Endocrine immune-related adverse events by immune checkpoint inhibitors and potential predictive markers: a prospective study from a single tertiary center.

Immune checkpoint inhibitors (ICIs) can trigger immune-related adverse events (irAEs). The appearance pattern of irAEs, who is prone to them, and their mechanisms are still uncertain. In this study, we aimed to monitor patients initiated on ICIs for endocrinological aspects and to investigate the potential predictive markers in the development of endocrine-irAE. The study prospectively included forty-three patients with metastatic disease scheduled for anti-PD-1/L1 therapy. Endocrinological follow-up was conducted at specified intervals as well as in response to any additional reported complaints. Serum concentrations of CXCL10, IL-1beta and IL-17A were measured prior to ICI and during the endocrine-irAE. A total of 39.5% of the patients experienced endocrine-irAEs, with a median onset time of 3 months. Among patients, 34.9% developed thyroid-related adverse events, and 4.6% experienced hypophysitis. Thyroid autoantibodies were associated with a higher incidence of thyroid-related irAE (p=0.004). In irAE group, median pre-ICI CXCL10 and baseline TSH levels were significantly higher, baseline total testosterone level in men was lower than non-irAE group (p<0.05), whereas IL-1beta and IL-17A levels did not differ (p<0.05). Serum CXCL10, IL-1beta, and IL-17A concentrations did not differ significantly pre-ICI and during adverse events (p<0.05). Pre-ICI CXCL10 concentration was correlated positively with anti-TPO levels in patients with at least one thyroid autoantibody positivity (r=0.706,p=0.01) and negatively with baseline total testosterone level of men (r=0.509,p=0.002). Our results suggest that higher pre-ICI serum CXCL10 and TSH levels might have a predictive role in the development of endocrinopathies. Besides, baseline thyroid antibody measurements could be beneficial in predicting thyroid dysfunction.

The impact of the expression level of growth differentiation factor 15 in tumor tissue on the response to immunotherapy in non-small cell lung cancer.

BACKGROUND: Growth differentiation factor-15 (GDF-15), a member of the TGF-ß superfamily, is overexpressed in various cancers and facilitates immune evasion by inhibiting T-cell activation. GDFATHER-TRIAL's phase 2a results demonstrated promising outcomes when combining the GDF-15 neutralizing antibody visugromab (CTL002) with nivolumab, enhancing the response to immunotherapy. This study evaluated the prognostic significance of GDF-15 expression in non-small cell lung cancer (NSCLC) tumor tissues in terms of immunotherapy response. METHODS: This retrospective study included 50 patients with metastatic NSCLC treated with nivolumab at Gazi University Hospital between January 2021 and July 2023. GDF-15 expression was evaluated using immunochemistry staining and categorized based on the intensity of cytoplasmic or membranous staining. Samples were divided into a low expression group (scores 0 and 1) and a high expression group (scores 2 and 3). The primary outcomes were progression-free survival (PFS) and overall survival (OS), which were analyzed using Kaplan‒Meier and Cox proportional hazards models. Objective response rates were assessed in secondary outcomes. RESULTS: Of the 50 patients, 43 were men (86%), with a median age of 63.9 years. Half of the patients exhibited low GDF-15 expression. High GDF-15 expression correlated with shorter PFS and OS. The median PFS was 7.8 months for the low-expression group versus 4.4 months for the high-expression group (HR, 0.41; 95% CI, 0.20-0.83; p = 0.013). The median OS was 18.1 months for the low-expression group compared to 11.8 months for the high-expression group (HR, 0.36; 95% CI, 0.16-0.78; p = 0.007). The objective response rate was significantly greater in the low GDF-15 group (52%) than in the high GDF-15 group (24%) (p = 0.040). CONCLUSION: Elevated GDF-15 expression in NSCLC tumor tissues is associated with poorer response to nivolumab, suggesting that GDF-15 is a potential prognostic biomarker for immunotherapy efficacy. These findings warrant further validation through prospective studies to optimize treatment strategies for NSCLC patients.

A propensity score-matched comparison of neoadjuvant chemoradiotherapy with cisplatin-5FU and carboplatin-paclitaxel in locally advanced esophageal squamous cell carcinoma: A Turkish oncology group study.

BACKGROUND: Neoadjuvant treatment is the standard treatment in locally advanced ESCC. However, the optimal chemotherapy regimen is not known. METHOD: This is a retrospective observational cohort study conducted with propensity score matching. Patients with resectable ESCC from 13 tertiary centers from Türkiye were screened between January 2011 and December 2021. We compared the efficacy and safety of neoadjuvant chemoradiotherapy with the CF and the CROSS regimens in patients with ESCC. RESULTS: Three hundred and sixty-two patients were screened. Patients who received induction chemotherapy (n = 72) and CROSS-ineligible (n = 31) were excluded. Two hundred and fifty nine patients received neoadjuvant chemoradiotherapy. After propensity score matching (n = 97 in both groups), the mPFS was 18.4 months (95% CI, 9.3-27.4) and 25.7 months (95% CI, 15.6-35.7; p = 0.974), and the mOS was 35.2 months (95% CI, 18.9-51.5) and 39.6 months (95% CI 20.1-59.2; p = 0.534), in the CF and the CROSS groups, respectively. There was no difference between subgroups regarding PFS and OS. Compared with the CF group, the CROSS group had a higher incidence of neutropenia (34.0% vs. 62.9%, p < 0.001) and anemia (54.6% vs. 75.3%, p = 0.003) in all grades. On the other hand, there was no significant difference in grade 3-4 anemia, grade 3-4 neutropenia, and febrile neutropenia between groups. There were more dose reductions and dose delays in the CROSS group than in the CF group (11.3% vs. 3.1%, p = 0.026 and 34.0% vs. 17.5%, p = 0.009, respectively). The resection rate was 52.6% in the CF-RT and 35.1% in the CROSS groups (p = 0.014). CONCLUSION: Favorable PFS and pCR rates and a comparable OS were obtained with the CROSS regimen over the CF regimen as neoadjuvant chemoradiotherapy in patients with ESCC.

Real-world evaluation of nivolumab in patients with non-nasopharyngeal recurrent or metastatic head and neck cancer: a retrospective multi-center study by the Turkish Oncology Group (TOG).

OBJECTIVES: Head and neck cancers (HNCs) represent a significant global health concern due to high morbidity and mortality rates. Despite therapeutic advances, the prognosis for advanced or recurrent cases remains challenging. Nivolumab obtained approval for recurrent or metastatic HNC based on the Phase III CheckMate 141 trial. This study aimed to evaluate the real-world outcomes of nivolumab in patients with non-nasopharyngeal HNC. DESIGN: In this multicenter retrospective study, we analyzed 124 patients with recurrent or metastatic non-nasopharyngeal HNC who received nivolumab in the second-line setting and beyond. Data were collected from 20 different cancer centers across Turkey. The effectiveness and safety of the treatment and survival outcomes were evaluated. RESULTS: Nivolumab exhibited favorable clinical responses, yielding an objective response rate of 29.9% and a disease control rate of 55.7%. Safety assessments revealed a generally well-tolerated profile, with no instances of treatment discontinuation or mortality due to side effects. Survival analysis disclosed a median overall survival (OS) of 11.8 (95% CI 8.4-15.2) months. Multivariate analysis revealed that ECOG-PS ≥ 1 (HR: 1.64, p = 0.045), laryngeal location (HR: 0.531, p = 0.024), and neutrophil-to-lymphocyte ratio > 3.5 (HR: 1.97, p = 0.007) were independent predictors of OS. CONCLUSIONS: Nivolumab is an effective and safe treatment option for patients with recurrent or metastatic non-nasopharyngeal HNC in real-world settings. Further studies are needed on factors affecting response to treatment and survival outcomes.

The relationship between clinical and pathological findings and FDG - PET uptake in metastatic colorectal cancers.

BACKGROUND: In metastatic colorectal cancer (mCRC), the genetic structure and cell metabolism of the primary tumor lesion might be different from metastatic lesions. It is thought that cell-level glucose metabolism may differ due to the difference in RAS wild and mutant mCRC patients' prognosis. In this study, we aimed to compare 2-deoxy-2-[fluorine-18]-fluoro-D-glucose Positron Emission Tomography (18F-FDG PET/CT) uptake levels for KRAS mutation status and primary-metastatic tumor localization. METHODS: Our study is a retrospective cohort analysis that included RAS mutation status study and staging-oriented 18F-FDG PET/CT conducted on mCRC patients. RESULTS: There was no significant relationship between metastasis and primary tumor maximum Standardized uptake value (SUVmax) values according to the KRAS mutational status (P > 0.05). Patients with liver metastasis along with mutant BRAF mutation status had significantly higher SUVmax values in PET-CT scans (P = 0.04). There was a negative correlation between SUVmax values of lung metastases and overall survival (r = -0.35, P = 0.04). Patients with high carcinoembryonic antigen (CEA) levels had significantly higher SUVmax values of lung metastasis than patients with normal CEA levels (P = 0.009). Patients with high CA19-9 levels had significantly higher SUVmax values of liver, peritoneal, and bone metastasis than patients with normal CA19-9 levels (P = 0.002, P = 0.001, P = 0.004, respectively). There was no significant correlation between SUVmax values of metastasis and Lactate dehydrogenase (LDH) values. Liver metastasis of right-sided mCRCs had significantly higher SUVmax values (P = 0.03). CONCLUSION: We could not demonstrate a significant association between KRAS mutation and SUVmax values of PET scan in primary or metastatic tumor sites in advanced CRC.

Visceral obesity and sarcopenia as predictors of efficacy and hematological toxicity in patients with metastatic breast cancer treated with CDK 4/6 inhibitors.

PURPOSE: We aimed to investigate whether visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and skeletal muscle area (SMA) index are predictive for efficacy and hematological toxicity in ER + HER2-metastatic breast cancer (BC) patients who received CDK 4/6 inhibitors. METHODS: This retrospective cohort study analyzed 52 patients who were treated with CDK 4/6 inhibitors between January 2018 and February 2021. The values of VAT, SAT, SMA indices and hematological parameters were noted before the start, at the third and sixth months of this treatment. The skeletal muscle area (SMA) and adipose tissue measurements were calculated at the level of the third lumbar vertebra. A SMA-index value of <40 cm2/m2 was accepted as the threshold value for sarcopenia. RESULTS: Patients with sarcopenia had a worse progression-free survival (PFS) compared to patients without sarcopenia (19.6 vs. 9.0 months, p = 0.005). Patients with a high-VAT-index had a better PFS (20.4 vs. 9.3 months, p = 0.033). Only the baseline low-SMA- index (HR: 3.89; 95% CI: 1.35-11.25, p = 0.012) and baseline low-VAT-index (HR: 2.15; 95% CI: 1.02-4.53, p = 0.042) had significantly related to poor PFS in univariate analyses. The low-SMA-index was the only independent factor associated with poor PFS (HR: 3.99; 95% CI: 1.38-11.54, p = 0.011). No relationship was observed between body composition parameters and grade 3-4 hematological toxicity. CONCLUSION: The present study supported the significance of sarcopenia and low visceral adipose tissue as potential early indicators of poor PFS in patients treated with CDK 4/6 inhibitors.

Retrospective Analyses of PD-L1, LAG-3, TIM-3, OX40L Expressions and MSI Status in Gastroenteropancreatic Neuroendocrine Neoplasms.

We investigated expressions of PD-L1, LAG-3, TIM-3, and OX40L as immune checkpoint proteins, and MSI (repetitive short-DNA-sequences due to defective DNA-repair system) status were analyzed with immunohistochemistry from tissue blocks. Of 83 patients, PD-L1 expression was observed in 18.1% (n = 15) of the patients. None of the patients exhibited LAG-3 expression. TIM-3 expression was 4.9% (n = 4), OX40L was 22.9% (n = 19), and 8.4% (n = 7) of the patients had MSI tumor. A low-to-intermediate positive correlation was observed between PD-L1 and TIM-3 expressions (rho: 0.333, p < 0.01). Although PD-L1 expression was higher in grade 3 NET/NEC, MSI status was prominent in grade 1/2 NET.

Niraparib-induced pure red cell aplasia.

INTRODUCTION: Niraparib, a strong poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, contributed significantly to progression-free survival as a maintenance therapy in the platinum-sensitive period in both first-line and recurrent ovarian cancer, regardless of the BRCA mutation. Grade 3-4 anemia, which has a manageable side effect profile, especially hematological, is seen in almost 1 out of every 4 patients. To the best of our knowledge, there has been no reported case of pure red cell aplasia (PRCA) induced by niraparib treatment. CASE REPORT: A 65-year-old woman diagnosed with stage 3 serous carcinoma of the tuba received niraparib front-line maintenance treatment had grade 4 anemia after 3 months of niraparib treatment. She underwent bone marrow aspiration and biopsy because of refractory anemia, which needs red blood cell (RBC) transfusions despite interruption of treatment. MANAGEMENT AND OUTCOME: The patient was treated with 1 mg/kg methyl prednisolone, after histopathological assessment was consistent with PRCA. The hemoglobin count returned to the normal range with steroid treatment. DISCUSSION: In daily practice, it should be kept in mind that in the case of refractory anemia induced by niraparib, the underlying cause might be PRCA and can be improved with steroid administration.

Oxaliplatin­induced changes in splenic volume and liver fibrosis indices: retrospective analyses of colon cancer patients receiving adjuvant chemotherapy.

The aim of our study was to evaluate the association between increased splenic volume (SV) and liver fibrosis indices in colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy. Patients who received adjuvant oxaliplatin-based regimens with the diagnosis of stage II and III colon cancer were evaluated. Splenic volume measurements, liver function tests, platelet count, and non-invasive liver fibrosis indices [NAFLD fibrosis score (NFS), AST to platelet ratio (APRI), and Fibrosis-4 (FIB-4)] were measured before and after treatment. A 30% increase in SV after chemotherapy compared to baseline was considered increased SV. The rate of increase in SV was 57.7% in the whole group. An increase in SV was shown at a higher rate in patients treated with capecitabine and oxaliplatin (CAPOX) than those treated with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) (66.3% vs. 36.8%, p = 0.002). Furthermore, the CAPOX regimen (OR: 2.831, 95% CI: 1.125-7.121; p = 0.027), and higher post-treatment FIB-4 score (OR: 3.779; 95% CI:1.537- 9.294, p = 0.004) were determined as independent risk factors for the increased SV. Our study revealed that increased SV had a significant association with higher FIB-4 score in patients treated with oxaliplatin-based chemotherapy.

Prognostic significance of nadir PSA value and time to nadir PSA in patients with metastatic castration-naive prostate cancer receiving first-line hormonotherapy.

BACKGROUND: The current study aimed to evaluate the effect of the time duration to reach the lowest prostate-specific antigen (PSA) from the onset of first-line hormonal treatment (time to nadir PSA, TTNpsa) on survival in castration-naive metastatic prostate cancer (CN-MPC) patients. METHODS: Eighty patients who had PSA response >80% with first-line hormonal therapy (luteinizing hormone-releasing hormone, LH-RH analog +/- bicalutamide) were included in this study. RESULTS: Under androgen deprivation therapy (ADT), a significant positive correlation was found between TTNpsa, nadir PSA (Npsa) duration, and progression-free survival (PFS) ( p < 0.001) and overall survival (OS) ( p < 0.001). There was no correlation between TTNpsa and Npsa duration. TTNpsa and Npsa durations were independently correlated with PFS and OS. In patients with TTNpsa value ≥19 weeks, the median PFS was 126 (95% CI, 68-184) weeks compared with TTNpsa <19-week group in which the median PFS was 44 (95% CI, 26-62) weeks ( p = 0.033). In patients with TTNpsa value ≥19 weeks, the median OS was 242 (95% CI, 169-315) weeks compared with TTNpsa <19-week group in which the OS was 156 (95% CI, 89-223) weeks ( p = 0.018). The median nadir PSA value was 1 ng/mL. The median PFS was significantly longer in the patient group with ≤1 ng/mL (137 weeks, 95% CI, 50-224) compared with the group with >1 ng/mL (41 weeks, 95% CI, 34-48) ( p < 0.001). The median OS was significantly longer in the patient group with nadir PSA ≤1 ng/mL (296 weeks, 95% CI, 220-272) compared to the group with >1 ng/mL (131 weeks, 95% CI, 84-178) ( p = 0.002). In patients with nadir PSA ≤1 ng/mL ( n = 40), there was no relationship between TTNpsa and Npsa duration with both PFS and OS. However, in patients with nadir PSA >1 ng/mL ( n = 40) subgroup, there was a significant positive correlation between TTNpsa and PFS, and OS ( p < 0.001, P = 0.016, respectively). CONCLUSION: In CN-MPC who received first-line ADT, especially in the group with the nadir PSA value >1 ng/mL, the duration of TTNpsa was positively correlated with PFS and OS.

Retrospective Evaluation of the Efficacy of Gemcitabine-Based Therapies After FOLFIRINOX Failure in Advanced Pancreatic Cancer, Multi-Center Real-Life Data.

OBJECTIVE: Combination therapies such as FOLFIRINOX or gemcitabine-nanoparticle albumin-bound paclitaxel (GnP) are recommended for the first-line treatment of patients with advanced pancreatic cancer. The purpose of this study was to evaluate the efficacy of gemcitabine-based second-line therapies in patients whose disease progressed on FOLFIRINOX. METHOD: Patients diagnosed with advanced pancreatic cancer in 7 tertiary hospitals in Turkey were included. Patients were divided into 3 different groups according to their treatment regimens: GnP, gemcitabine doublet (gemcitabine-cisplatin or gemcitabine-capecitabine), and gemcitabine monotherapy. RESULTS: A total of 144 patients were included in the study. In the second-line treatment, 65% of patients were given GnP, 20% were given gemcitabine doublet, and 15% were given gemcitabine monotherapy. The median exposure of the patients to gemcitabine-based therapy was 3 cycles, whereas the median progression-free survival was calculated as 3.4 months. The median overall survival for patients who received GnP was 4.6 months, 6.4 months for patients who received gemcitabine doublet therapy, and 3.7 months for patients who received gemcitabine monotherapy ( P = 0.248). CONCLUSION: In conclusion, it has been shown that gemcitabine-based second-line treatments contribute to survival in patients with advanced pancreatic cancer. In addition, there was no difference in efficacy between gemcitabine monotherapy or combination treatments.

Comparison of PD-L1 and VISTA expression status in primary and recurrent/refractory tissue after (chemo)radiotherapy in head and neck cancer.

BACKGROUND: PD-L1 and VISTA are thought to play a role in escape from the immune system, tumor progression, and treatment response in tumoral tissue. The current study aimed to evaluate the effects of radiotherapy (RT) and chemoradiotherapy (CRT) on PD-L1 and VISTA expression in head and neck cancers. METHODS: PD-L1 and VISTA expression were compared between the primary biopsy taken at the time of diagnosis and refractory tissue biopsies of patients who received definitive CRT or recurrent tissue biopsies of patients who had surgery followed by adjuvant RT or CRT. RESULTS: In total, 47 patients were included. Radiotherapy had no effect on the expression levels of PD-L1 and VISTA in patients with head and neck cancer (p = 0.542 and p = 0.425, respectively). A positive correlation was found between PD-L1 and VISTA expression (p < 0.001; r = 0.560). PD-L1 and VISTA expression in the first biopsy were found to be significantly higher in clinical lymph node-positive patients compared to node-negative patients (PD-L1 p = 0.038; VISTA p = 0.018). The median overall survival of patients with ≥ 1% VISTA expression in the initial biopsy was significantly shorter than that of patients with < 1% VISTA expression (52.4 vs. 110.1 months, respectively; p = 0.048). CONCLUSION: It was found that PD-L1 and VISTA expression did not change with RT or CRT. Further studies are needed to evaluate the relationship of PD-L1 and VISTA expression with RT and CRT.

The possible relation between temporal muscle mass and glioblastoma multiforme prognosis via sarcopenia perspective.

BACKGROUND: The optimal sarcopenia measurement method in patients with a diagnosis of glioblastoma multiforme (GBM) is unknown. It has been found that temporal muscle thickness (TMT) may reflect sarcopenia and be associated with survival, but the relationship between temporal muscle area (TMA) and GBM prognosis has never been evaluated before. The primary outcome of the study was to evaluate the relationship between TMA/TMT and overall survival (OS) time in newly diagnosed GBM patients. METHODS: The data of patients who presented at the university hospital between January 2009 and January 2019 with a confirmed diagnosis of glioblastoma multiforme at the time of diagnosis were analyzed retrospectively. Temporal muscle thickness and TMA were measured retrospectively from preoperative MRIs of patients diagnosed with GBM. Due to the small number of patients and the failure to determine a cut-off value with acceptable sensitivity and specificity using ROC analysis, the median values were chosen as the cut-off value. The patients were basically divided into two according to their median TMT (6.6 mm) or TMA (452 mm2 ) values, and survival analysis was performed with the Kaplan-Meier analysis. RESULTS: The median TMT value was 6.6 mm, and the median TMA value was 452 mm2 . The median overall survival (OS) was calculated as 25.8 months in patients with TMT < 6.6 mm, and 15.8 months in patients with TMT ≥ 6.6 mm (p = 0.29). The median overall survival (OS) of patients with TMA < 452mm2 was 26.3 months, and the group with TMA ≥ 452mm2 was 14.6 months (p = 0.06). The median disease-free survival was 18.3 months (%95 CI: 13.2-23.4) in patients with TMT < 6.6mm, while mDFS was 10.9 (%95 CI: 8.0-13.8) months in patients with TMT ≥ 6.6mm (p = 0.21). The median disease-free survival was found to be 21.0 months (%95 CI: 15.8-26.1) in patients with TMA < 452 mm2 and 10.5 months (%95 CI: 7.8-13.2) in patients with TMA ≥ 452 mm2 (p = 0.018). DISCUSSION: No association could be demonstrated between TMT or TMA and OS of GBM patients. In addition, the median DFS was found to be longer in patients with low TMA. There is an unmet need to determine the optimal method of sarcopenia in GBM patients.

Retrospective Analysis of Real-Life Data Evaluating the Optimal Time Between Gastrectomy and Adjuvant Chemotherapy in Resected Gastric Cancer.

PURPOSE: Although adjuvant chemotherapy (AC) increases survival in early-stage gastric cancer, the effect of the time between gastrectomy and the initiation of AC on survival has not been clearly demonstrated. This study aimed to examine the effect of AC timing on survival. METHODS: The data of patients who received AC in the postoperative period with the diagnosis of stage II and stage III gastric cancer were analyzed retrospectively. The patients were separated into two groups based on a 4-week cut-off value between the date of gastrectomy and the initiation of AC. RESULTS: There were 151 patients enrolled in the study. It was determined that 63 (41.7%) patients started AC in the first 4 weeks and 88 (58.3%) patients after the first 4 weeks. Patients who received AC during the first 4 weeks had a median recurrence-free survival (RFS) of 46 months, while those who received AC after 4 weeks had a median RFS of 29 months (p = 0.039). The median overall survival (OS) for patients administered AC in the first 4 weeks was 65 months, compared to 45 months for those administered AC after 4 weeks (p = 0.036). The early time interval from surgery to AC resulted as an independent prognostic factor for both OS and RFS. CONCLUSION: The optimal time to start AC in patients with gastric cancer who underwent curative resection is unknown. This study reported that an interval shorter than 4 weeks was an independent prognostic risk factor for both OS and RFS.