Epidermal growth factor receptor and programmed cell death-1 expression levels in peripheral T cell subsets of patients with non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths, in part due to its late diagnosis. Increased epidermal growth factor receptor (EGFR) expression in cancer cells is associated with a poor prognosis, and EGFR tyrosine kinase inhibitors are widely used in cancer treatment. This study aimed to clarify the relationship between EGFR expression on T cells and cancer prognosis in patients with non-small cell lung cancer (NSCLC). Forty patients with NSCLC and 40 healthy volunteers were included in this study. Peripheral CD4+T helper (Th1, Th2, Th9, Th17, Th1Th17, follicular and peripheral Th) and cytotoxic T lymphocyte (CD8+follicular and peripheral T) subsets were identified with flow cytometry according to their chemokine receptors. EGFR expression on T lymphocytes in relation to overall survival (OS) was investigated in patients with NSCLC. The patients [mean age (min-max) = 64.03 (45-83); 20 stage I-III and 20 stage IV] had increased EGFR expression on CD3+T, CD4+Th, Th1, Th2, and Th17 cells compared to the controls (p < 0.05). High EGFR expression on CD3+T, CD4+Th, Th1, and Th2 cells was associated with poor OS. Also, PD-1 expression on lymphocytes, CD3+T, and Th cells was increased in patients with NSCLC compared to controls. The high expression of EGFR and PD-1 on Th cells and the reduced percentage of lymphocytes and Th cells, especially in stage IV patients with NSCLC, revealed that increased EGFR activity may trigger apoptosis of Th cells and promote the development of metastases, while high EGFR expression on CD3+T, CD4+Th, Th1, and Th2 cells may be an independent poor prognostic marker in NSCLC.

Efficacy of Systemic Treatments in Patients With Metastatic Lung Invasive Mucinous Adenocarcinoma.

BACKGROUND: Invasive mucinous adenocarcinoma (IMA) is a rare histological subtype of lung invasive adenocarcinoma with unique clinical, radiological, histopathological, and genomic characteristics. There have been limited studies on the effectiveness of systemic therapy for lung IMA, with conflicting results reported. METHODS: We retrospectively investigated the medical records of patients diagnosed with lung IMA. Patients who were ≥ 18 years of age and received at least 1 course of treatment for metastatic or locally advanced inoperable disease were included in the study. Archive records of 113 patients diagnosed with IMA were screened for the study. RESULTS: A total of 41 patients with lung IMA were included. The targetable mutation rate was 20.6% (in 6 of 29 patients). Most patients (83.1%) had received platinum-based chemotherapy as a first-line treatment. The objective response rate (ORR) was 25.7%, and median progression-free survival (PFS) and overall survival (OS) were 8.1 months (95% CI, 5.02-11.2) and 17.5 months (95% CI, 11.7-23.3 months), respectively, in the patients who received chemotherapy. The median PFS and ORR were 20.6 (95% CI, 18.9-66.5) and 66.6%, respectively, in epidermal growth factor receptor (EGFR) mutation-positive patients (n = 3) with relevant targeted therapy. Only 1 patient used oxaliplatin and capecitabine combination (XELOX) as chemotherapy in the second-line treatment and achieved a partial response (PR) at 7.2 months. CONCLUSION: Platinum-based chemotherapies moderately enhance IMA patients' survival rates. Anti-EGFR-targeted drugs are seen as potentially effective in patients with EGFR driver mutation positive. Large, prospective studies are needed to confirm our findings.

The effect of concomitant beta-blocker use on survival in patients with metastatic renal cell carcinoma treated with a vascular endothelial growth factor receptor inhibitors in the first line.

PURPOSE: Vascular endothelial growth factor (VEGF) inhibition is one of the cornerstones of treatment in the treatment of metastatic renal cell carcinoma (mRCC). Since RCC is a disease of advanced age and hypertension as a side effect of VEGF receptor inhibitors, beta-blocker use is common in these patients. We aimed to compare the treatment efficacy and survival results in case of concomitant use of these two drugs due to the inhibition of VEGF in beta-blockers. METHODS: A total of 121 patients with a diagnosis of mRCC who used sunitinib or pazopanib in first-line therapy were included in the study. These patients were divided into two groups as those using concomitant beta-blockers and those not using them. RESULT: The median overall survival (mOS) of the patient using sunitinib or pazopanib and concomitant beta-blocker was 47 (95% CI 29.0-65.0) months, and the mOS of those not using concomitant beta-blocker was 18 (95% CI 8.9-27.1) months (p < 0.001). The median progression-free survival (mPFS) of the patients using sunitinib or pazopanib and concomitant beta-blocker was 20.4 (95% CI 4.5-40.1) months, and the mPFS of those not using it was 11.4 (95% CI 5.9-16.9) months (p = 0.042). Concomitant beta-blocker use was found to be a good prognostic factor for OS in the multivariate analysis (p = 0.029). In the multivariate analysis, concomitant beta-blocker use had a trend towards statistical significance for PFS (p = 0.062). CONCLUSION: Concomitant use of betablockers with sunitinib or pazopanib is associated with longer overall survial and progression free survival.

PROPSEA, safety evaluation of palbociclib and ribociclib in older patients with breast cancer: A prospective real-world TOG study.

INTRODUCTION: In this study, the toxicities and management of palbociclib and ribociclib in older patients (≥65 years) with metastatic breast cancer patients were investigated. MATERIALS AND METHODS: Among older patients receiving palbociclib and ribociclib, Geriatric 8 (G8) and Groningen Frailty Index were used to evaluate frailty status. Dose modifications, drug withdrawal and other serious adverse events (SAEs) were recorded and analyzed according to baseline patient characteristics. RESULTS: A total of 160 patients from 28 centers in Turkey were included (palbociclib = 76, ribociclib = 84). Forty-three patients were ≥ 75 years of age. The most common cause of first dose modification was neutropenia for both drugs (97% palbociclib, 69% ribociclib). Liver function tests elevation (10%) and renal function impairment (6%) were also causes for ribociclib dose modification. Drug withdrawal rate was 3.9% for palbociclib and 6% for ribociclib. SAEs were seen in 11.8% of those taking palbociclib and 15.5% of those on riboclib. An ECOG performance status of ≥2 and being older than 75 years were associated with dose reductions. Severe neutropenia was more common in patients with non-bone-only metastatic disease, those receiving treatment third-line therapy or higher, coexistance of non-neutropenic hematological side effects (for ribociclib). Neutropenia was less common among patients with obesity. DISCUSSION: Our results show that it can be reasonable to start palbociclib and ribociclib at reduced dose in patients aged ≥75 years and/or with an ECOG performance status ≥2.

Is the Prognostic Nutritional Index a Prognostic Marker for the Survival of Patients with Lymph-Node Positive Stage II-III Gastric Cancer Who Receive Adjuvant Chemotherapy?

PURPOSE: The prognostic nutritional index (PNI), like other systemic inflammatory markers, has been shown to be a prognostic factor in various cancer patients. In this study, we aimed to show whether PNI calculated before adjuvant chemotherapy is a prognostic factor for overall survival (OS) and disease-free survival (DFS) in patients with lymph node-positive stage II-III gastric cancer. METHODS: The PNI was calculated using the albumin and lymphocyte count. The PNI cut-off value was found to be 39.5. They were divided into two groups as being ≤ 39.5 (PNI low group) and > 39.5 (PNI high group). RESULTS: Our study included 168 patients with lymph node-positive stage II-III gastric cancer who received adjuvant chemotherapy. Of the patients, 116 (69.0%) were 65 years or younger, and 52 (31.0%) were over 65 years old. Of the patients, 117 (69.6%) were pT3, 51 (30.4%) were pT4. Seventy-three (43.4%) patients had pN1-2 disease and 95 (56.6%) patients had pN3 disease. The number of stage II patients was 73 (43.5%) and the number of stage III patients was 95 (56.5%). There were 73 patients with PNI ≤ 39.5 and 95 patients with PNI > 39.5. The mOS of the patients with low PNI group was 39.5 months, while the OS of the patients with high PNI group was 96.8 months (p = 0.002). In the group of patients with PNI low group, mDFS 24.4 months was significantly higher than those with PNI high group was 50.7 months (p = 0.021). The PNI score was statistically significant in univariate and multivariate analyzes for both DFS and OS. CONCLUSION: PNI can be used as an independent prognostic factor for both OS and DFS in patients lymph node-positive, stage II-III gastric cancer who will receive adjuvant chemotherapy.

Low-dose (7.5 mg/kg) bevacizumab may be a viable option in recurrent ovarian cancer: A retrospective study.

Objective: Bevacizumab (BEV) is a humanized monoclonal antibody of vascular endothelial growth factor receptors and, as a result of clinical trials, was approved for the treatment of recurrent ovarian cancer (ROC). The aim of this study was to assess the clinical utility of BEV in patients with ROC in real-world practice beyond clinical trials. Materials and Methods: In this single-center retrospective cohort study, we evaluated the medical data of all patients with ROC who were treated with BEV between October 2013 and March 2020. Results: A total of 76 females were evaluated. Forty-nine (64.5%) patients were platinum sensitive and 27 (35.5%) patients were platinum resistant. BEV was used in combination with chemotherapy agents in all patients, and the most preferred combinations were gemcitabine/carboplatin (GC) (78.9%) and carboplatin/paclitaxel (14.5%). In all patients, the BEV dose was 7.5 mg/kg every 3 weeks. The median progression-free survival (PFS) was 11.1 months (95% confidence interval [CI]: 9.6-12.6), and the median overall survival (OS) was 22.3 months (95% CI: 17.5-27.2). In multivariate analysis, serous histological type (P = 0.01), maintenance BEV administration (P = 0.001), and combination of GC-BEV (P < 0.001) were associated with better PFS, while serous histological type (P = 0.016) and good performance status (P = 0.006) were associated with prolonged OS. Conclusions: Low-dose (7.5 mg/kg) BEV was found to be effective in the second-line treatment of patients with ROC in our real-life study. In addition, the combination of BEV with GC was shown to be a viable option, especially in the treatment selection of platinum-resistant patients.

Sunitinib-induced small bowel wall edema as a prognostic marker in metastatic renal cell carcinoma.

Aim: The aim of this study was to evaluate the presence of small bowel wall edema (SBWE) on computed tomography (CT) images in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib and to investigate the relationship between the presence of SBWE and survival. Materials and Methods: We retrospectively evaluated the presence of SBWE on CT images of 27 mRCC patients who received at least one cycle of sunitinib. Then, we analyzed the relationship between the presence of SBWE and progression-free survival (PFS) and overall survival (OS). RESULTS: All 27 patients had SBWE on at least one CT scan. The median value of SBWE thickness was 2.5 mm. SBWE thickness was ≤2.5 mm in 13 patients (group A) and >2.5 mm in 14 patients (group B). The median OS was significantly higher in group B (55 vs. 18 months, respectively, P = 0.02). Although it was not statistically significant (13 vs. 8 months, respectively, P = 0.69), the median PFS was longer in group B than in group A. CONCLUSIONS: This study showed that sunitinib treatment caused SBWE in all patients with mRCC who received the drug. Also, this study demonstrated an association between higher SBWE thickness and better survival outcomes.

Prognostic biomarkers in metastatic colorectal cancer: delta prognostic nutritional index, delta neutrophil to lymphocyte ratio, and delta platelet to lymphocyte ratio.

BACKGROUND: The aim of this study is to determine the prognostic value of the prognostic nutritional index (PNI), the neutrophil to lymphocyte ratio (NLR), and the platelet to lymphocyte ratio (PLR) and their dynamic changes on survival outcomes in metastatic colorectal cancers (mCRC). METHODS: The data of 199 patients with mCRC were retrospectively analyzed. To evaluate the temporal relation between the PNI, NLR, and PLR values and survival, pre-chemotherapy PNI, NLR, and PLR levels were assessed from peripheral blood cell counts on admission; post-chemotherapy PNI, NLR, and PLR levels were assessed with follow-up blood cell counts within two weeks after chemotherapy; and the difference between pre-chemotherapy PNI, NLR, and PLR levels and post-chemotherapy PNI, NLR, and PLR levels was evaluated as delta PNI, delta NLR, and delta PLR. RESULTS: The median PNI, PLR, and NLR were 39.01, 150.2 and 2.53 before chemotherapy and 38.2, 146.6, and 3.31 after chemotherapy, respectively. The median OS was 23.7 months (95%CI:17.8-29.7) and 28.9 months (95%CI:24.8-33.08) for pre-chemotherapy PNI level < 39.01 vs. PNI level ≥ 39.01, respectively(p = 0.035) The positive delta PNI was significantly higher for OS than the negative delta PNI(p < 0.009). Delta PLR and delta NLR were not significant for OS and PFS(p > 0.05 for all). CONCLUSIONS: The results of this study clearly show that the negative delta PNI to be an independent predictor of poor OS and poor PFS in patients with colon cancer who received first line treatment. In addition, delta NLR and delta PLR were shown not to predict survival outcomes.

The Effect of RAS/BRAF Mutation Status on Prognosis and Relapse Pattern in Early Stage Colon Cancers.

PURPOSE: It is known that the RAS and BRAF mutations are predictive for targeted therapies in treating metastatic colon cancer and negatively affect the prognosis of the disease. However, there are limited studies in early-stage colon cancer about the relationship of this mutational condition with the prognosis and relapse pattern of the disease. In this study, we evaluated the effects of mutational status on the clinical pattern of recurrence and survival in early-stage colon cancer in addition to classical risk factors. METHODS: Patients with early-stage colon cancer at the first time of diagnosis and developing recurrence or metastasis on following up were included in this study. Patients were divided into two groups according to the at the time of relapse RAS/BRAF mutation status: mutant or non-mutant/wild types. Then, mutation analysis was performed again from the early-stage tissue of the patients if available. The relationship between early-stage mutation status and progression-free survival (PFS), overall survival (OS), and relapse pattern was analyzed. RESULTS: The number of patients with mutant and non-mutations in the early stage was 39 and 40, respectively. Mutant and non-mutant patients with stage 3 disease were similar (69% and 70%, respectively). OS (47.27 months vs. 67.53 months; p = 0.02) and PFS (25.12 vs. 38.13 months; p = 0.049) were statistically significantly lower in mutant patients, respectively. Most patients had distant metastases on both sides at recurrence (61.5% vs. 62.5%, respectively). There was no significant difference between mutant and non-mutant patients regarding distant metastasis and local recurrence rates (p = 0.657). A discordance of 11.4% between early-stage and late-stage tissue mutation status. CONCLUSION: The presence of mutation in early-stage colon cancer is associated with shorter OS and PFS. The mutational status did not have a significant effect on the recurrence pattern. Because of the discordance of early-stage and late-stage mutational status, it is recommended to perform mutation analysis from tissue at relapse.

The effect of concomitant proton pump inhibitor use on survival outcomes of Nivolumab-treated renal cell carcinoma patients: a multicenter study.

AIM: We aimed to evaluate the effect of concomitant proton pump inhibitors (PPI) use with nivolumab on survival outcomes in metastatic renal cell carcinoma (mRCC) in second-line setting. METHODS: The study was designed as a multicenter and retrospective involving patients with metastatic renal cell carcinoma receiving second-line nivolumab therapy. One hundred and nine patients with mRCC were divided into two groups based on whether they use PPI concomitantly with nivolumab: concomitant PPI users and non-users. Overall survival (OS) and progression-free survival (PFS) were compared between the groups with and without concurrent PPIs. RESULTS: Of 109 patients in our study, 59 were not using PPI concomitantly with nivolumab and 50 were using PPI concomitantly. The median PFS was 6.37 (5.2-7.5) months in the concomitant PPI group and 9.7 (4.5-15) months in the non-users (p = 0.03). The median OS was 14.6 (7.1-22.1) months in patients on PPI concurrently with nivolumab and 29.9 (17.1-42.7) months in the non-users (p = 0.01). Accordingly, PPI use for PFS (Non-use vs. Use = HR: 0.44, 95%Cl 0.28-0.96, p = 0.014) and PPI use for OS (Non-use vs. Use = HR: 0.68, 95%Cl 0.22-0.88, p = 0.01) were found to be as independent risk factors. CONCLUSIONS: Concomitant use of PPIs is associated with worse survival outcomes in patients with mRCC treated with nivolumab. Clinicians should carefully consider the concomitant use of PPIs in such patients.

The prognostic role of HIF-1α and NF-κB expression in RAS wild-type metastatic colorectal cancer: A Turkish Oncology Group (TOG) study.

BACKGROUND: Not all RAS wild-type metastatic colorectal cancer (mCRC) patients experience the same benefit from anti-epidermal growth factor receptor (EGFR) treatments. Studies have shown that nuclear factor-κB (NF-κB), hypoxia-inducible factor-1α (HIF-1α), interleukin 8 (IL-8) and transforming growth factor ß (TGF-ß) may be therapeutic targets for mCRC. The aim of this study was to clarify the prognostic value of NF-κB, HIF-1α, IL-8, and TGF-ß expression in patients with left-sided mCRC receiving EGFR inhibitors. METHODS: Patients with RAS wild-type, left-sided mCRC treated with anti-EGFR on the first line between September 2013 and April 2022 were included. Immunohistochemical staining for NF-κB, HIF-1α, IL-8 and TGF-ß was performed from tumor tissues of 88 patients. Patients were divided into NF-κB, HIF-1α, IL-8 and TGF-ß expression positive and negative group, moreover, expression positive group were also divided into two group as expression intensity low and high group. The median follow-up was 25.2 months. RESULTS: Median progression-free survival (PFS) was 8.1 (6-10.2) months in the cetuximab group, 11.3 (8.5-14) months in the panitumumab group (p = 0.09). Median overall survival (OS) was 23.9 (4.3-43.4) months in the cetuximab group, 26.9 (15.9-31.9) months in the panitumumab group (p = 0.8). Cytoplasmic NF-κB expression was present in all patients. The mOS was 19.8 (11-28.6) months in NF-κB expression intensity low group and 36.5 (20.1-52.8) months in high group (p = 0.03). The mOS of the HIF-1α expression negative group was significantly longer compared with expression positive group (p = 0.014). There was no significant difference in IL-8 and TGF-ß expression status on mOS and mPFS (for all, p > 0.05). Positive expression of HIF-1α was poor prognostic for mOS in the univariate analysis (HR:2.7, 95% CI 1.18-6.52, p = 0.02) and in multivariate analysis (HR 3.69, 95% CI 1.41-9.6, p = 0.008). High cytoplasmic expression intensity of NF-κB was found to have a good prognostic value for mOS (HR 0.47, 95% CI 0.26-0.85, p = 0.01). CONCLUSION: High cytoplasmic expression intensity of NF-κB and negative expression of HIF-1α could be a good prognostic marker for mOS in RAS wild-type left-sided mCRC.

Could the concomitant use of beta blockers with bevacizumab improve survival in metastatic colon cancer?

AIM: Drug-drug interactions are sometimes neglected in oncology practice. Due to drug pharmacokinetic and pharmacodynamic interactions, clinically increased or decreased drug effects and increased or decreased adverse effects may occur. Considering that the concomitant use of these two drugs that affect vascular endothelial growth factor receptor (VEGFR) may cause pharmacological potentiation or additive interaction, we aimed to evaluate the survival outcomes of concomitant use of bevacizumab and beta blockers in patients with metastatic colorectal cancer (mCRC). METHODS: In total, 181 patients with mCRC administered with bevacizumab plus cytotoxic chemotherapy regimen in a first-line setting were divided into two groups: concomitant beta-blocker user and nonuser. RESULTS: The median overall survival (mOS) was 35.9 (95% CI: 27.9-43.9) months in the beta-blocker-using group and 29.6 (95% CI: 27.9-43.9) months in the beta-blocker-non-using group (p = 0.054). The median progression-free survival (mPFS) was 16.1 (95% CI: 12.4-19.9) months in the beta-blocker-using group and 12.8 (95% CI: 10.6-15.0) months in the beta-blocker-non-using group (p = 0.006). The multivariate analysis revealed that beta-blocker use was an independent predictor of mPFS (HR: 0.66, 95% CI: 0.46-0.93, p = 0.018) and mOS (HR: 0.57, 95% CI: 0.36-0.91, p = 0.02). CONCLUSION: This study demonstrated that concomitant usage of beta blockers improved both survival outcomes, irrespective of the kind of beta blocker.

The effect of concomitant use of proton pump inhibitors with CDK 4/6 inhibitors on survival in metastatic breast cancer.

AIM: To evaluate the difference of progression free survival between the patients using concomitant proton pump inhibitors and non-users in the patients using CDK 4/6 inhibitors with HR + and HER2 negative mBC. METHODS: We included 86 patients with HR + and HER 2 negative mBC treated with CDK 4/6 inhibitors in this study. Patients were divided into two categories according to their status of PPI use. The primary end points was progression free survival (PFS). We compared PPI users and non-users. RESULTS: Forty-five (52.3%) patients used a PPI concomitantly with a CDK 4/6 inhibitor, and 41 (47.7%) did not. The median duration of follow-up was 10.68 (1.94-27.56) months. Of the patients, 50 (58.1%) palbociclib and 36 (41.9%) received ribociclib. The median progression free survival (mPFS) was 10.9 months (95% CI: 7.5-14.27) in the group with concomitant PPI use with a CDK 4/6 inhibitor, whereas the median progression free survival could not be reached in the group without concomitant PPI use (p = 0.04). In addition, concomitant PPI use with palbociclib was associated with a shorter PFS; there was no significant difference between the concomitant PPI users and non-users in terms of PFS in the patients using ribociclib. CONCLUSION: Palbociclib and ribociclib are weak base drugs so their bioavailability is pH-dependent. PPIs can affect their solubility and their concentration in the plasma. Therefore, we must avoid concomitant use of PPIs and CDK 4/6 inhibitors. If we need to use concomitant PPI and CDK 4/6 inhibitors, we should prefer ribociclib than palbociclib.

Is Neuregulin-4 a predictive marker of microvascular complications in type 2 diabetes mellitus?

BACKGROUND AND AIMS: Neuregulin-4 (Nrg-4) is a new adipokine released from brown adipose tissue. It plays pivotal role in regulating systemic energy balance, glucose and lipid metabolism and in reducing chronic inflammation. We aimed to investigate the relation between diabetic microvascular complications (DMC) and serum (Nrg-4) levels in patients with type 2 diabetes mellitus. METHODS: Patients with type 2 diabetes mellitus were divided into DMC and diabetic patients without microvascular complications (non-DMC). Nrg-4 levels of the patients were compared. RESULTS: Fifty and 29 patients enrolled to the DMC and non-DMC groups, respectively. Nrg-4 was 1.23 (0.02-5.1) ng/mL and 2.5 (0.21-6.01) ng/mL in DMC and in non-DMC groups, respectively (P < .001). In patients with DMC, FPG was 189.5 (89-446) mg/ dL, whereas it was 128 (95-278) mg/dL in non-DMC diabetic patients (P < .001). HbA1c was also significantly higher in the DMC group than in the non-DMC group (P < .001). Negative correlation was found between Nrg-4 and FPG (r = -0.231, P = .03), HBA1c (r = -0.312, P = .003) and microalbuminuria (r = -0.277, P = .009). Logistic regression analysis showed a 1-unit decrease in Nrg-4 to increase the presence of DMC by 1.9 times. The best cut-off value of Nrg-4 was 1.56 ng/mL with 82.1% sensitivity and 64% specificity, in predicting DMC. CONCLUSION: In patients with diabetes, Nrg-4 levels may be a good predictor of early detection of one or more DMC, as microvascular dysfunction in an organ system is considered to be an initial onset of subclinical systemic damage.