Tyrosine kinase inhibitor-induced immune hemolytic anemia; three different drugs in three separate cases.

INTRODUCTION: Molecular multitargeted small tyrosine kinase inhibitory (TKI) agents such as axitinib, sunitinib and pazopanib are commonly used in several types of solid tumors. Anemia is not a rare effect of these drugs which may occur at all grades. However, drug-induced immune hemolytic anemia (IHA), a very rare condition is distinctive from other types of anemia with its specific mechanism and management strategy. CASE REPORTS: We reported three different TKI-induced IHA cases that occurred due to axitinib, sunitinib, and pazopanib, respectively. The first two cases were diagnosed with renal cell carcinoma and the last one was diagnosed with soft tissue sarcoma. They all presented with the characteristic symptoms of anemia and hemolysis. All the cases were detected positive for the complement C3d direct antiglobulin (direct coombs) test. MANAGEMENT AND OUTCOMES: Discontinuation of the causative drug and 1 mg/kg/day dose of corticosteroid treatment were able to control IHA in all three cases. Excluding the other factors of IHA and an evident laboratory and clinical benefit after withholding the TKI led to the diagnosis of TKI-related IHA in each case. DISCUSSION: TKIs are relatively new in clinical practice and are being used for more indications and in more patients. To our knowledge#these three cases are unique in terms of axitinib#sunitinib#and pazopanib-related IHA.

Metronomic maintenance chemotherapy in patients presenting with paraneoplastic autoimmune hepatitis with recurrent thymic carcinoma.

Autoimmune hepatitis is a rarely seen autoimmune paraneoplastic syndrome of thymic carcinoma. Chemotherapy may be an effective choice in the treatment of primary tumor and paraneoplastic disorder. In this case, we report a 32-year-old man presented with increased liver enzymes and cholestasis with a history of thymoma surgically removed four years ago. Liver biopsy showed chronic active autoimmune hepatitis. Computed tomography scan showed pulmonary metastases and pleural mass as a recurrence of thymic carcinoma, proven by biopsy. After four cycles of cisplatin plus adriamycin plus cyclophosphamide plus vincristine and six cycles of paclitaxel plus gemcitabine, maintenance metronomic cyclophosphamide plus etoposide regimen was offered to the patient. Complete biological signs of hepatitis without need for steroids or immune suppressors and complete radiologic response in primary tumor were achieved. Maintenance metronomic chemotherapy regimens may be an alternative to the current treatment options in patients with thymic carcinomas.

Sorafenib-induced severe urticaria in a patient with hepatocellular cancer.

Sorafenib which is used in the treatment of renal, thyroid and hepatocellular cancers is a multi-targeted tyrosine kinase inhibitor. Though sorafenib is associated with some side effects, it is known that sorafenib is generally well tolerated compared to other tyrosine kinase inhibitors. In the present case, hepatocellular cancer was diagnosed seven months ago. The disease was in stage IIIB at the time of diagnosis. Sorafenib was initiated with a dose of 400 mg twice daily because of disease progression after two cycles of doxorubicin. The reactions on the skin of the arms and the body of the patient occurred in the eighth week of treatment. Skin biopsy was performed and urticaria was diagnosed after pathologic examination. No other disorders or drugs which may cause urticaria were detected in the patient. Skin reactions disappeared one week after sorafenib discontinuation without any further intervention.

Is there any relation between PET-CT SUVmax value and prognostic factors in locally advanced breast cancer?

PURPOSE: To investigate the relation between PET-CT SUVmax value and prognostic factors in locally advanced breast cancer. METHODS: Data of 73 patients were retrospectively analyzed. Relations between SUVmax value, clinical stage, tumor grade and breast cancer molecular subtypes were analyzed by using one-way ANOVA and x(2) tests. Correlations between age, ki-67 scores and SUVmax were evaluated by using Pearson's correlation test. A p value <0.05 was considered statistically significant. RESULTS: Median SUVmax values for clinical stages 1, 2 and 3 were 5 (range 2.1-4.1), 10.6 (range 2.9-19.6), and 12.2 (range 3.2-23.3), respectively. Statistically significant difference was noticed between stage 1 and 2 (p=0.014) and stage 1 and 3 (p=0.001). Median SUVmax values of triple negative, luminal A, luminal B and non-luminal HER2 positive groups were 14.4 (range 6.6-23.3), 8.2 (range 2.1-18.2), 10.1 (range 3.5-19.6), and 14 (range 4.1-22.9), respectively. Statistically significant differences were noticed in SUVmax values between triple-negative and luminal A groups (p=0.005) and between non-luminal HER2 positive and luminal A groups (p=0.02). Median SUVmax values of grade 1, 2 and 3 were 5.7 (range 2.1-18.2), 9.5 (range 2.2-21.3), and 11.6 (range 3.5-23), respectively. Statistically significant difference was noticed only between SUVmax values of grade 1 and 3 (p=0.035). There was negative correlation between age and SUVmax value (r=-0.23, p=0.047) and positive correlation between ki-67 and SUVmax value (r=0.43, p=0.016). CONCLUSION: There were significant positive relations between PET-CT SUVmax value and clinical stage, tumor grade, and certain breast cancer molecular subtypes (triple-negative and non-luminal HER2 positive groups. Moreover, positive correlation was found between SUVmax value and ki-67 and negative correlation between SUVmax value and age.

Efficacy of first-line CDK 4-6 inhibitors in premenopausal patients with metastatic breast cancer and the effect of dose reduction due to treatment-related neutropenia on efficacy: a Turkish Oncology Group (TOG) study.

The only phase 3 study on the effectiveness of CDK 4-6 inhibitors in first-line treatment in premenopausal patients with hormone receptor (HR) positive, HER2 negative metastatic breast cancer is the MONALEESA-7 study, and data on the effectiveness of palbociclib is limited. Data are also limited regarding the effectiveness of CDK 4-6 inhibitors in patients whose dose was reduced due to neutropenia, the most common side effect of CDK 4-6 inhibitors. In our study, we aimed to evaluate the effectiveness of palbociclib and ribociclib in first-line treatment in patients with premenopausal metastatic breast cancer and the effect of dose reduction due to neutropenia on progression-free survival. Our study is a multicenter, retrospective study, and factors affecting progression-free survival (PFS) were examined in patients diagnosed with metastatic premenopausal breast cancer from 29 different centers and receiving combination therapy containing palbociclib or ribociclib in the metastatic stage. 319 patients were included in the study. The mPFS for patients treated with palbociclib was 26.83 months, and for those receiving ribociclib, the mPFS was 29.86 months (p = 0.924). mPFS was 32.00 months in patients who received a reduced dose, and mPFS was 25.96 months in patients who could take the initial dose, and there was no statistical difference (p = 0.238). Liver metastasis, using a fulvestrant together with a CDK 4-6 inhibitor, ECOG PS 1 was found to be a negative prognostic factor. No new adverse events were observed. In our study, we found PFS over 27 months in patients diagnosed with premenopausal breast cancer with CDK 4-6 inhibitors used in first-line treatment, similar to post-menopausal patients. We did not detect any difference between the effectiveness of the two CDK 4-6 inhibitors, and we showed that there was no decrease in the effectiveness of the CDK 4-6 inhibitor in patients whose dose was reduced due to neutropenia.

Comparison of two different carboplatin and weekly paclitaxel schedule in elderly advanced non-small cell lung cancer patients.

PURPOSE: In this study our aim was to compare efficacy and toxicity profiles of two different schedule of carboplatin-paclitaxel regimen in elderly advanced non-small cell lung cancer (NSCLC) patients. METHODS: Data from the charts of 59 elderly patients with metastatic NSCLC, treated with weekly paclitaxel combined with two different schedule of carboplatin were collected retrospectively from three medical oncology centers in Turkey between September 2002 to March 2018. No prior systemic therapy or radiotherapy was allowed. Brain metastases were not considered as exclusion criteria unless symptomatic. Patients were analyzed in two treatment groups; CP3 (who received 3 weekly carboplatin and weekly paclitaxel), and CP1 (weekly carboplatin and weekly paclitaxel). Overall survival (OS) was the primary endpoint of the study. Secondary end points were as follows: progression free survival (PFS), response rates (RR), grade 3-4 toxicities, skipped cycles, dose reductions, and treatment discontinuation rates. RESULTS: Twenty-four patients received 3 weekly carboplatin and weekly paclitaxel schedule (CP3) while weekly carboplatin and weekly paclitaxel schedule (CP1) was performed in 35 patients. CP3 had a median OS of 14 months whereas CP1 had 9 months of median OS (p = 0.084). Both treatments (CP3 vs CP1) had similar median PFS (7 months vs 4 months, p = 0.109) and objective RR (20.9% vs 29.4%, p = 0.465). There was an increased incidence of grade 3-4 anemia and grade 3-4 neutropenia in CP3 compared to CP1 (p = 0.003 in both), but no major differences in febrile neutropenia and infection toxicity profiles (p = 0.289 and p = 0.770, respectively). Weekly schedule (CP1) had a tendency of increased grade 3-4 neurotoxicity (33.3% vs 42.9%, p = 0.461). CONCLUSION: Weekly carboplatin and paclitaxel might be more tolerable and is as effective as 3 weekly carboplatin and weekly paclitaxel schedule in metastatic elderly NSCLC patients.

Palliative resection of primary site in advanced gastroenteropancreatic neuroendocrine tumors improves survivals.

BACKGROUND/AIMS: Gastroenteropancreatic neuroendocrine tumors are rarely seen and have heterogeneous clinical outcomes. Mostly half of the patients had metastatic disease at presentation. Palliative resection of primary site in metastatic disease is still controversial. The aim of this study was to find out the influence of resection of primary tumor site on progression-free survival and overall survival in metastatic non-functioning gastroenteropancreatic neuroendocrine tumors. The secondary end point is to determine the prognostic factors influencing the survivals. MATERIALS AND METHODS: This study was conducted at a single medical oncology center, Antalya Education and Research Hospital. Patients who had non-functioning metastatic gastroenteropancreatic neuroendocrine tumors with primary site resected or unresected were compared retrospectively. Resection of metastases was excluded. RESULTS: Fifty-three patients were included in the study and 29 patients had primary tumor resection. The primary site resected group had favorable outcomes with the overall survival (median unreached) compared to the median overall survival of 30 months in the unresected group (p=0.001). Median progression-free survival was also better in the primary site resected group than the unresected group (60 months vs. 14 months, respectively) (p=0.013). In multivariate analysis, unresected primary site and high-grade tumors were found to be independent prognostic factors on low survivals (Hazard ratio (HR): 4.6; 95% CI: 1.21-17.47 and HR: 10.1; 95% CI: 1.15-88.84, respectively). Age (p=0.131), gender (p=0.051), chromogranin A level (p=0.104), Ki-67 index (p=0.550), tumor size (p=0.623), and primary tumor area (p=0.154) did not influence the overall survival. CONCLUSION: Gastroenteropancreatic neuroendocrine tumors with primary site resected had improved survivals when compared to the unresected group.

Local Immune Response in Helicobacter pylori Infection.

There have been few studies concerning the cytokine profiles in gastric mucosa of Helicobacter pylori-infected patients with normal mucosa, chronic gastritis, and gastric carcinoma (GAC).In the present study, we aimed to elucidate the genomic expression levels and immune pathological roles of cytokines-interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, transforming growth factor (TGF)-ß, IL-17A, IL-32-in H pylori-infected patients with normal gastric mucosa (NGM; control), chronic active gastritis (CAG), and GAC. Genomic expression levels of these cytokines were assayed by real-time PCR analysis in gastric biopsy specimens obtained from 93 patients.We found that the genomic expression levels of IFN-γ, TNF-α, IL-6, IL-10, IL-17A mRNA were increased in the CAG group and those of TNF-α, IL-6, IL-10, IL-17A, TGF-ß mRNA were increased in the GAC group with reference to H pylori-infected NGM group.This study is on the interest of cytokine profiles in gastric mucosa among individuals with normal, gastritis, or GAC. Our findings suggest that the immune response of gastric mucosa to infection of H pylori differs from patient to patient. For individual therapy, levels of genomic expression of IL-6 or other cytokines may be tracked in patients.