Five-Year Outcome and Safety in Patients Treated With Immune Checkpoint Blockade Therapies for Urothelial Carcinoma: Experience From Real-World Clinical Practice.

BACKGROUND: In this study, we report real-world results from the 5-year follow-up data of urothelial carcinoma patients treated with immune checkpoint blockade therapies (ICTs). PATIENTS AND METHODS: Metastatic urothelial carcinoma patients treated with at least one course of ICT were included in the study. The primary endpoint was overall response rate (ORR), and secondary endpoints were overall survival (OS), progression-free survival (PFS), duration of treatment with ICT, and safety. Median follow-up, PFS, and OS were estimated by using the Kaplan-Meier method. RESULTS: Data of 201 eligible patients were analyzed. The median age of the patients was 66 (37-86) years, and 156 (84.3%) were male. The majority of patients (94.6%) had Eastern Cooperative Oncology Group (ECOG) PS scores of 0 to 1 and primary tumor in the bladder was predominant (87.5%). The median follow-up time was 54 (1.15-65) months. The rate of complete response (CR) to ICT, partial response (PR) rate, and ORR were 10.4% (n = 21), 22.4% (n = 45), and 32.4% (n = 66), respectively. The median duration of response (DOR) was 34.8 months (95% confidence interval [CI], 29.2-42.1). Of the 66 patients who responded to treatment, 28 (42%) had an ongoing response at the time of the analysis. Median PFS and OS were 3.8 (2.6-5.8) months and 9.4 (7.4-11.4) months, respectively. The 5-year PFS and OS rates were 9.8% and 12.8%, respectively. Fifty-eight percent of patients experienced a treatment-related adverse event of any grade, and 33 (16.4%) patients had a grade 3 to 4 adverse event. CONCLUSION: This 5-year analysis of real-world data confirms the durable response and long-term survival with ICT in metastatic urothelial carcinoma patients.

Relationship between survival outcomes and microsatellite instability, tumor infiltrating lymphocytes and programmed cell death ligand-1 expression in patients with bladder cancer and radical cystectomy.

PURPOSE: Platin-based chemotherapies are first-line treatment methods after surgery in bladder cancer. Recently, novel immunotherapies emerged after platin-based regimens. The purpose of this study was to evaluate the prognostic significance of microsatellite instability (MSI), tumor infiltrating lymphocytes (TILs) and programmed cell death ligand-1 (PD-L1) expression which are used as predictive biomarkers in immunotherapy. METHODS: Clinical and pathological features of bladder cancer patients who underwent radical cystectomy were retrospectively analyzed from their records in this single-center study. PD-L1, PD-L1 on TIL, PMS2, MSH2, MSH6 and MLH1 immunohistochemistry staining were carried out to archieve resected tumor specimens of the eligible patients. MSI was evaluated according to existing of PMS2, MSH2, MSH6 and MLH1. RESULTS: MSI was high in 24.6% of 61 patients. PD-L1 expression on tumor cells and PD-L1 expression on TIL were positive in 14.8% and 16.4% of the patients, respectively. Intratumoral TIL rate was >10% in 12 patients (19.7%). There was no statistically significant relationship between PD-L1, PD-L1 on TIL, MSI and TIL rate and patients' characteristics including sex, stage, pathologic grade and lymph node status. There was a positive trend between MSI-high patients and overall survival (OS) (p=0.089). Univariate analysis did not reveal any significant difference at 3-years OS with PD-L1 tumor expression and PD-L1 expression on TIL and TIL rate >10% (p=0.822, p=0.638, p=0.318, respectively) Conclusion: This study revealed that there is a positive trend between OS and MSI but no prognostic significance of PD-L1 and TIL which are proven predictive biomarkers of immunotherapy in patients with bladder cancer.

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences.

BACKGROUND: Atezolizumab (ATZ) has demonstrated antitumor activity and manageable safety in previous studies in patients with locally advanced or metastatic platinum-resistant urothelial carcinoma. OBJECTIVE: To compare the real-life experience and data of clinical trials on ATZ treatment in metastatic urothelial carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Patients with urothelial cancer treated with ATZ after progression on first-line chemotherapy from an expanded access program were retrospectively studied. Data of patients were obtained from their files and hospital records. Safety was evaluated for patients treated with at least one cycle of ATZ. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR). The secondary endpoints are overall survival (OS), progression-free survival (PFS), duration of response, and safety profile of patients. Kaplan-Meier methods were used to calculate median follow-up and estimate PFS and OS. RESULTS AND LIMITATIONS: Data of 115 enrolled patients were analyzed. Most of the patients (92.3%, n = 106) had received chemotherapy regimen only once prior to ATZ. The median follow-up duration was 23.5 mo. The complete response rate, partial response rate, and ORR were 8.7% (n = 10), 20.0% (n = 23), and 28.7% (n = 33), respectively. The median duration of response was 20.4 mo (95% confidence interval [CI], 6.47-28.8). Of the 33 patients who responded to treatment, 60% (n = 20) had an ongoing response at the time of the analysis. PFS and OS with ATZ were 3.8 mo (95% CI, 2.25-5.49) and 9.8 mo (95% CI, 6.7-12.9), respectively. All-cause and any-grade adverse events were observed in 113 (98%) patients. Of the patients, 64% experienced a treatment-related adverse event of any grade and 24 (21.2%) had a grade 3-4 treatment-related adverse event. Limitations of the study included its retrospective design, and determination of treatment response based on clinical notes and local radiographic studies. CONCLUSIONS: In these real-life data, ATZ was effective and well tolerated in patients with metastatic urothelial carcinoma who have progressed with platinum-based first-line chemotherapy. ATZ is an effective and tolerable treatment for patients with locally advanced or metastatic platinum-resistant urothelial carcinoma in our study, similar to previously reported trials. PATIENT SUMMARY: Atezolizumab is effective and well-tolerated in patients with metastatic urothelial cancer who progressed with first-line chemotherapy, consistent with the outcomes of the previous clinical trials in this setting.

Retrospective Analysis of Survival in Patients with Brain Metastases from an Unknown Primary Tumor.

AIM: To evaluate the patients with brain metastases from unknown primary (BMUP) cancers, and to analyze the prognostic factors and survival rates. MATERIAL AND METHODS: We conducted a retrospective study with 110 patients (mean age: 62.8 years [range 23?90], n=85- 77.3% male and n=25-22.7% female) with BMUP cancers at the time of diagnosis, who presented to our outpatient oncology clinic between January 2015 and December 2019. We employed the following variables as significant prognostic factors for a prominent index of patients? survival: age, gender, Karnofsky performance score (KPS), number of metastatic lesions, primary site, and type of treatment were analyzed for their prognostic effects on survival outcomes. Patients? survival was evaluated from plotted Kaplan? Meier curves, and the log-rank test was used for univariate analysis. RESULTS: The mean follow-up was 13 months (range 4?60 months). The means of survival after the diagnosis of brain metastasis was 18.7 months for the study group. Lung cancer was the most common primary tumor (74, 5%). The KPS and number of lesions were found to have a prognostic effect on survival. Survival analysis showed no statistical significance with age and gender, primary site, type of treatment. CONCLUSION: This study showed that KPS, and the number of lesions affect the survival outcomes but both the other variables. Therefore, BMUP cancer is indeed related to poor prognosis.

The effect of PD-L1 status on survival outcomes in patients with stage II-III non-small cell lung cancer treated with chemotherapy.

PURPOSE: There are conflicting results in the literature about the relationship between PD-1/PD-L1 expression and prognosis in non-small cell lung cancer (NSCLC). The purpose of this study was to identify the relationship between NSCLC patients' clinicopathologic characteristics and PD-1/PD-L1 expression. METHODS: Pathology specimens of eligible stage II-III NSCLC patients were immunohistochemically stained with PD-1 and PD-L1 antibodies. Patient files and digital records were retrospectively reviewed for demographic and clinical features such as age, gender, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status (PS), histological tumor subtype, applied chemotherapeutic types and their dates and survival data. Statistical analyses were performed to evaluate prognostic effects of staining status of PD-L1 and PD-1 in tumor cells and PD-L1 in tumor infiltrating inflammatory cells. RESULTS: In a total 74 patients, 45.9% of them were positive for PD-L1 in tumor cells, 67.9% positive for PD-L1 in tumor infiltrating inflammatory cells and 83.8% positive for PD-1 in tumor cells (p>0.05). There was a statistically significant relationship between the positive staining of PD-L1 tumor cells and increased overall survival (OS) in univariate analysis (3-year OS; PD-L1(+) 76.6% vs PD-L1(-) 41%, p=0.031). In multivariate analysis only stage and ECOG PS were statistically significant. CONCLUSIONS: PD-L1 positivity in tumor cells was a positive prognostic factor for OS in patients with stage II and III NSCLC.

Safe use of nivolumab in a patient with renal cell carcinoma and hepatitis B.

INTRODUCTION: Immunotherapy with checkpoint inhibitors gains a major role in bladder cancer. Because of the treatment's immune modulatory effects, patients may develop hepatitis. Hepatitis B was an exclusion criterion in clinical trials that investigated nivolumab. Therefore, its effects and risk of hepatitis B reactivation in nivolumab are not clinically investigated in renal cell carcinoma patients with hepatitis B. CASE REPORT: In this case report, we presented a metastatic renal cell carcinoma patient who was treated with anti-viral treatment for hepatitis reactivation caused by previous sunitinib therapy. After progression, nivolumab was commenced and the patient was closely monitored with hepatic function tests. MANAGEMENT AND OUTCOME: Nivolumab was well tolerated and no treatment-related adverse effect occurred. Hepatitis or viral hepatitis reactivation was not detected. DISCUSSION: This case supports the safety of nivolumab in patients with renal cell carcinoma and viral hepatitis.

PTEN loss is a predictive marker for HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.

PURPOSE: The purpose of this study was to retrospectively investigate the response to trastuzumab in breast cancer patients in terms of the potential roles of several oncogenic pathways (phosphatase and tensin homolog (PTEN) and phosphatidylinositol 3-kinase (PI3K)) in relation to HER2 status. METHODS: Paraffin-embedded primary tumor tissues of 100 HER2 positive metastatic breast cancer patients who received trastuzumab were analyzed with immunohistochemistry for p85 (PI3K) and PTEN. The relationship between variables was tested via chi-square, Fischer's exact test and Mann-Whitney U test, where appropriate. Progression-free survival (PFS) and overall survival (OS) were calculated with the Kaplan-Meier method and survival curves of subgroups were compared with the log-rank test. Results: The level of immunohistochemical expression of PI3K was 42%. Loss of PTEN was observed in 43% of the patients. PTEN-expressing tumors had statistically higher response rates for trastuzumab than tumors not-expressing PTEN (p=0.012). PI3K expression had no significant effect on trastuzumab response. Median PFS for PTEN-expressing and not-expressing tumors were 15.3 months (95% CI, 12.6-34) and 12.1 months (95% CI, 7.9-16.2), respectively (p=0.04). The level of PI3K expression had no effect on PFS and OS in our patient population. CONCLUSIONS: Loss of PTEN predicted poorer response to trastuzumab treatment and shorter PFS but not OS. We could not find an effect of PI3K expression on the above-mentioned parameters.

Clinicopathological characteristics, prognosis and survival outcome of gastric cancer in young patients: A large cohort retrospective study.

PURPOSE: To investigate the survival outcome of patients with gastric cancer ≤40 years of age and to compare them to older patients with gastric cancer. METHODS: The study included gastric cancer patients treated between1990 and 2014. Patient demographics, tumor histopathological characteristics and outcome were registered. Patients were classified according to the International Classification of Diseases for Oncology. Two subgroups of patients were created based on age: group 1 (40 years and less at the time of diagnosis, and group 2 (patients older than 40 years). Categorical and continuous variables were analyzed with x2 and Mann-Whitney U tests, respectively. Overall survival (OS) rates were estimated by the Kaplan-Meier method. RESULTS: Diffuse adenocarcinoma was more common in the young group (48.9%) than in the older group (28.9%) (p<0.0001). No statistically significant survival difference was noted between younger (11 months) and older patients (12 months) (p=0.79]. Early stage (p<0.0001), absence of perineural invasion (PNI) (p<0.0001), absence of lymphovascular invasion (LVI) (p<0.0001), and non-cardia tumors (p<0.0001) were associated with better OS rates in univariate analysis. Non-cardia tumors (p=0.016) and stage (p=<0.0001) were independent prognostic factors of survival outcome in multivariate analysis. CONCLUSIONS: This study demonstrated that young and older patients with gastric cancer have similar outcomes in terms of OS.

Hepatitis D reactivation in a patient with metastatic renal cell carcinoma receiving sunitinib therapy.

BACKGROUND: Cytotoxic and immunosuppressive therapies for cancer treatment may allow hepatitis reactivation. Hepatitis due to viral hepatitis reactivation is detected in 14%-25% of hepatitis B surface antigen (HBsAg)-positive cancer patients undergoing anticancer treatments. Drug toxicity may be confused with hepatitis reactivation, which may cause a delay in diagnosis. CASE REPORT: A 60-year-old man with metastatic renal cell carcinoma was treated with sunitinib. Sixteen months after sunitinib inception, liver enzymes were elevated and viral hepatitis reactivation was detected as hepatitis delta virus infection in the HBsAg-positive patient. CONCLUSION: Cancer patients should be screened for viral hepatitis prior to immunosuppressive therapy or chemotherapy.

Hepatitis B Reactivation Rate Is Higher Undergoing Some Cytotoxic Chemotherapy in Patients with Solid Tumors: A Large Retrospective Study.

OBJECTIVE: The reactivation rate of chronic hepatitis B virus infection in cancer patients and chemotherapy regimens thought to be associated with hepatitis reactivation were investigated. PATIENTS AND METHODS: In all, 3,890 cancer patients were included in this study. Mortality rates, chemotherapy regimens, cancer types, number of positive hepatitis serology and reactivation rates were obtained. RESULTS: Only 354 patients had positive hepatitis serology results (HBsAg+). Twenty-four patients (6.7%) with HBsAg positive serology had reactivation. In patients with hepatitis reactivation, the rates of usage of 5-fluorouracil (5-FU), cisplatin, cyclophosphamide, doxorubicin, steroid, rituximab, and vincristine were found to be significantly higher than corresponding rates in patients with positive hepatitis serology results but without hepatitis reactivation (p < 0.05 for all). CONCLUSION: Increased reactivation rates were detected with usage of 5-FU, cisplatin, cyclophosphamide, doxorubicin, steroid, rituximab, and vincristine.

Late relapse of testicular cancer: Recurrence after 24 years and treatment with chemotherapy alone.

Late relapse of testicular cancer, defined as >2 years interval between initial treatment and recurrence, is a rare disease with the incidence rate of 2.6%. Due to its chemoresistant features, treatment options of late relapses are controversial while surgical approach and cisplatin-based chemotherapies can be considered. We report here a patient with nonseminomatous germ cell tumor who experienced relapse 24 years after his first diagnosis. After detecting left supraclavicular lymphadenopathy and absence of any other malignant lesion in positron emission tomography-computerized tomography, patient was treated with three cycles of VeIP regimen (vinblastine/ifosfamide/cisplatin). Second complete response to this treatment was achieved with chemotherapy alone.

Cancer pain prevalence and its management.

Pain is a public health problem affecting more than half of cancer patients. Despite the success of the protocols currently used, pain cannot still be reduced satisfactorily in the large majority of patients. In order to improve pain management, all healthcare professionals involved with pain should have sufficient knowledge on pain assessment and treatment, and should inform patients to prevent patient-related barriers. In this compilation, the prevalence values and the treatment methods of cancer pain, and the barriers to pain management have been assessed.

Severe liver dysfunction and safe use of 5-fluorouracil leucovorin and oxaliplatin in one patient with metastatic colorectal carcinoma.

The liver is the most frequent site of metastases in colorectal cancer. Commonly used anticancer drugs in colorectal cancer are 5-fluorouracil, oxaliplatin and irinotecan 5-fluorouracil (5-FU) and oxaliplatin have very few numbers of studies that support their safety in hepatic dysfunction, but pharmacokinetic studies of anticancer drugs focused on the single-agents; however, there is lack of data about drug combinations such as 5-fluorouracil leucovorin and oxaliplatin (FOLFOX) and 5-fluorourocil, leucovorin and irinotecan (FOLFIRI) regimens. We demonstrated one patient with colorectal cancer and severe liver dysfunction secondary to hepatic metastases. Laboratory investigation on admission showed total bilirubin 22.5 mg/dl, alkaline phosphatase 1137 IU/l, aspartate amino transferase 254 IU/l, alanine aminotransferase 164 IU/l and carcinoembryonic antigen levels 863 ng/ml. We initiated a 5-FU/oxaliplatin-based combination chemotherapy. Our data supports the safety and feasibility of FOLFOX regimen in patients with severe liver dysfunction secondary to liver metastases of colorectal cancer.

P95 HER2 fragments and breast cancer outcome.

HER2 is a 185-kDa transmembrane oncoprotein encoded by the HER2 gene. It is located on chromosome 17q21 and is overexpressed in approximately 15% of invasive breast cancers. In addition, it is a poor prognostic factor for survival and disease progression. Approximately 30% of HER2-positive tumors also express a series of carboxy-terminal HER2 fragments known as p95HER2, in addition to the full-length HER receptor. Previous studies have found that p95HER2 represents an independent prognostic marker in patients with HER2-positive disease. Moreover, p95HER2 status might be a decisive factor when choosing between different therapies because p95HER2 fragment-positive tumors are resistant to trastuzumab but respond to tyrosine kinase inhibitors, such as lapatinib, as do p95HER2-negative tumors. p95HER2 fragments arise through at least two different mechanisms: proteolytic shedding of the full-length p185HER2 receptor extracellular domain and translation of HER2 mRNA from internal initiation codons. The present review is based primarily on recent studies suggesting p95HER2 constitutes a new surrogate marker for an aggressive HER2-positive breast cancer subtype with distinct clinical and biological features.

PET-CT changes the management and improves outcome in patients with recurrent colorectal cancer.

BACKGROUND: The present study aims to analyze the impact of positron emission tomography/computed tomography (PET/CT) on management change in patients with suspected or proven colorectal cancer recurrence, and to assess the effect of this management change on progression-free survival (PFS) and overall survival (OS). MATERIALS AND METHODS: We retrospectively evaluated 122 patients with suspected potentially resectable recurrent colorectal cancer who underwent PET/CT scan. We determined management plans for these patients before and after the PET/CT examination. RESULTS: While previous conventional imaging studies had revealed solitary metastases, additional sites of disease were determined by PET/CT scan in 52/122 (42%) patients. PET/CT examination results changed the treatment plan to curative intent in 35 (37%) patients. While the median PFS was 22 months (95% CI, 11.2-32.6 months) among the patients planned to receive curative treatment after the PET/CT scan, it was 11 months (95% CI, 8.1-13.9 months) in patients planned to receive curative treatment before the PET/CT examination, and the difference between median PFS durations was statistically significant (HR, 0.51 [95% CI, 0.32 - 0.88], P = 0.004). Furthermore, OS was significantly longer in patients planned to receive curative treatment after the PET/CT scan (27 months [95% CI, 22.1-31.9]) compared with those who received curative treatment before the PET/CT scan (21 months [95% CI, 15.6 - 26.4]), and the difference was statistically significant (HR, 0.63 [95% CI, 0.42 - 0.89], P = 0.045). CONCLUSION: The present study demonstrates the significant impact of PET/CT on the management and outcome in patients with recurrent colorectal cancer.

Analysis of PTEN, BRAF and PI3K status for determination of benefit from cetuximab therapy in metastatic colorectal cancer patients refractory to chemotherapy with wild-type KRAS.

We investigated predictive values of BRAF, PI3K and PTEN in cetuximab responses in KRAS wild-type (+) chemotherapy refractory, metastatic colorectal cancer (CRC) patients. Primary tumour tissues of 41 KRAS wild-type mCRC patients receiving cetuximab-based chemotherapy were investigated for PI3K, PTEN, KRAS and BRAF mutations. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and the Cox proportional hazards model was used. PTEN and PI3K expressions were 63 and 42 %, respectively. BRAF mutation was observed as 9.8 % among patients. Tumours with BRAF mutation had statistically lower response rates (RR) for cetuximab-based treatment than tumours with BRAF wild type (0 vs. 58 %, p = 0.02). PTEN expressing tumours had statistically higher RR for cetuximab-based treatment than tumours with PTEN loss (42 vs. 12 %, p = 0.04). PI3K expression had worse significant effect on cetuximab RR than PI3K non-expressed tumours (15 vs. 44 %, p = 0.023). Median PFS was significantly longer in patients with PTEN expression (14 months) than in patients with PTEN loss (5 months) (HR, 0.4; p = 0.028). Median PFS was significantly longer in patients with PI3K non-expression (15.2 months) than in patients with PI3K expression (4.1 months) (HR, 0.31; p = 0.001). Significant difference in PFS and OS between patients with BRAF mutated and BRAF wild-type tumours was not detected. However, patients with PTEN expression had significantly longer OS (15.1 months) than patients with PTEN loss tumour (9.9 months) (HR, 0.34; p = 0.008). Patients without PI3K expression had significantly longer OS (18.2 months) than patients with PI3K expression (10.1 months) (HR, 0.27; p = 0.001). Multivariate analyses revealed that PTEN expression (HR, 0.48; p = 0.02) and absence of PI3K expression (HR, 0.2; p = 0.001) were independent prognostic factors for increased PFS. Similarly, PTEN overexpression (HR, 0.62; p = 0.03) and absence of PI3K expression (HR, 0.27; p = 0.005) were independent prognostic factors for increased OS. In PTEN loss, PI3K expression may be used as biomarkers to further select KRAS wild-type patients undergoing anti-epidermal growth factor receptor treatment.

Herbal administration and interaction of cancer treatment.

The widespread impact of cancer worldwide and noncurative treatment methods despite all developments drive patients towards investigating and using nonconventional treatment methods. Herbs, which have an important role in complementary and alternative medicine practices, may cause unfavorable results when used especially with chemotherapeutics in cancer patients due to the substances they contain and due to the properties of some, which still cannot be clarified. Further overshadowing the success of the treatments, patients do not talk about these issues with their doctors and physicians are unable to comprehend these properties of herbs. In this compilation we aimed to clarify the concepts of complementary and alternative medicine, to gather the properties of important and frequently used herbs, and to increase the awareness of physicians on this subject.