AZD-7648, a DNA-PK Inhibitor, Induces DNA Damage, Apoptosis, and Cell Cycle Arrest in Chronic and Acute Myeloid Leukemia Cells.

The non-homologous end joining pathway is vital for repairing DNA double-strand breaks (DSB), with DNA-dependent protein kinase (DNA-PK) playing a critical role. Altered DNA damage response (DDR) in chronic (CML) and acute myeloid leukemia (AML) offers potential therapeutic opportunities. We studied the therapeutic potential of AZD-7648 (DNA-PK inhibitor) in CML and AML cell lines. This study used two CML (K-562 and LAMA-84) and five AML (HEL, HL-60, KG-1, NB-4, and THP-1) cell lines. DDR gene mutations were obtained from the COSMIC database. The copy number and methylation profile were evaluated using MS-MLPA and DDR genes, and telomere length using qPCR. p53 protein expression was assessed using Western Blot, chromosomal damage through cytokinesis-block micronucleus assay, and γH2AX levels and DSB repair kinetics using flow cytometry. Cell density and viability were analyzed using trypan blue assay after treatment with AZD-7648 in concentrations ranging from 10 to 200 µM. Cell death, cell cycle distribution, and cell proliferation rate were assessed using flow cytometry. The cells displayed different DNA baseline damage, DDR gene expressions, mutations, genetic/epigenetic changes, and p53 expression. Only HEL cells displayed inefficient DSB repair. The LAMA-84, HEL, and KG-1 cells were the most sensitive to AZD-7648, whereas HL-60 and K-562 showed a lower effect on density and viability. Besides the reduction in cell proliferation, AZD-7648 induced apoptosis, cell cycle arrest, and DNA damage. In conclusion, these results suggest that AZD-7648 holds promise as a potential therapy for myeloid leukemias, however, with variations in drug sensitivity among tested cell lines, thus supporting further investigation to identify the specific factors influencing sensitivity to this DNA-PK inhibitor.

A prospective cohort study of TIMP1 as prognostic biomarker in gastric and colon cancer.

BACKGROUND: Tissue inhibitor metalloproteinase 1 (TIMP1) inhibits proteins which has proteolytic activity, but in cancer it contributes for tumoral invasion and metastization. The authors investigated the expression of TIMP1 in different digestive cancer types. The aim of this study was to test TIMP1 as a serum marker since in clinical practice there is a lack of biomarkers to monitor the response to treatments or to detect early relapses. METHODS: It was performed a prospective study with recently diagnosed patients with gastrointestinal cancers. Patients with esophageal, gastric, colon, rectal, hepatocarcinoma, and cholangiocarcinoma at any stage, that did not perform any type of treatment, were included. Enzyme-linked immunosorbent assays and chemiluminescence were used to quantify levels of TIMP1. The differences of the Kaplan-Meier survival curves were tested for statistical significance with the log rank test, and the 95% confidence intervals were calculated. Multivariate analysis was done using the COX proportional hazard model and a forward stepwise method. Statistical analyses were done using the IBM SPSS Statistics version 26.0. P value inferior to 0.05 was considered significant. RESULTS: A total of 190 patients were recruited: 54.7% males, median age of 68 years old, 57.9% with colorectal cancer followed by esophagogastric disease with 22.6%. TIMP1 level were increased in 29.5%. In colon cancer, patients with higher levels of TIMP1 are associated with worse progression free survival (PFS) (P=0.007) and overall survival (OS) (P=0.036). No relationship was seen with Rat sarcoma virus (RAS), B-raf (BRAF) and Microsatellite instability status (MSI). In gastric cancer, patients with higher levels of TIMP1 are associated with worse OS (P=0.020), with no difference in PFS. CONCLUSIONS: Higher TIMP1 levels in gastric and colon cancer patients are associated with worse prognosis. Further studies are needed: higher number of patients and sequential measurements of TIMP1 during patient treatments.

Biomarker guided treatment in oncogene-driven advanced non-small cell lung cancer in older adults: A Young International Society of Geriatric Oncology report.

Lung cancer remains the leading cause of cancer-related deaths worldwide, with most patients diagnosed at an advanced age. The treatment of non-small cell lung cancer (NSCLC) has been revolutionized with the introduction of molecular guided therapy. Despites the challenges when considering treatment of older adults, they are still systematically underrepresented in registrational trials. This review aims to summarize the existing evidence on treatment of older patients with lung cancer with a targetable driver mutation or alteration (EGFR, ALK, ROS, BRAFV600E, MET, RET, KRASG12C and NTRK), and consider the evidence from a geriatric oncology perspective. Early generation EGFR-tyrosine kinase inhibitors (TKIs). TKIs are fairly well-studied in older adults and have been shown to be safe and efficient. However, older adult-specific data regarding the standard-of-care first-line agent osimertinib are lacking. Erlotinib, dacomitinib, and afatinib may be more toxic than other EGFR-TKIs. Next generation ALK-TKIs are preferred over crizotinib due to increased efficacy, as demonstrated in phase III trials. Alectinib seems to be safer than crizotinib, while brigatinib is associated with increased toxicity. Lorlatinib overcomes most resistance mutations, but data regarding this agent have only recently emerged. Regarding ROS1-fusion positive NSCLC, crizotinib is an option in older adults, while entrectinib is similarly effective but shows increased neurotoxicity. In BRAFV600E-mutant NSCLC, the combination darbafenib/tramectinib is effective, but no safety data for older adults exist. MET alterations can be targeted with capmatinib and tepotinib, and registrational trials included primarily older patients, due to the association of this alteration with advanced age. For RET-rearranged-NSCLC selpercatinib and pralsetinib are approved, and no differences in safety or efficacy between older and younger patients were shown. KRASG12C mutations, which are more frequent in older adults, became recently druggable with sotorasib, and advanced age does not seem to affect safety or efficacy. In NTRK-fusion positive tumors, larotrectinib and entrectinib have tumor agnostic approval, however, not enough data on older patients are available. Based on currently available data, molecularly-guided therapy for most alterations is safe and efficacious in older adults with oncogene-driven advanced NSCLC. However, for many TKIs, older adult-specific data are lacking, and should be subject of future prospective evaluations.

Acceptance of SARS-CoV-2 vaccination among cancer patients in Portugal: attitudes and associated factors.

OBJECTIVE: COVID-19 vaccines have shown efficacy and safety in healthy people. However, cancer patients under active immunosuppressive treatment were not included in the clinical trials conducted to test vaccines' efficacy and safety. This study aimed to evaluate the COVID-19 vaccine acceptance in cancer patients undergoing immunosuppressive therapy. METHODS: A total of 200 adult cancer patients received a questionnaire between March 8 and April 2, 2021, before the beginning of cancer patients' vaccination in Portugal. The questionnaire adapted from previously conducted studies included 11 close-ended items, evaluating variables such as patient sociodemographic and clinical characteristics, and the acceptance and underlying reasons to be or not to be vaccinated. The primary outcome was the intended acceptance of the COVID-19 vaccine in cancer patients. Multiple logistic regression was performed to identify factors associated with intended acceptance. RESULTS: Among the 200 delivered questionnaires, only 169 were included in this study. From those, 142 (84%) patients intended to be vaccinated against COVID-19. Only 27 participants (16%) had not yet decided or were reluctant to COVID-19 vaccination. High school degree (odds ratio (OR) 0.133, 95% confidence interval (C.I.) 0.031-0.579, p = 0.007], rural residence (OR 0.282, 95% C.I. 0.081-0.984, p = 0.047), and reluctance in believing in the vaccine efficacy (OR 0.058, 95% C.I. 0.016-0.204, p < 0.001] were identified predictors factor for COVID-19 vaccine hesitancy. CONCLUSION: Most patients intended to be vaccinated against COVID-19, and specific factors such as education level, rural residence and the belief in vaccine efficacy were related to vaccine acceptance.

Giant Metastatic Breast Phyllodes Tumour with an Elusive Diagnosis: A Case Report and Literature Review.

BACKGROUND: The term phyllodes tumours, which account for less than 1% of breast neoplasms, describes a spectrum of heterogenous tumours with different clinical behaviours. Less than 30% present as metastatic disease. Complete surgical resection is the standard of care so that recurrence rates are reduced. The role of adjuvant chemotherapy or radiation therapy is controversial. Patients with metastatic disease have a median overall survival of around 30 months. CASE DESCRIPTION: The authors present the case of a 57-year-old woman with an exuberant left malignant phyllodes tumour with bilateral involvement, as well as lung and axillar metastasis. The patient underwent haemostatic radiation therapy and started palliative chemotherapy with doxorubicin, achieving partial response with significant improvement in quality of life. A posterior simple mastectomy revealed a small residual tumour. DISCUSSION: Metastatic malignant phyllodes tumours are rare, so therapeutic strategies rely on small retrospective studies and guidelines for soft tissue sarcoma. Palliative chemotherapy protocols include anthracycline-based regimens, either as monotherapy with doxorubicin or doxorubicin together with ifosfamide. With few treatment options, management of these patients must rely on a continuum of care. LEARNING POINTS: Phyllodes tumours are a rare type of breast neoplasm.The differential diagnosis of breast cancer should include phyllodes tumours.Accurate and rapid diagnosis is required.

Prognostic factors for early relapse in non-metastatic triple negative breast cancer - real world data.

BACKGROUND: Triple negative breast cancer (TNBC) has the worst prognosis amongst all subtypes. Studies have shown that the achievement of pathologic complete response in the breast and axilla correlates with improved survival. The aim of this study was to identify clinical or pathological features of real-life TNBC patients with a higher risk of early relapse. MATERIALS AND METHODS: Single-centre retrospective analysis of 127 women with TNBC, stage II-III, submitted to neoadjuvant treatment and surgery between January 2016 and 2020. Multivariate Cox regression analysis for disease free survival (DFS) at 2 years was performed and statistically significant variables were computed into a prognostic model for early relapse. RESULTS: After 29 months of median follow-up, 105 patients (82.7%) were alive and, in total, 38 patients (29.9%) experienced recurrence. The 2-year DFS was 73% (95% CI: 21.3-22.7). In multivariate analysis, being submitted to neoadjuvant radiotherapy [HR 2.8 (95% CI: 1.2-6.4), p = 0.017] and not achieving pathologic complete response [HR 0.3 (95% CI: 0.1-1.7), p = 0.011] were associated with higher risk of recurrence. In our prognostic model, the presence of at least one of these variables defined a subgroup of patients with a worse 2-year DFS than those without these features (59% vs. 90%, p < 0.001, respectively). CONCLUSIONS: In this real-life non-metastatic TNBC cohort, neoadjuvant radiotherapy (performed due to insufficient clinical response to neoadjuvant chemotherapy or significant toxicity) impacted as an independent prognostic factor for relapse along with the absence of pathologic complete response identifying a subgroup of higher risk patients for early relapse that might merit a closer follow-up.

Targeted agents in older patients with gastrointestinal cancers - An overview.

Targeted agents have been increasingly used in different malignancies and are associated with improved survival outcomes, including gastrointestinal cancers. Their use in the treatment of older patients is appealing given their favorable toxicity profile. In the last years, this subgroup of patients has been attracting increased interest given their representativeness and specific clinical needs. Nonetheless, the lack of data on efficacy and safety of standard treatments in older patients hinders proper evidence-based decision-making, leaving most therapeutic recommendations to be extrapolated from registration trials with low representation of older and frail patients. However, even if most decisions regarding the use of targeted agents in older patients with gastrointestinal cancer remain guided by subanalyses of large trials, data from recent older adult-specific trials are beginning to emerge, particularly in colorectal cancer. This review aims to summarize the existing evidence on treatment of older patients with gastrointestinal carcinomas (colon and rectum, stomach, esophagus, liver, and pancreas) with targeted agents (cetuximab, panitumumab, bevacizumab, ramucirumab, aflibercept, regorafenib, encorafenib, trastuzumab, sorafenib, lenvatinib, cabozantinib, erlotinib, olaparib), and place the evidence in a geriatric oncology perspective.

Immunotherapy and predictive immunologic profile: the tip of the iceberg.

The interplay between cancer and the immune system has been under investigation for more than a century. Immune checkpoint inhibitors have changed the outcome of several tumors; however, there is a significant percentage of patients presenting resistance to immunotherapy. Besides the action mechanism, it is essential to unravel this complex interplay between host immune system and tumorigenesis to determine an immune profile as a predictive factor to immune checkpoint blockade agents. Tumor expression of programmed death-ligand 1 (PD-L1), tumor mutational burden, or mismatch repair deficiency are recognized predictive biomarkers to immunotherapy but are insufficient to explain the response rates and heterogeneity across tumor sites. Therefore, it is crucial to explore the role of the tumor microenvironment in the diversity and clonality of tumor-infiltrating immune cells since different checkpoint molecules play an influential role in cytotoxic T cell activation. Moreover, cytokines, chemokines, and growth factors regulated by epigenetic factors play a complex part. Peripheral immune cells expressing PD-1/PD-L1 and the biologic roles of soluble immune checkpoint molecules are the subject of new lines of investigation. This article addresses some of the new molecules and mechanisms studied as possible predictive biomarkers to immunotherapy, linked with the concept of immune dynamics monitoring.

Acute toxicity and tolerability of anthracycline-based chemotherapy regimens in older versus younger patients with breast cancer: real-world data.

OBJECTIVES: To compare the non-cardiac acute toxicity and tolerability profile of anthracycline-based regimens between older versus younger women diagnosed with breast cancer in a real-world setting. METHODS: Retrospective cohort of female patients diagnosed with breast cancer and treated with neoadjuvant or adjuvant anthracycline-based regimens between 2017 and 2019. Patients were grouped in young versus older, using an age of 65 as cut-off. Differences in non-cardiac acute toxicity and change in treatment plan were examined. RESULTS: Among the 559 patients, 19.5% were aged ≥ 65 years. Regimens used were fluorouracil, epirubicin, and cyclophosphamide in 56.2% of patients, doxorubicin and cyclophosphamide in 33.3%, and epirubicin and cyclophosphamide in 10.5%; there were no differences in incidence of grade 3 or 4 toxicities between regimens (p = 0.184). Acute grade 3 or 4 toxicities occurred more frequently in the older group (33.9% versus 10.7%, p < 0.0001, OR 4.304, 95%-CI [2.619-7.073]). Delay of at least one chemotherapy cycle due to toxicity occurred more frequently in the older group (24.8% versus 9.3%, p < 0.0001, OR 3.199, 95%-CI [1.867-5.481]). Early termination of treatment also occurred more frequently in the older group (11.9% versus 1.6%, p < 0.0001, OR 8.571, 95%-CI [3.331-22.048]). CONCLUSION: Although acute grade 3 or 4 toxicities were more frequent in older patients, which resulted in increased cycle delay and/or premature termination of treatment, overall treatment was still reasonably well-tolerated, with 88.1% of older patients completing the planed anthracycline regimen.

ACE-27 as a prognostic tool of severe acute toxicities in patients with head and neck cancer treated with chemoradiotherapy: a real-world, prospective, observational study.

PURPOSE: To evaluate the association between comorbidities as assessed by the "Adult Comorbidity Evaluation 27" (ACE-27) and the development of severe acute toxicities in patients with head and neck cancer treated with chemoradiotherapy. METHODS: Prospective, single-center cohort of patients with head and neck cancer treated with chemoradiotherapy (cisplatin 100 mg/m2 on days 1, 22, and 43; intensity-modulated radiotherapy 60 to 69.96 gray, in 30 to 33 fractions,) between June 2018 and December 2019. ACE-27 was assessed before the start of treatment. Patients were divided in two groups based on ACE-27 grading (none to mild versus moderate to severe comorbidities). Differences in incidence of severe acute toxicity and change in treatment plan between groups were examined. RESULTS: A total of 101 patients were included: 90.1% were male, and median age was 57 years. ACE-27 grading was none in 6.9% of patients, mild in 52.5%, moderate in 29.7%, and severe in 10.9%. Severe acute toxicities occurred more frequently in patients with moderate to severe comorbidities (75.6% versus 48.3%), with a statically significant difference (p = 0.006, OR 3.314, 95%-CI (1.382-7.944)). In the group with moderate to severe comorbidities, omission of at least one cisplatin cycle (75.6% versus 60.0%) and premature ending of radiotherapy (12.2% versus 5.0%) also occurred more frequently (p ≥ 0.05). CONCLUSION: In patients with head and neck cancer treated with chemoradiotherapy, the presence of moderate to severe comorbidities seems to correlate with higher incidences of severe acute toxicities. ACE-27 may identify patients at higher risk of major toxicities and assist decisions regarding treatment.

Encephalopathy in a kidney transplant recipient.

A 60-year-old man presented several times to the emergency department due to confusion and behavioral changes. He was a kidney transplant recipient dependent on hemodialysis due, presumably, to chronic nephropathy of the transplanted kidney, and was not under any immunosuppressive therapy. He was admitted to the hospital ward due to elevation of C reactive protein and severe proteinuria, leukocyturia and erythrocyturia. The alterations found in the spot urine examination were suggestive of nephritic syndrome, consistent with chronic nephropathy of the transplanted kidney. The neurologic deterioration, however, remained unexplained. CT of the brain and cerebrospinal fluid examination were unremarkable. Infection, auto-immune disease and malignancy were excluded. Corticoid therapy was started for rejection nephropathy. The patient improved dramatically and ultimately the transplanted kidney was removed. Chronic nephropathy of the transplanted kidney was confirmed histologically and the patient remained clinically asymptomatic, without corticoid therapy.

Bowel obstruction in advanced cancer.

PURPOSE: Assessment of treatment of cancer patients with bowel obstruction, identification of prognostic factors, and assessment of reference to palliative care. METHODS: Records of patients with a diagnosis of bowel obstruction over a 6-month (January-June 2013) period were reviewed. RESULTS: Seventy-five patients were diagnosed with bowel obstruction. Fifty-one (68%) were female and the median age was 65 years (27-100). The most frequent cancer was colorectal, 30 (40%), followed by gynecological cancer, 20 (27%). Forty-three (57%) patients underwent conservative treatment; 26 (35%) underwent surgery; and 6 (8%) had a stent placement. In 68 (91%), the bowel obstruction was resolved. Three years after the bowel obstruction episode, 15 (20%) patients were still alive. An analysis of the possible association of variables recorded with mortality was carried out, and for death at the first admission, only the resolution of the obstruction was significant (P < .001); for the 3-year survival the significant factors were hemoglobin >10.7 g/dL (P < .001) and ascites (P = .001) at the time of obstruction. Thirty-seven (49%) patients were referred to palliative care. CONCLUSIONS: Although bowel obstruction in cancer patients is usually associated with a short life expectancy, some patients have relatively long survivals. Only about half of the patients were referred to palliative care.

DesinFix TM 135 in fermentation process for bioethanol production.

Brazil has the world's largest ethanol production from sugarcane, but bacterial contamination decreases the ethanol yields. It was shown that the biocide DesinFix™ 135 can reduce the contamination without decreasing the yeasts' viability or negatively affecting the ethanol production.

DesinFix TM 135 in fermentation process for bioethanol production

Brazil has the world's largest ethanol production from sugarcane, but bacterial contamination decreases the ethanol yields. It was shown that the biocide DesinFixTM 135 can reduce the contamination without decreasing the yeasts' viability or negatively affecting the ethanol production.

Synthesis, characterization, and antibacterial activity of three palladium(II) complexes of tetracyclines.

Pd(II) complexes with three antibiotics of the tetracycline family (tetracycline, doxycycline and chlortetracycline) were synthesized and characterized by elemental, thermogravimetric, and conductivity analyses, and infrared spectroscopy. The interactions between Pd(II) ions and tetracycline were investigated in aqueous solution by (1)H NMR. All the tetracyclines studied form 1:1 complexes with Pd(II) via the oxygen of the hydroxyl group at ring A and that of the amide group. The effect of the three complexes on the growth of bacterial strains sensitive and resistant to tetracycline was studied. The Pd(II) complex of tetracycline is practically as efficient as tetracycline in inhibiting the growth of two Escherichia coli (E. coli) sensitive bacterial strains and 16 times more potent against E. coli HB101/pBR322, a bacterial strain resistant to tetracycline. Pd(II) coordination to doxycycline also increased its activity in the resistant strain by a factor of 2.