and safety of prolgolimab, as real-world patients differ from the refined population in clinical trials.

Aim. To evaluate the real-world efficacy and safety of prolgolimab in patients with metastatic and/or inoperable melanoma.

Materials and methods. From October 2020 to October 2022, the study enrolled 700 patients with metastatic and/or inoperable melanoma receiving prolgolimab in real clinical settings in oncological institutions of various levels in the Russian Federation. The main inclusion criteria were: pathology-confirmed diagnosis of melanoma, metastatic and/or inoperable type, use of prolgolimab outside of clinical trials, and signed informed consent by the patient. Objective response rate (ORR) was considered the main criterion for evaluating the efficacy of therapy, and the safety criterion was the incidence of grade 3–4 adverse events. Statistical analysis was performed using the SPSS 20.0 software package.

Results. The ORR for patients with skin melanoma treated with prolgolimab in the first line therapy (n= 207/337) was 48.3% (n=100), the disease stabilization was reported in 30.4% (n=63), and progression in 21.3% (n=44) of patients. There were no significant differences in response to therapy between patients with/without BRAF mutation, although ORR was higher in patients with BRAF mutation: the ORR for patients with BRAF mutation was 57.9% (n=33), and for BRAF non-mutated patients, 44.4% (n=52; p=0.222). At a median follow-up of 5 months, the median PFS was 10 months (95% confidence interval 7.35–12.64). The incidence of grade 3–4 treatment-related adverse events according to CTCAE 5.0 was 2% (n=12), and 12% (n=82) for grade 1–2 adverse events.

Conclusion. The results confirm the high efficacy and satisfactory tolerability of prolgolimab in patients with metastatic and/or inoperable melanoma in real-world settings. There were no significant differences in ORR between patients with or without BRAF mutation.

Journal of Modern Oncology. 2022;24(4):413-425
pages 413-425 views

Efficacy of immunotherapy (Prolgolimab) and targeted therapy (Trametinib and Dabrafenib, Cobimetinib and Vemurafenib) in adult patients with metastatic or unresectable skin melanoma: matching-adjusted indirect comparison

Sapozhnikov K.V., Sokolova V.D., Sableva N.A., Tolkacheva D.G.

Abstract

Aim. To assess the comparative clinical efficacy of Prolgolimab monotherapy versus combination therapy with BRAF/MEK inhibitors (Dabrafenib and Trametinib, Vemurafenib and Cobimetinb) in adult patients with metastatic or unresectable skin melanoma implementing a matching-adjusted indirect comparison (MAIC).

Materials and methods. We conducted a systematic search for randomized clinical trials of Prolgolimab, combinations of Dabrafenib and Trametinib, Cobimetinib and Vemurafenib. Unanchored MAIC was applied due to the absence of common comparator between trials. We determined effect modifiers based on an expert survey. The population from Prolgolimab studies was weighted using defined effect modifiers, followed by the approximation of survival curves.

Results. Systematic literature search revealed 4 RCTs that met the inclusion criteria: MIRACULUM, coBRIM, combi-v and combi-d. To increase the power of prolgolimab comparison, data from the observational study FORA were included in evidence synthesis and combined with data from MIRACULUM. We selected M staging and the proportion of patients with elevated LDH levels as effect modifiers. No significant differences (all p>0.05) were established between Prolgolimab and combination therapy with BRAF/MEK inhibitors for both OS after 1 year and PFS outcomes after 2 years from initiation.

Discussion. Despite the inclusion of observational data and the limitations of adjusted indirect comparison method, the results of this analyses are consistent with both other comparisons of anti-PD1 inhibitors with BRAF/MEK inhibitors, and with real world data. It is necessary to recompare targeted therapy and immunotherapy after five-year follow-up period due to peculiarities of time of onset of their effect with the presence of a primary “failure” with a gradual exit to a long “plateau” on anti-PD1 inhibitor’s therapy.

Conclusion. In these unanchored MAICs, Prolgolimab monotherapy showed comparable efficacy with combinations of BRAF/MEK inhibitors (Dabrafenib + Trametinib, Vemurafenib + Cobimetinib) in first line therapy of patients with metastatic or unresectable melanoma. This analysis may be relevant for clinical decision-making about the choice of the first line therapy for patients with BRAF mutation.

Journal of Modern Oncology. 2022;24(4):426-439
pages 426-439 views

Development of a prognostic model in patients with metastatic bone lesions to choose surgical treatment: retrospective study

Buharov A.V., Kurilchik A.A., Barashev A.A., Derzhavin V.A., Yadrina A.V., Erin D.A., Elkhov D.O., Aliev M.D., Kaprin A.D.

Abstract

Choosing surgical management for patients with metastatic bone lesions is one of the essential problems of modern oncology. Surgical interventions are aimed at palliative treatment in most patients with metastatic skeletal lesions. However, curative resections with reconstruction and plasty steps may be considered in selected cases of a solitary metastatic lesion. The life expectancy prognosis based on the histological structure of the tumor is a significant and decisive factor in choosing the appropriate surgery.

Aim. To develop a prognostic model for choosing surgical treatment for metastatic bone lesions.

Materials and methods. Treatment analysis of 715 patients with a history of surgery for metastatic bone lesions of various localizations is presented. A total of 780 surgical interventions were performed. Surgeries for the complications of bone metastases were mainly performed on the spine (48.5% of all surgeries), followed by long bones with 247 (35%) surgeries, pelvic bones with 81 (11%) interventions, and the chest wall with 40 (5.5%) surgeries.

Results. The most unfavorable prognostic factors in patients with metastatic bone lesions are the histological type of the primary tumor of the rapid growth group (risk ratio [RR]=5.11), visceral metastases (RR=3.1), Charlson Comorbidity Index over 10 (RR=3.07) and presence of critical laboratory abnormalities (RR=2.91), as they have the highest rates of impact on survival (over 2.9).

Conclusion. The developed 14-point mathematical score of life expectancy prognosis, which includes five oncological and four clinical factors, defines with an accuracy of 91% the risk groups of good (estimated life expectancy over one year), moderate (6 to 12 months), and poor (less than six months) prognosis in patients with metastatic bone lesions.

Journal of Modern Oncology. 2022;24(4):440-445
pages 440-445 views

Results of surgical treatment of patients with malignant peripheral nerve sheath tumors: a retrospective and prospective study

Abdulzhaliev A.T., Sushentsov E.A., Boulytcheva I.V., Senderovich A.I., Nikulin M.P., Sofronov D.I., Bugaev V.E.

Abstract

Background. Peripheral nerve sheath malignancies (PNSM) are a rare and aggressive group of sarcomas that can occur sporadically, after radiation therapy, or related to neurofibromatosis type 1. Loss of function of NF1, TP53, and CDKN2A genes is thought to contribute to the progression of benign neurofibroma to PNSM and is a poor prognostic sign. The optimal management of patients with this disease is currently unresolved, and specific prognostic factors have not been established.

Aim. To analyze the results of surgical treatment in patients with PNSM and establish prognostic factors of overall and recurrence-free survival rate.

Materials and methods. The retrospective and prospective studies enrolled adult patients with histologically confirmed PNSM treated between 1998 and 2021 at the N.N. Blokhin National Medical Research Center for Oncology. Surgical intervention was performed on 61 patients, 38 (62%) females and 23 (38%) males. The most common PNSM localization was paravertebral (22 [36%] patients), followed by retroperitoneal (14 [23%] patients), and upper and lower extremities (13 [21%] and 12 [20%] patients, respectively).

Results. For PNSM patients with a history of surgery, the median overall survival (OS) was 46 months (95% confidence interval 26.1–65.9). The 3-year and 5-year OS was 46% and 31%, respectively. The median recurrence-free survival (RFS) was 27 months (8.7–45.3), and 3-year and 5-year RFS was 26% and 13%, respectively. Median OS for grade 1 malignancies was not achieved, while grade 2 and grade 3 malignancy was 53 and 33 months, respectively (p=0.033). The median RFS for grade 1, 2, and 3 tumors was 119, 43, and 15 months, respectively (p=0.078). Patients who underwent radical (R0) surgery had higher RFS (p=0.006) and OS (p<0.0001). After radical (R0) surgery, the median OS was not achieved; after nonradical (R1/R2) surgery, the median was 34 months. The median RFS was 124 months after R0-resection and 48 months after R1/R2.

Conclusion. The most significant prognostic factors in PNSM patients are the radicality of the surgery performed and the malignancy grade. In our study, tumor size and localization did not affect the long-term treatment results.

Journal of Modern Oncology. 2022;24(4):446-453
pages 446-453 views

Opportunities of ICG-fluorescent imaging of lymph nodes during radical cystectomy in patients with bladder cancer: A review

Pavlov V.N., Urmantsev M.F., Bakeev M.R.

Abstract

Today, the "golden standard" for the treatment of aggressive forms of bladder cancer is radical cystectomy. An important stage is the pelvic lymphadenectomy. This procedure is crucial for staging the tumor process, determining the subsequent treatment tactics and improving the results of surgery. Currently, the concept of a signaling lymph node (LN) is actively developing, which allows reducing the necessary level of dissection of the pelvic LN. Reducing the number of resected LN increases the level of surgical safety of the patient. The leading method of intraoperative visualization of signal LN is the fluorescence of indocyanine green in the near infrared range of the spectrum. The prospects of this diagnostic method for radical cystectomy in patients with bladder cancer determine the vector of future scientific research in this area.

Journal of Modern Oncology. 2022;24(4):454-457
pages 454-457 views

Combination of microspheres and gadoteridol for the determination of non-target ovarian embolization during uterine artery embolization. A case series

Sharafutdinov B.M., Ryzhkin S.A., Galim'yanov D.A., Gaziev E.A.

Abstract

Background. Uterine myoma is the most common benign tumor of the pelvic organs in women. One of the effective therapies for myomas is uterine artery embolization (UAE), which can be associated with unintended ovarian embolization. However, there is no certainty about the effect of unintended ovarian embolization on fertility and ovarian function since no precise evidence-based ways of identifying unintended embolization have been described.

Aim. To develop a highly accurate method for identifying unintended ovarian embolization during UAE.

Materials and methods. A series of clinical cases of the utilization of combined embolization material based on the paramagnetic contrast agent gadoteridol and saturable HepaSphere microspheres are presented.

Results. On admission, patients underwent magnetic resonance imaging (MRI) of the pelvic organs with contrast enhancement. After UAE with this combined embolization material, another pelvic MRI without contrast enhancement was performed on the in-hospital day 2. In the first clinical case, no hyperintensive zones were detected in the ovarian stroma. However, in the second case, a previously undetected hyperintensive signal up to 6 mm in diameter was seen in the stroma of the left ovary by repeat MRI.

Conclusion. Using this combined material during UAE significantly increases the accuracy of possible unintended ovarian embolization detection as soon as in the early postoperative period.

Journal of Modern Oncology. 2022;24(4):458-463
pages 458-463 views

Remote multimodal prehabilitation in the presence of cachexia and resectable gastric cancer: a clinical case

Lyadov V.K., Boldyreva T.S., Achkasov E.E., Gorshkov A.Y., Chashchin M.G., Protsenko E.V., Starodubova V.V., Galkin V.N.

Abstract

Background. The high frequency of cachexia and sarcopenia (skeletal muscle depletion) in patients with cancer led to the development of “prehabilitation” concept. Multimodal prehabilitation includes physical training, nutritional and psychological support before anticancer treatment.

Aim. To present the results of treatment of a patient with cachexia who underwent a multimodal prehabilitation program before surgery for gastric cancer.

Materials and methods. A 74-year-old woman with early stage cancer of the gastric antrum had lost 28% of total body weight in the previous 6 months because of a dysphoric disorder. The patient underwent a multimodal prehabilitation for 2 weeks prior to surgery, which included nutritional (600 ml siping per day) and psychological support as well as a supervised remote physical exercise program based on nordic walking.

Results. The patient increased functional walking capacity from low to medium, grip strength and gait speed. The postoperative period went uneventfully and the patient was discharged home 8 days after surgery.

Conclusion. Multimodal remote prehabilitation is a potentially beneficial option in cachectic patients with gastric cancer who need surgery.

Journal of Modern Oncology. 2022;24(4):464-467
pages 464-467 views

Anemia and iron deficiency in cancer patients: the role of intravenous iron supplements (a literature review)

Sakaeva D.D.

Abstract

Anemia in patients with malignancies is a common disorder that has a markedly negative impact on quality of life and overall prognosis. The pathogenesis of anemia is complex and multifactorial, depending on the type and stage of malignancy, nutritional status, renal function, age and gender, cytostatic drug, dose, and chemotherapeutic regimen, with iron deficiency often being the main and potentially treatable factor for anemia. In cancer patients, it can be caused by various concomitant mechanisms, including bleeding (e.g., in malignant gastrointestinal tumors or after surgery), malnutrition, medication, and hepcidin-induced iron sequestration in macrophages, with subsequent iron-deficient erythropoiesis. The variety of clinical manifestations of anemia makes it challenging to establish universal criteria to develop optimal treatments. Current therapy for anemia in malignant tumors includes replacement therapy with an iron supplement, erythropoiesis-stimulating agents (erythropoietins), and blood transfusions. However, blood transfusions should be minimized due to the high risks and costs. Therapy with an iron supplement is an effective approach to correcting the iron deficiency. It can increase the efficacy of erythropoiesis-stimulating drugs and reduce the need for blood transfusions. Published guidelines suggest the wide use of intravenous iron supplements. This article discusses possible approaches to treating iron deficiency in cancer patients in various clinical settings. We build on current guidelines and emphasize the need for further research in this area.

Journal of Modern Oncology. 2022;24(4):468-476
pages 468-476 views

Fosaprepitant: current options to prevent chemotherapy-induced nausea and vomiting: A review

Ognerubov N.A.

Abstract

Background. Chemotherapy (CT) is a mainstay of treatment for malignant tumors. CT-induced nausea and vomiting are observed in 30–90% of patients within 0–120 h after moderate and highly emetogenic CT administration. These adverse events can severely impact the quality of treatment, daily life, and adherence to treatment, thus reducing the effectiveness of therapy and survival.

Materials and methods. The author provides the results of a systematic review of research papers, including clinical studies, on the efficacy of the neurokinin-1 receptor antagonist fosaprepitant to prevent CT-induced nausea and vomiting. Data from the PubMed database were reviewed.

Results. The prevention and treatment of CT-associated nausea and vomiting are vital during special therapy, including symptomatic therapy. International organizations recommend using a triple combination with antagonists of neurokinin-1 and 5-hydroxytryptamine-3 receptors and dexamethasone. According to the data obtained, the efficacy of fosaprepitant has been proven in delayed and general phases in several large, well-planned studies; the drug reduces the incidence of adverse events by 2.7–4.4 times compared with aprepitant.

Conclusion. Fosaprepitant is an antagonist of neurokinin-1 receptors; when administered intravenously, it rapidly converts into aprepitant. When used as part of a triple combination with 5-hydroxytryptamine-3 receptor antagonists and dexamethasone in patients receiving moderate and highly emetogenic CT leads to a higher rate of complete response when controlling nausea and vomiting. In general, fosaprepitant is well tolerated.

Journal of Modern Oncology. 2022;24(4):477-486
pages 477-486 views

The NETosis phenomena as a functional features of peripheral blood neutrophils and its role in the pathogenesis of infections and oncological diseases: A review

Glukhareva A.E., Afonin G.V., Melnikova A.A., Grivtsova L.Y., Kolobaev I.V., Ivanov S.A., Kaprin A.D.

Abstract

The review is devoted to the analysis of the mechanism of NETosis and the formation of extracellular traps by neutrophils. Neutrophil traps are DNA strands, histones and proteins that are involved in autoimmune diseases, COVID-19, as well as in the pathogenesis of other non-communicable diseases. Based on the literature data, the role of NETosis in the development oncological diseases is analyzed. Two types of neutrophils have been characterized: low-density neutrophils and high-density neutrophils. In particular, the significance of this phenomenon in the progression and metastasis of the cancer. A detailed study of this issue will be useful both from a fundamental standpoint regarding the disclosure of the mechanisms of the metastatic cascade, and from a practical point of view for the development of new immunotherapeutic approaches in the treatment of metastatic tumors.

Journal of Modern Oncology. 2022;24(4):487-493
pages 487-493 views

Disability-Adjusted Life Year (DALY) assessment and economic damage from premature death of cervical uterine and ovarian cancers in the Tomsk Region

Zhuikova L.D., Ananina O.A., Sirotina A.S., Pikalova L.V., Fokin V.A., Kononova G.A.

Abstract

Background. Disability-adjusted life year (DALY) is one of the well-known methods of comprehensive health assessment in the world. The method was developed by the World Bank and the World Health Organization. The DALY units and gross domestic product per capita are used for the assessment of the indirect economic damage from premature death of cancer.

Aim. To estimate the number of years of life lost (DALY method) and economic losses due to death from cervical, uterine and ovarian cancers in the population of the Tomsk region.

Materials and methods. The data of the Tomsk Region Federal State Statistics Service on the mortality of the population of the reporting form C51 “Distribution of the dead by sex, age groups and causes of death”, data on the sex and age distribution of the population, life expectancy, gross regional product per capita for 2018 of the Tomsk region were used.

Results. In 2018, due to the death from gynecological cancer of the population of the Tomsk Region, 1616 DALY units were lost in absolute numbers. Of these, cervical cancer accounts for 44.3% (717 DALY units), uterine corpus cancer accounts for 24.8% (401 DALY units), ovarian cancer accounts for 30.8% (498 DALY units). At working age (16–54 years), the absolute losses amounted to 694 DALYs. The economic damage to the Tomsk Region due to the mortality of the population from cancer of the cervix, uterine body and ovaries in 2018 amounted to 918.2 million rubles. Economic losses as a result of mortality from cancer of the cervix amounted to 407.4 million rubles, from cancer of the ovaries – 283.0 million rubles, from cancer of the body of the uterus – 227.8 million rubles. The economic damage from gynecological cancers in working age amounted to 394.3 million (42.9% of the total economic damage).

Conclusion. Determining the socio-economic losses associated with mortality from malignant neoplasms of the female genital organs is necessary for the effective use of health care resources, which can be used to justify the need of the population for oncological care.

Journal of Modern Oncology. 2022;24(4):494-498
pages 494-498 views

What drug combinations are best for preventing and treating anemia in people with cancer (Russian Translation of Cochrane Plain Language Summary (PLS))

Abstract

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Adams A, Scheckel B, Habsaoui A, Haque M, Kuhr K, Monsef I, Bohlius J, Skoetz N. Intravenous iron versus oral iron versus no iron with or without erythropoiesis-stimulating agents (ESA) for cancer patients with anaemia: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2022;6(6):CD012633. DOI:10.1002/14651858.CD012633.pub2

Journal of Modern Oncology. 2022;24(4):499-500
pages 499-500 views

Oxycodone for cancer-related pain in adults (Russian Translation of Cochrane Plain Language Summary (PLS))

Abstract

This publication is the Russian translation of the Plain Language Summary (PLS) of the Cochrane Systematic Review: Schmidt-Hansen M, Bennett MI, Arnold S, Bromham N, Hilgart JS, Page AJ, Chi Y. Oxycodone for cancer-related pain. Cochrane Database Syst Rev. 2022;6(6):CD003870. DOI:10.1002/14651858.CD003870.pub7

Journal of Modern Oncology. 2022;24(4):500-501
pages 500-501 views


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