Tocilizumab in the treatment of steroid refractory immune-related hepatotoxicity: a case series and review of the literature.

With the widespread use of immune checkpoint inhibitors, management of immune-related adverse effects specific to these treatments became an important research era in patient management. Among these, immune-related hepatotoxicity (IRH) is an adverse event that can be fatal. While the first-line treatment of IRH is well established, there is still no consensus regarding the management approach for steroid-refractory, severe IRH. Here, we report four patients with metastatic melanoma who developed IRH during antiprogrammed cell death protein-1 plus anticytotoxic T-lymphocyte-associated protein-4 combination therapy and review of the literature. All of our patients were steroid-refractory and were successfully treated with tocilizumab. Given the rapid improvement in liver enzymes and patient's clinical status with tocilizumab, this treatment should be prioritized in steroid-refractory IRH.

Rare immune-related adverse effect of pembrolizumab: pulmonary hypertension.

Pembrolizumab is an immune checkpoint inhibitor that acts via PD-1 blockade. Recent studies have shown its effectiveness in treating various solid organ tumours. However, unlike cytotoxic chemotherapeutic agents, pembrolizumab may cause immune-related adverse effects. These immune-related adverse effects are generally mild, although patients who experience grade-three or higher side effects may require hospitalisation. In particular, cardiopulmonary side effects are associated with high mortality rates. We report the case of a 24-year-old female patient with alveolar soft part sarcoma accompanied by rare and difficult-to-treat pulmonary hypertension induced by pembrolizumab.

Successful application of chemosaturation with percutaneous hepatic perfusion in metastatic uveal melanoma patient progressing after systemic treatment options: a case report.

Uveal melanoma (UM) is a rare subtype of melanoma, accounting for less than 5% of all melanoma cases. Metastatic UM differs notably from cutaneous melanoma, exhibiting variations in etiology, prognosis, driver mutations, metastatic patterns, and poor responses to immune checkpoint inhibitors (ICI). Beyond local treatment options, such as resection, radiation therapy, and enucleation, and systemic treatments, such as ICIs, the approval of tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T-cell engager, marks a breakthrough in treating HLA-A*02:01 metastatic UM. Despite the advancements in treatment options, the long-term survival rates remain inadequate. We report a patient with metastatic UM who previously received ICI and progressed on tebentafusp treatment but subsequently exhibited a remarkable response to local treatment targeting liver metastasis. Such observations highlight the significance of exploring sequential therapeutic strategies for advanced UM, offering potential avenues to enhance treatment efficacy and patient prognosis.

Efficacy of local ablative therapies in patients with solid tumors treated with immune checkpoint inhibitors and oligoprogression: a single-center analysis.

The concept of oligoprogression reflects a situation where a limited number of metastatic tumor sites have progressed and other metastatic sites are under control with current systemic therapy. The optimal management of oligoprogression remains unclear. In this retrospective study, we evaluated the contribution of local ablative treatment approaches after oligoprogression to progression-free survival and response rates (RRs) in patients with renal cell carcinoma ( N : 5), nonsmall cell lung cancer ( N : 1) and melanoma ( N : 21) who received immunotherapy. We found that patients received local ablative therapies after oligoprogression had longer progression-free survival and higher RR compared to those who did not. Specifically, patients who received concurrent radiotherapy had a median survival time of 24.7 months compared to 14.5 months in those who did not. Our results suggest that local ablative therapies may have a beneficial impact on progression-free survival and RR in patients with oligoprogression who are being treated with immune checkpoint inhibitors. Further studies are needed to confirm these findings and determine the optimal use of local ablative therapies in this setting.

Treatment Process of Primary Prostate Leiomyosarcoma: A Rare Case Report.

Prostate sarcoma is an extremely rare malignancy that accounts for only %0.1 of all neoplasms of the prostate gland. Primary prostate leiomyosarcoma (PLSOP) is the most common subtype in adults. Due to the fact that it is an extremely rare malignancy, case reports have been reported frequently and several publications in the form of case series. The number of case reports in the world is less than 200. Our opinion is that publishing such rare diseases and bringing them to the literature will have positive benefits both scientifically and for the patients. We present a patient with PLSOP and discuss the clinical, diagnostic and therapeutic aspects of this rare malignancy. Keywords: Prostate, Leiomyosarcoma, Cancer, Prognosis.

Effects of leptin on the viability of human ovarian cancer cells and changes in cytokine expression levels.

Background: Obesity is associated with increased mortality among ovarian cancer and is a poor prognostic factor. There are significant links between the leptin hormone, a product of the obesity gene, and the development of ovarian cancer. Leptin is a vital hormone-like cytokine secreted from adipose tissue and is mainly involved in the maintenance of energy homeostasis. It regulates several intracellular signaling pathways and also interacts with various hormones and energy regulators. It acts as a growth factor by stimulating cell proliferation and differentiation and in this way contributes to cancer cell development. The aim of the study was to investigate the effects of leptin on human ovarian cancer cells. Methods: In this study, the effects of increasing the concentration of leptin were investigated on the cell viability of OVCAR-3 and MDAH-2774 ovarian cancer lines by MTT assay. Moreover, to elucidate the molecular mechanisms of leptin in ovarian cancer cells, changes in the expression levels of 80 cytokines were evaluated after leptin treatment via a human cytokine antibody array. Results: Leptin increases the proliferation of both ovarian cancer cell lines. IL-1 level was increased in OVCAR-3 cells and TGF-ß level was increased in MDAH-2774 cells after leptin treatment. A decrease in IL-2, MCP-2/CCL8 and MCP-3/CCL7 levels was detected in both ovarian cancer cell lines with leptin administration. An increase in IL-3 and IL-10 expressions, insulin-like growth factor binding proteins (IGFBP) IGFBP-1, IGFBP-2 and IGFBP-3 levels were detected in both ovarian cancer cell lines with leptin administration. In conclusion; leptin has a proliferative effect on human ovarian cancer cell lines and affects different cytokines in different types of ovarian cancer cells.

Immunotherapy-induced granulomatous reaction in patients with melanoma.

Immune checkpoint inhibitors (ICIs) represent a new era in stage IV melanoma treatment. These agents are generally well tolerated but have specific side effects. The granulomatous reaction is one of such ICI-related adverse events. In this report, we present the cases of three patients with stage IV melanoma who all developed mediastinal and hilar lymphadenopathy during ICI treatment. While a complete response was observed in one patient, near complete responses were observed in the other two patients. Amid these favorable outcomes, all patients developed mediastinal and hilar lymphadenopathy approximately 6 months after the initiation of immunotherapy. Biopsies were performed to explore the underlying pathology of the lymph nodes, which revealed granulomatous reactions rather than metastases. Hence, immunotherapy was continued in all patients. The development of granulomatous lymphadenitis associated with ICIs may mimic disease recurrence/progression clinically and radiographically. Awareness of such type of adverse event is crucial to decide whether to continue therapy or not.

Trastuzumab in combination with AT-101 induces cytotoxicity and apoptosis in Her2 positive breast cancer cells.

Aim: AT-101 is a polyphenolic compound with potent anti-apoptotic effects in various cancers. In this study, the possible synergistic cytotoxic and apoptotic effect of trastuzumab/AT-101 combination was investigated in HER2-positive breast cancer cell lines. Materials & methods: SKBR-3, MDA-MB-453 and MCF-10A cell lines were treated with a trastuzumab/AT-101 combination. Synergistic cytotoxicity and apoptosis effects were shown and then PI3K and Akt protein levels were studied. Result: The trastuzumab/AT-101 combination induced synergistic cytotoxicity and apoptosis in both breast cancer cells but not in MCF-10A cells. Combination treatment induced cytotoxicity via inhibiting PI3K/AKT but not the MAPK/ERK pathway. Conclusion: The trastuzumab/AT-101 combination may be a good candidate for patients with trastuzumab-resistant Her2-positive breast cancer and inhibition of the PI3K/AKT pathway may be one of the underlying mechanisms.

Biweekly cetuximab in combination with platinum and 5-fluorouracil in metastatic head and neck carcinoma.

BACKGROUND AND AIM: The combination of cetuximab with platinum and 5-fluorouracil (5-FU) chemotherapy prolongs survival in patients with metastatic or recurrent squamous-cell carcinoma of the head and neck (SCCHN). Biweekly (once in 2 weeks) administration of cetuximab requires fewer hospital visits and decreases treatment costs; therefore, it is more convenient both for the patients and for the healthcare providers. Here, we assessed the efficacy, safety, and tolerability of an alternative biweekly regimen of cetuximab in combination with platinum and 5-FU chemotherapy as a first-line treatment for these patients. METHODS AND MATERIALS: Medical records of patients with metastatic or recurrent non-nasopharyngeal SCCHN who were treated with a biweekly regimen of cetuximab (500 mg/m2 on day 1), cisplatin (40 mg/m2 on day 1) or carboplatin (target area under the curve 3.5 mg/ml × min on day 1), folinic acid (400 mg/m2 on day 1), and 5-FU (400 mg/m2 bolus on day 1 followed by continuous infusion of 2,400 mg/m2 5-FU over 46 h) were retrospectively reviewed. Survival estimates were calculated with the Kaplan-Meier method. RESULTS: In total, 60 patients were included. The median age of the patients was 60.5. The objective response rate was 53.3% (95% confidence interval [CI] = 40.7-65.9). The median progression-free survival duration was 6.8 months (95% CI = 5.5-8.1) and the median overall survival duration was 13.3 months (95% CI = 8.4-18.2). The most common grade 3 or 4 adverse events were neutropenia (28.3%) and leucopenia (13.3%). Grade 3 or 4 rash was observed in 3.3% of the patients. CONCLUSION: Biweekly administration of cetuximab, cisplatin, and 5-FU is an effective regimen with a favorable toxicity profile for the first-line treatment of metastatic or recurrent SCCHN. These results warrant further evaluation of this regimen in prospective trials.

Middle East observational study in metastatic soft tissue sarcoma: an epidemiological study on the treatment patterns (MOON).

PURPOSE: Soft tissue sarcomas (STS) are a heterogeneous group of rare mesenchymal neoplasms, accounting for < 1% of all newly diagnosed malignancies. These tumors can occur in almost any anatomic site though they most frequently occur in the extremities. The objective of the study was to describe the epidemiology, treatment paradigm, and real-world outcomes in the clinical management of metastatic STS (mSTS) in the Middle East and North Africa (MEA) region. METHODS: MOON was an observational, multicenter, retrospective patient chart review study which included 200 patients with mSTS in the final analysis. The primary objective of the study is exploratory, so it is presented using descriptive statistics. RESULTS: At the time of presentation, 62.0% patients had metastatic disease, 27.5% had received only their primary diagnosis and 10.0% had experienced a local recurrence. The most frequent STS localizations were lower extremities (74%), trunk (28.5%) and upper extremities (10.5%). Primary tumor was staged as T2b in the majority (60%) of patients. Surgical treatment was performed most often for the primary disease, whereas radiation therapy and chemotherapy were predominantly administered with palliative intent. A total of 38 patients received treatment with pazopanib. Thirteen adverse events (AEs) were attributed to pazopanib in eight patients. CONCLUSION: Adult patients treated for STS have al most equal gender ratio and mostly are middle aged. The majority of patients have metastatic disease and disease progression, and half of the patients died from the disease during the period of evaluation. This study obtained real-life data on the clinical management of STS in MEA countries which could be shared with the medical community.

Electrochemotherapy with anti-PD-1 treatment induced durable complete response in heavily pretreated metastatic melanoma patient.

Metastatic melanoma (MM) is one of the most lethal types of cancer. Although novel immunotherapeutics have been developed recently, still, these drugs fail to save the lives of a third of MM patients. Electrochemotherapy (ECT) is a local treatment of cancer based on a combination of electroporesis and low-dose chemotherapy. In this case report, we present the treatment history of a MM patient treated successfully with ECT and immunotherapy combination as a fifth-line treatment. Our patient was a 39 year-old woman who was diagnosed with nodulary melanoma stage II. Due to a local recurrence, she was given interferon-α treatment. After 6 months, her disease relapsed in the axillary lymph nodes, and temozolamide treatment 150 mg/m2 was initiated. After six cycles on temozolamide, she progressed both in the axillary site and in the lungs. Her BRAF mutation analysis revealed V600E positivity. Hence, BRAF inhibitor-vemurafenib 2'4 tablets per day was initiated. Within 3 months, she responded dramatically both in the axillary site and in the lungs. At the ninth month of treatment, she progressed again, at which time ipilimumab 3 mg/kg was started as a fourth line treatment. However, shortly after, she progressed again and developed a solitary brain metastasis. She was operated and had whole brain radiotherapy. At that point, nivolumab, an antiprogrammed cell death ligand-1 blocker, was the only remaining option. She showed a biphenotypical response to nivolumab; a mass on the anterior axilla was progressing while the other lymph nodes had regressed. Owing to the accessibility of the subcutaneous lesion with external electrodes, ECT was performed using IGEA Cliniprator device through a hexagonal electrode on the progressive mass, while on nivolumab treatment. A complete response was achieved, with no evidence of disease at 4 years since her local recurrence. Eradication of symptomatic, refractory lesions using ECT meets an important clinical need. Whenever a disseminated disease presents with cutaneous/subcutaneous lesions, high efficacy of ECT should be deployed to augment tumor immunogenicity and complement systemic immunotherapies.

Risk factors for poor mobilization in solid tumors: How effectively can we mobilize patients with solid tumors?

BACKGROUND: In the literature, risk factors for poor mobilization were tried to identify. However, most of the studies consisted heterogeneous group of patients including both hematologic and oncologic malignancies. In this study, we aimed to identify the risk factors for poor mobilization in adults with solid tumors. METHODS: We enrolled 49(47 men, 2 women) adult patients with solid tumor who were mobilized between September 2007 and February 2017. All the mobilization procedures were performed with G-CSF(10µg/kg/day) with chemotherapy. Mobilization insufficiency was defined as peripheral blood CD34+stem cell number less than 10/µl and/or total collected CD34+cells less than 2.5×10 6/kg. RESULTS: The patients were divided into two groups, patients with successful mobilization at the first attempt(group 1, 36 patients,73.5%) and poor mobilizers (group 2, 13 patients 26.5%). Second and third mobilization attempt was needed in 11 and 2 patients, respectively. The median number of CD34+cells collected was 7,08×106/kg(0,6-19) with a median 4(1-6) apheresis. There was no statistical difference between two groups in terms of patient's and mobilization characteristics. Only number of CD 34+stem cells collected was statistically different (median 9,07×106/kg CD34+cells in group 1 versus 2,14×106/kg in group 2, p<0.05). The only possible risk factor that we could define was presence of organ metastasis. CONCLUSIONS: Since several methods and new drugs are available for peripheral stem cell collecting, risk factors should be identified clearly in adult population with solid tumors. So multicenter studies should be constructed for resolving this problem.

Pazopanib: a novel treatment option for aggressive fibromatosis.

BACKGROUND: Aggressive fibromatosis (AF), also known as desmoid tumor, is an uncommon soft tissue neoplasm. AF does not metastasize, but it is locally invasive and its propensity for recurrence after conservative resection is well documented. No effective cytotoxic treatment has been reported, hence there is a need for novel treatment strategies. CASE PRESENTATION: We present the case of an AF successfully treated with an oral tyrosine kinase inhibitor, pazopanib, with mild side effects. As far as we know, this is the first case of AF with complete response to pazopanib. CONCLUSION: Pazopanib might be an effective treatment option for AF.

Combination of zoledronic acid and serine/threonine phosphatase inhibitors induces synergistic cytotoxicity and apoptosis in human breast cancer cells via inhibition of PI3K/Akt pathway.

The aim of this study was to investigate the cytotoxic and apoptotic effects of zoledronic acid (ZA) in combination with serine/threonine protein phosphatase inhibitors, calyculin-A (CA) and okadaic acid (OA), in human MCF-7 and MDA-MB-231 breast cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. DNA fragmentation and caspase-3/7 activity assays were performed to evaluate apoptosis. Activities of phosphatase 1 (PP1) and phosphatase 2A (PP2A) were measured by serine/threonine phosphatase ELISA kit. Expression levels of PI3K, p-PI3K, Akt, p-Akt, Bcl-2, p-Bcl-2, Bad, and p-Bad proteins were evaluated by Western blot analysis. Combination of ZA with either CA or OA showed synergistic cytotoxicity and apoptosis as compared to any agent alone in both MCF-7 and MDA-MB-231 breast cancer cells. Combination treatment also resulted in inhibition of both PP1 and PP2A activities. Both agents used alone or in combination did not induce significant changes in total PI3K, Akt, Bcl-2, and Bad expressions, while p-PI3K, p-Akt, p-Bcl-2, and p-Bad levels were reduced by the combination treatment as compared to agents alone. Moreover, apoptotic effect of combination treatment was significantly inhibited in the presence of LY294002, a specific PI3K inhibitor, in both breast cancer cell lines. In conclusion, synergistic apoptotic effect of the combination treatment is correlated with the block of the PI3K/Akt signal pathway in breast cancer cells.

Adjuvant chemotherapy may contribute to an increased risk for metabolic syndrome in patients with breast cancer.

PURPOSE: Cytotoxic treatment may cause weight gain and important alterations in the metabolic status of breast cancer (BC) patients. The aim of this study was to investigate the changes in metabolic and anthropometric parameters of patients with BC who received adjuvant chemotherapy. METHODS: All consecutive women treated with adjuvant TAC (docetaxel 75 mg/m(2), doxorubicine 50 mg/m(2), cyclophosphamide 500 mg/m(2)) chemotherapy for node-positive breast carcinoma at our Institution between 2008 and 2010 were included. RESULTS: Among 104 patients, 84 of them were stage II and 20 of them were stage III. When we compared the measurements between 1(st) and 6(th) adjuvant chemotherapy, we observed statistically significant increases in weight and serum triglyceride levels, and decreases in high density lipoprotein, apolipoprotein A-1, transferrin, albumin and prealbumin levels. An elevation of follicle stimulating hormone, luteinizing hormone together with the decrease of estradiol was detected. Waist-to-hip ratio has also increased significantly. In subgroup analyses, we observed dramatic changes in body mass index in pre-menopausal women whereas no significant change was seen in the post-menopausal group. CONCLUSIONS: Adjuvant chemotherapy may contribute to an increased risk for metabolic syndrome in patients with BC and these changes are more profound in pre-menopausal patients.

Octreotide in combination with AT-101 induces cytotoxicity and apoptosis through up-regulation of somatostatin receptors 2 and 5 in DU-145 prostate cancer cells.

Prostate cancer (PCa) is the most common type of cancer among males. Although survival rate of early-stage PCa is high, treatment options are very limited for recurrent disease. In this study, the possible synergistic cytotoxic and apoptotic effect of octreotide in combination with AT-101 was investigated in DU-145 hormone and drug refractory prostate cancer cell line. To enlighten the action mechanisms of the combination treatment, expression levels of somatostatin receptors 2 and 5 (SSTR2 and SSTR5) were also investigated. Cell viability was measured by XTT assay. Apoptosis was assessed through DNA fragmentation analysis and caspase 3/7 assay. mRNA and protein levels of SSTR2 and SSTR5 were evaluated by qRT-PCR and western blot analysis, respectively. Octreotide in combination with AT-101 inhibited cell viability and induced apoptosis synergistically in DU-145 cells as compared to any agent alone. Combination treatment increased both SSTR2 and SSTR5 mRNA and protein levels in DU-145 cells. The data suggest that this combination therapy may be a good candidate for patients with advanced metastatic PCa do not respond to androgen deprivation.

Capecitabine maintenance therapy following docetaxel/capecitabine combination treatment in patients with metastatic breast cancer.

The present study aimed to analyze the efficacy of maintenance therapy with single agent capecitabine for human epidermal growth factor receptor (HER2) negative metastatic breast cancer (MBC) patients following disease control with 6 cycles of docetaxel plus capecitabine chemotherapy as the first-line treatment. As an initial treatment, 6 cycles of docetaxel plus capecitabine followed by maintenance therapy with capecitabine were administered. A total of 55 patients received combination therapy and 48 patients proceeded to maintenance therapy: Of these, 32 patients (66.7%) were postmenopausal and 37 (77.1%) had estrogen and progesterone receptor positive disease. The median progression-free survival rate with maintenance therapy was 5.5 months (95% CI, 0-11.4 months) and the median overall survival (OS) was 26.6 months (95% CI, 21.8-30.1 months). The use of maintenance therapy improved previous responses in 4 patients (8.3%; 2 partial and 2 complete responses) and 32 patients (66.7%) had stable disease. The median number of maintenance therapy cycles applied was 6.5 (range 1-28, total 441). The observation of side effects, including grade 3/4 neutropenia, febrile neutropenia and fatigue was more common during combination therapy. The results of the present study indicate that maintenance with single agent capecitabine therapy is an effective and tolerable treatment option for HER2 negative MBC patients in which disease control with 6 cycles of docetaxel plus capecitabine chemotherapy is achieved in the first-line setting.

The Role of Body Mass Index in Triple Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) has none of the targeted treatment choices due to its distinct biological property, making this subtype a unique disease. In this study, we evaluated the impact of obesity on clinical outcomes of TNBC. METHODS: The data of breast cancer patients admitted to our department were collected. TNBC was defined as lack of estrogen receptor (ER), progesterone receptor (PR) and HER-2. The body mass index (BMI) of 112 TNBC patients was calculated with weight at the time of diagnosis and height. The patients were classified into groups with a BMI of < 25 (normal/underweight), 25-29.9 (overweight) or ≥ 30 (obese). After a mean follow-up of 23.2 ± 15.5 months, there were 12 recurrences (10.71%) and 6 deaths (5.35%). Disease-free survival (DFS) and overall survival (OS) were assessed. RESULTS: The survival analyses of all the patients did not demonstrate any differences in OS or DFS in obese as compared to non-obese patients. However, we showed that obesity was associated with a poorer OS for postmenopausal TNBC patients (p < 0.05). CONCLUSION: Obesity is related to a poorer OS in postmenopausal TNBC patients. Due to the heterogeneous disease profile of TNBC, larger randomized studies will be needed to clarify the exact role of obesity in TNBC.

Cutaneous melanoma in Turkey: analysis of 1157 patients in the Melanoma Turkish Study.

PURPOSE: To develop a large Turkish National Melanoma registry in order to define demographic and clinicopathologic characteristics of patients with melanoma. METHODS: The data was collected from 1635 patients with melanoma through a web-based registry system in 22 centers. Herein we present the results of 1157 patients with cutaneous melanoma. RESULTS: The patient median age was 56.4 years and 646 (55.8%) were males. The commonest subtype was superficial spreading type (357, 30.9%). The commonest primary site was the lower extremities (N=353, 30.5%). The most common Breslow thickness was 1-2 mm (361 patients, 43.5%). Only 104 (12.5%) patients had a thickness <1mm. Among 694 patients with available data, 136 (19.6%) presented with stage 4 disease while the most frequent stage was stage 3, encountered in 393 (56.6% patients). CONCLUSION: Our melanoma registry is the largest in our country providing a snapshot view of cutaneous melanoma and its care. Our patients presented with more advanced stages and they had worse prognosis compared to SEER database.