Longitudinal analysis of complete blood count parameters in advanced-stage lung cancer patients.

BACKGROUND: Metastatic lung cancer is a debilitating disease, but with the advances in immunotherapy, therapeutic options have vastly increased. Numerous complete blood count parameters (CBC) have been described as easily accessible biomarkers that might predict response to immunotherapy. However, to date, no comprehensive study has been performed on the longitudinal changes of these parameters during cancer progression. METHODS: The clinicopathological variables and CBC parameters of 986 advanced stage lung cancer patients were retrospectively analyzed. Blood tests were performed as part of the routine checkup and the results were recorded at the time of the diagnosis of the primary tumor, the diagnosis of brain or bone metastases, and also during the last available follow-up. RESULTS: In the experimental subcohort, 352 and 466 patients were diagnosed with brain and bone metastases, respectively. The control group consisted of 168 patients without clinically detectable or other distant organ metastases. In our longitudinal analyses, we found significantly decreasing absolute lymphocyte count (ALC: P < 0.001), and significantly increasing absolute neutrophil count (ANC: P < 0.001) levels in all patient subgroups, irrespective of histopathological type and metastatic site. Interestingly, patients with brain metastases had significantly descending-ascending platelet count (PLT) trendlines (P < 0.001), while the bone metastatic subgroup exhibited significantly ascending-descending trendlines (P = 0.043). CONCLUSIONS: Significantly decreasing ALC, significantly increasing ANC and fluctuating PLT levels may be found in brain and bone metastatic lung cancer patients during disease progression. Our findings might contribute to improve personalized healthcare in this devastating malignancy. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Significantly decreasing ALC, and significantly increasing ANC levels can be found in advanced-stage lung cancer patients during disease progression Patients with brain metastases have descending-ascending PLT trendlines, while patients with bone metastases exhibit ascending-descending trendlines during disease progression WHAT THIS STUDY ADDS: The descending values for ALC, and the ascending mean values for PLT and ANC, might be suggestive of poor response to second- or third-line immunotherapy in advanced-stage lung cancer patients. The current study might help to improve patient selection and treatment strategies for brain and/or bone metastatic lung cancer patients.

Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung Cancer Patients with Bone Metastasis.

Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for changes in renal function parameters. Comorbidities included hypertension (50%), COPD (33%) and diabetes mellitus (15%). Statistical analysis was performed with Fisher's exact tests and a Cox proportional hazards model. In patients suffering from hypertension, both median serum creatinine and blood urea nitrogen (BUN) were higher (81.9 versus 75.8 µmol/L, p < 0.001 and 6.0 versus 5.7 mmol/L, p = 0.005, respectively). Such a difference could not be observed in patients with diabetes. In patients with COPD, only serum creatinine was higher (81.1 versus 77.3 µmol/L, p = 0.004). In the whole cohort, we found that while at the time of lung cancer diagnosis the ratio of patients in the pathological range (PRR) was 8.67% for serum creatinine (median: 75 µmol/L) and 14.16% for BUN (median: 5.4 mmol/L), at the time of bone metastasis the PRR for serum creatinine increased to 16.11% (median: 77.0 µmol/L) and for BUN to 24.07% (median: 6.0 mmol/L), which is a significant increase for both parameters (p < 0.001). For the whole cohort, the last laboratory results showed a 26.37% PRR for serum creatinine and 45.66% PRR for BUN (significant increase for both, p < 0.001). Multivariate analysis revealed that patients with hypertension had a higher chance for switching to the pathological range sooner (p = 0.033, HR: 1.372, CI: 1.025-1.835). Also, the appearance of the bone metastasis correlated with an acceleration of the onset of such a switch (p < 0.001, HR: 2.655, CI: 1.581-4.456). Our results suggest that renal function is impaired in a significant proportion of patients with lung cancer and highlight the importance of non-nephrotoxic drug in the management of bone metastases.

Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung Cancer Patients with Bone Metastasis.

Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for changes in renal function parameters. Co-morbidities included hypertension (50%), COPD (33%) and diabetes mellitus (15%). Statistical analysis was performed with Fisher's exact tests and a Cox proportional hazards model. In patients suffering from hypertension, both median serum creatinine and blood urea nitrogen (BUN) were higher (81.9 versus 75.8 µmol/l, p<0.001 and 6.0 versus 5.7 mmol/l, p=0.005, respectively). Such a difference could not be observed in patients with diabetes. In COPD patients, only serum creatinine was higher (81.1 versus 77.3 µmol/l, p=0.004). In the whole cohort, we found that while at the time of lung cancer diagnosis the ratio of patients in the pathological range (PRR) was 8.67% for serum creatinine (median: 75 µmol/l) and 14.16% for BUN (median: 5.4 mmol/l), at the time of bone metastasis the PRR for serum creatinine increased to 16.11% (median: 77.0 µmol/l) and for BUN to 24.07% (median: 6.0 mmol/l), which is a significant increase for both parameters (p<0.001). For the whole cohort, the last laboratory results showed a 26.37% PRR for serum creatinine and 45.66% PRR for BUN (significant increase for both, p<0.001). Multivariate analysis revealed that patients with hypertension had a higher chance for switching to the pathological range sooner (p=0.033, HR: 1.372, CI: 1.025-1.835). Also, the appearance of the bone metastasis correlated with an acceleration of the onset of such a switch (p<0.001, HR: 2.655, CI: 1.581-4.456). Our results suggest that renal function is impaired in a significant proportion of lung cancer patients and highlight the importance of non-nephrotoxic drug in the management of bone metastases. This article is protected by copyright. All rights reserved.

Drug discovery in the kinase inhibitory field using the Nested Chemical Library technology.

Kinase inhibitors are at the forefront of modern drug research, where mostly three technologies are used for hit-and-lead finding: high throughput screening of random libraries, three-dimensional structure-based drug design based on X-ray data, and focused libraries around limited number of new cores. Our novel Nested Chemical Library (NCL) (Vichem Chemie Research Ltd., Budapest, Hungary) technology is based on a knowledge base approach, where focused libraries around selected cores are used to generate pharmacophore models. NCL was designed on the platform of a diverse kinase inhibitory library organized around 97 core structures. We have established a unique, proprietary kinase inhibitory chemistry around these core structures with small focused sublibraries around each core. All the compounds in our NCL library are stored in a big unified Structured Query Language database along with their measured and calculated physicochemical and ADME/toxicity (ADMET) properties, together with thousands of molecular descriptors calculated for each compound. Biochemical kinase inhibitory assays on selected, cloned kinase enzymes for a few hundred NCL compound sets can provide sufficient biological data for rational computerized design of new analogues, based on our pharmacophore model-generating 3DNET4W QSPAR (quantitative structure-property/activity relationships) approach. Using this pharmacophore modeling approach and the ADMET filters, we can preselect synthesizable compounds for hit-and-lead optimization. Starting from this point and integrating the information from QSPAR, high-quality leads can be generated within a small number of optimization cycles. Applying NCL technology we have developed lead compounds for several validated kinase targets.