Lazar Popovic

Checkpoint inhibitors in the treatment of urological malignancies

Checkpoint inhibitors are monoclonal antibodies attach to several different receptors on T-cells or tumour cells expressing receptors for cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death-1 (PD-1) and their ligand (PD-L1). Since 2010, numerous trials on different tumour types have been conducted, which was resulted in these drugs being approved for the treatment of melanoma, lung cancer, Hodgkins lymphoma and head and neck cancers. Urological cancers, especially urothelial and renal-cell carcinomas, are immunogenic tumours. Since the late 70s, the bacillus Calmette-Gurin (BCG) vaccine has been used for intravesical instillation in non-muscle invasive bladder cancer from the mid-90s up until the discovery of tyrosine kinase inhibitors (TKIs) in 2007, interleukin-2 (IL-2) and interferon alpha (IFNα), which were the standard of care for metastatic renal-cell cancer. Two checkpoint inhibitors are already approved by the Food and Drug Administration: atezolizumab for metastatic urothelial cancer and nivolumab for metastatic renal-cell carcinoma. There are many drugs are in different phases of clinical development. Here we review the current status of checkpoint inhibitors in the treatment of urological tumours.

High dose chemotherapy with stem cell support in the treatment of testicular cancer.

Testicular germ cell cancer (TGCC) is rare form of malignant disease that occurs mostly in young man between age 15 and 40. The worldwide incidence of TGCC is 1.5 per 100000 man with the highest rates in North Europe. After discovery of cisplatin cure rates of TGCC are very favorable between 90%-95% and unlike most solid tumors, cure rate for metastatic TGCC is around 80%. Metastatic TGCC is usually treated with 3-4 cycles of bleomycin, etoposide, cisplatinum chemotherapy with or without retroperitoneal surgery and cure rates with this approach are between 41% in poor risk group and 92% in good risk group of patients. Cure rates are lower in relapsed and refractory patients and many of them will die from the disease if not cured with first line chemotherapy. High dose chemotherapy (HDCT) approach was used for the first time during the 1980s. Progress in hematology allowed the possibility to keep autologous haematopoietic stem cells alive ex-vivo at very low temperatures and use them to repopulate the bone marrow after sub-lethal dose of intesive myeloablative chemotherapy. Despite the fact that there is no positive randomized study to prove HDCT concept, cure rates in relapsed TGCC are higher after high dose therapy then in historical controls in studies with conventional treatment. Here we review clinical studies in HDCT for TGCC, possibilities of mobilising sufficient number of stem cells and future directions in the treatment of this disease.

Treatment of acute hepatitis C in breast cancer patient: a case report.

Abstract Oncologists worldwide are often dealing with hepatitis C virus positive breast cancer patients, questioning adequate chemotherapy protocol, reduction of doses, delays, or even interruptions of treatment. We present a case of a woman in stage IIIB breast cancer, who after the completion of neoadjuvant treatment developed significant increase in liver enzymes and was diagnosed positive for HCV. She was treated with interferon and after the resolving of acute liver disease continued concomitant treatment with interferon, ribavirin, docetaxel, and trastuzumab. Grade 4 neutropenia and grade 3 hepatotoxicity occurred after the third cycle of chemo and 5 months of antiviral therapy. Interferon and chemotherapy were postponed for 1 week. There are no sufficient data in order to recommend the concomitant antiviral and antineoplastic therapy. Hepatitis C virus and antiviral therapy may increase the toxicities of antineoplastic treatment. However, when lifesaving oncologic treatment is necessary, concomitant antiviral therapy can be administered with more intensive follow up.

Male breast cancer in the era of modern therapies: Serbian single centre experience report.

To the Editor: Male breast cancer is a rare disease, accounting for less than 1% of total malignant diseases and less than 1% of all breast cancer cases (1). Inspired by the Ruddy and Winer’s article published in Annals of Oncology (2), we analyzed our group of patients treated at the Oncology Institute of Vojvodina from 2006 to 2010. We analyzed the medical records of 44 patients managed at our Institute. The median follow-up was 50 months (25–83). Diagnosis was established after radical mastectomy in case of 72% of studied patients; the rest of patients underwent less radical surgery or biopsy in case with primary metastatic disease. Adjuvant radioand chemotherapy were administered according to standard protocols (3). The Kaplan–Meier estimator and Mann–Whitney U-test were used for statistical analyses. In our group, 34% of patients had T1 disease, while 50%, 3%, and 13% had T2, T3, and T4, respectively. Lymph node status was—N0 32%, N1 32%; also, N3 and N4 both by 18%. Seventeen patients (39%) had stage IV disease in the time of diagnosis while stage I, II, and III was found in 9%, 41%, and 11%, respectively. Hormone receptor positive disease in our group of male patients was diagnosed in 78% of patients, while three patients (10%) had HER2 positive disease from 32 patients with known HER2 status. Grade two was the most often determined (62%), while G1 and G3 disease was diagnosed in 21% and 17% of patients. In the time of diagnosis, 27 patients had no metastases and 21 of them were treated with adjuvant chemotherapy. FAC protocol (5-flurouracil, doxorubicin, and cyclophosphamide) was applied in case of 81% of patients; combination of AC protocol (doxorubicin and cyclophosphamide) and taxanes was administered in two patients (10%), and CMF (cyclophosphamide, methotrexate, and 5-flurouracil) was also applied in two patients. Tamoxifen was given to all patients with positive estrogen receptors. After disease progression, the patients were mostly treated with taxane therapy and/or capecitabine. None of the patient was given trastuzumab therapy. Primary metastatic disease was found in 17 studied patients and 14 (82%) of them were given FAC therapy and followed with tamoxifen in case of hormone positive disease; two patients were treated with taxanes initially, and one patient was treated with hormonal therapy only. The median of progression free survival (PFS) in the analyzed group of patients was 29 months, and median overall survival (OS) was 40 months. Fouryear PFS was 28% and OS was 43%. In addition, we analyzed survival based on clinical and histopathologic parameters. The univariate analysis showed that tumor size and number of involved lymph nodes in axilla had no significant impact to 4-year PFS and OS. Patients with stage III and stage IV disease had shorter 4-year PFS (5% versus 64%, p = 0.0006) and OS (19% versus 70%, p = 0.0044), mainly on the account of 17 patients with primary metastatic disease. Four-year survival of the patients with metastases was 17% with the median time to progression of 11 months and median time for overall survival of 35 months. These data speak in favor of the efficacy of larger number of therapies administered in metastatic stage of disease. Hormone receptor status did not influence PFS and OS. None of the patients with HER2 positive or grade 3 disease survived more than 3 years, but we didn’t find statistical significance because of the small number of studied patients. Patients with primary metastatic disease had more often tumors of ≥5 cm (p = 0.03) and ≥4 positive ipsilateral axillary lymph nodes (p = 0.01). In contrast to the majority of studies that have been analyzed by Ruddy and Winer (2) our study was a report of the 44 patients who were treated after the year 2005, with more recent standards in adjuvant treatment and with more drugs to treat metastatic Address correspondence and reprint requests to: Lazar Popovic, MD, TA, Clinic for medical Oncology, Oncology Institute of Vojvodina, Put dr Goldmana 4, Sremska Kamenica 21204, Serbia, or e-mail: lazar.popovic@ yahoo.com

Proteomics in the Assessment of the Therapeutic Response of Antineoplastic Drugs: Strategies and Practical Applications.

Uncovering unknown pathological mechanisms and body response to applied medication are the driving forces toward personalized medicine. In this post-genomic era, all eyes are turned to the proteomics field, searching for answers and explanations by investigating the gene end point functional units-proteins and their proteoforms. The development of cutting-edge mass spectrometric technologies and bioinformatics tools have allowed the life-science community to discover disease-specific proteins as biomarkers, which are often concealed by high sample complexity and dynamic range of abundance. Currently, there are several proteomics-based approaches to investigate the proteome. This chapter focuses on gold standard proteomics strategies and related issues toward candidate biomarker discovery, which may have diagnostic/prognostic as well as mechanistic utility in cancer drug resistance.

Editorial Comment to Clinical analysis of severe psychiatric disorders in patients with testicular cancer: A single-center experience.

Psychiatric disorders are often diagnosed in cancer patients. Studies found that delirium, anxiety disorders and major depression occur in 10–34% of patients with malignant disease. Most of those are diagnosed after diagnosis of cancer, but there are also patients with pre-existing psychiatric diseases, which often execerbate after diagnosis of cancer. In this issue of International Journal of Urology, Kishimoto et al. retrospectively analysed survival of 88 testicular cancer patients with or without pre-existing psychiatric disease (PSD). The most important finding of that study was a lower overall survival rate of seven patients with PSD (57.1% vs 91.8%; P = 0.02), but not lower cause-specific survival (85.7% and 94.7%; P = 0.37) for patients with and without PSD, respectively. The reason for this result is that only one of seven patients analyzed died from testicular cancer. Another two patients died from severe asthma attack and unknown reason 38 months after orchiectomy as the sole treatment. In contrast, two relapsed patients with PSD were succesfully salvaged with chemotherapy after relapse. Patients with cancer require special attention and have needs that are often unmet. The Institute of Medicine recommendations for the psychological care of cancer patients stress psychological needs as an integral part of quality cancer care, and also incorporate psychologists, psychiatrists and trained nurses as important members of oncological teams. In contrast, Meyer et al. showed that, of 17 metastatic breast cancer patients, two refused therapy and 10 did not comply with therapy. They did not report the survival of those patients. The conclusion was that patients with shizophrenia fail to understand the severity of their malignant disease and the need to comply with oncological treatment. Kishimoto et al. reported that the Osaka Center is able to carry out chemotherapy within the psychiatry ward, and they had good compliance for chemotherapy and good salvage results in two relapsed patients. However, they still reported lower all-cause survival. We probably need more screening for psychiatric disorders in cancer patients before any oncological treatment takes place. Sharpe et al. in the Symptom Management Research Trials (SMaRT-Oncology 2) trial showed that early intervention in cancer patients with major depression, by psychiatrists and trained nurses, resulted in an improvement in the depression scale. They did not report survival results. In conclusion, PSD could compromise treatment in cancer patients. Paying close attention to psychiatric symptoms and PSDs in cancer paitents and early intevention could avoid loss of treatment compliance and other causes of death in those patients. Good explanations of the disease course and strong psychiatric follow up are of special interest for young and curable patients, such as patients with testicular cancer.

Paratesticular rhabdomyosarcoma of a young adult

Sarcomas represent large and diverse group of malignant tumours, originating from mesenchymal cells. Nearly 15% of all childhood tumours and about 1% of all tumours in adults are sarcomas [1]. The incidence of adult soft tissue sarcomas in Europe is 5/100,000 [2]. Rhabdomyosarcoma accounts for 4.6% of all soft tissue sarcomas and it is the most common paediatric sarcoma, while it is extremely rare in adults [3].

Concurrent Chronic Lymphocytic Leukemia and Merkel Cell Carcinoma in Primary Skin Tumor and Metastatic Lymph Node

Association between chronic lymphocytic leukemia and other malignancies has been known for a long time. This epidemiological phenomenon is explained by immunosuppression caused by disease itself or by the applied therapy. Merkel cell carcinoma is a rare malignant tumor of the skin of neuroendocrine origin diagnosed almost exclusively in immunocompromised host. We presented an unique case of coexisting infiltration of chronic lymphocytic leukemia cells within primary cutaneous Merkel cell carcinoma and metastatic lymph node in young HIV-negative female patient.

Hepatitis B reactivation after therapy for non-Hodgkin lymphoma: A case report with review of literature

The natural course of hepatitis B virus (HBV) infection depends on the immune status of the host. In cancer patients, as the consequence of immune suppression due to chemotherapy and malignant disease itself, the balance between replicative potential of the virus and immune response of the host is disrupted leading to acute HBV infection or reactivation. We present a case of HBsAg positive, diffuse large B cell gastric lymphoma patient CD20+ staged IB, treated with six cycles of R-CHOP protocol and two cycles with rituximab monotherapy. Five months after the successful anticancer treatment, patient developed reactivation of chronic HBV infection (ten-fold increase in liver enzymes, HBsAg+, IgM antiHBc+, HBeAg(-), and HBV DNA 5×10 copies/ml). Antiviral therapy with lamivudine was started. Four weeks after the antiviral therapy initiation liver enzymes were in normal ranges. One year after the start of antiviral treatment HBV DNA PCR test did not detect any viral particles. The patient is in complete remission of malignant disease, and still receiving therapy with lamivudine. HBV screening in cancer patients is necessary in order to provide a prompt antiviral therapy and to prevent postponement or even cessation of planned anticancer treatment. HBsAg positive patients should start prophylactic antiviral treatment before the start of immunosuppressive treatment. Chemotherapy protocols consisting rituximab and corticosteroids significantly increase the risk of reactivation. If reactivation is diagnosed in course of chemotherapy, the therapy should be stopped and antiviral treatment should be applied as soon as possible. Treatment with lamivudine is continued at least 6 months after the chemotherapy end.

Melanoma During Pregnancy

Melanoma is the most malignant cutaneous tumor. The incidence of melanoma accounts for the sixth place among malignant diseases, 5% of malignancies among men and 4% of malignancies among women; it stands for 1.4% of deaths caused by malignant disease (Fisher et al., 2008). The incidence of malignant melanoma has constantly been increasing and it has reached 3% per year in the last several years. At the beginning of the 20th century, the population risk for malignant melanoma was in the ratio 1:500 but today 1:73 of women and 1:49 of men are at risk (Fisher et al., 2008). It is anticipated that there will be 68,130 newly diagnose cases of melanoma and approximately 8,700 deaths from the disease in the USA (Jamal et al., 2010). Among the population aged between 20 to 39 years malignant melanoma is on the second place by incidence. Although the disease is more frequent among men, its incidence during the reproductive period is higher among women. In Great Britain, the third of all diagnosed melanomas arise before 50 years of age and about 30% to 35% develop during the reproductive period of women (Anonymus, 2003; Cancer Research UK 2006). The actual incidence of melanoma during pregnancy is unknown. Smith and Randall (Smith RS & Randall, 1969) gave the first reports based on the source documents of a small non-reference Plattsburg Air Force Base Hospital, New York. The incidence of melanoma was 2.8 per 1000 deliveries but studies that are more recent showed that it is between 2.8 and 5 per 100,000 of pregnancies; the registry of German Dermatological Society shows that 1% of female patients affected with melanoma is pregnant (Dillman et al., 1996; Garbe, 1993). A group of Swedish authors analyzed the period from 1973 to 1984 and reported that melanoma is the most common cancer appearing in pregnancy and accounts for 24.5% of cancer cases in pregnant women (Matthiasen & Berg, 1989). From 1958 to 1999, 19,337 women with melanoma were included in the most extensive epidemiology study based on Swedish and regional registries; 0.9% of malignant melanomas were diagnosed during the pregnancy. Of all included patients, 5,533 of women were in reproductive age and 185 (3.3%) of them were diagnosed with melanoma during the pregnancy (Lens et al., 2004.). The prognostic features for melanoma depend on the stage it has been diagnosed. Although the 5-year survival for stage IV melanoma is still less than 5%, overall mortality from melanoma has a decreasing tendency (Rigel et al., 1996). The effect of pregnancy to the course of melanoma has been a researching issue for years. The results of uncontrolled studies conducted from 1950 to 1980 show that pregnancy is an unfavorable prognostic factor in