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.

Assessing recovery rates of distinct exogenous controls for gDNA extraction efficiency using phenol-chloroform or silica-column based extractions.

Assessment of genomic DNA (gDNA) extraction efficiency is required for accurate bacterial quantification by qPCR. Exogenous DNA molecules are often added after bacterial cultures are lysed, but before DNA purification steps, to determine extraction efficiency. Herein we found that different exogenous DNA controls have different recovery rates, suggesting distinct DNA extraction efficiencies. Recovery rates are also affected by the gDNA extraction method being more affected in silica-based columns than in phenol-chloroform extraction. Overall, we determined that the use of long DNA fragments, such as gDNA, as exogenous controls have a higher recovery rate than use of smaller size DNA molecules.

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.

Prognostic significance of MUC2, CDX2 and SOX2 in stage II colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) remains a serious health concern worldwide. Despite advances in diagnosis and treatment, about 15 to 30% of stage II CRC patients subjected to tumor resection with curative intent, develop disease relapse. Moreover, the therapeutic strategy adopted after surgery is not consensual for these patients. This supports the imperative need to find new prognostic and predictive biomarkers for stage II CRC. METHODS: For this purpose, we used a one-hospital series of 227 stage II CRC patient samples to assess the biomarker potential of the immunohistochemical expression of MUC2 mucin and CDX2 and SOX2 transcription factors. The Kaplan-Meier method was used to generate disease-free survival curves that were compared using the log-rank test, in order to determine prognosis of cases with different expression of these proteins, different mismatch repair (MMR) status and administration or not of adjuvant chemotherapy. RESULTS: In this stage II CRC series, none of the studied biomarkers showed prognostic value for patient outcome. However low expression of MUC2, in cases with high expression of CDX2, absence of SOX2 or MMR-proficiency, conferred a significantly worst prognosis. Moreover, cases with low expression of MUC2 showed a significantly clear benefit from treatment with adjuvant chemotherapy. CONCLUSION: In conclusion, we observe that patients with stage II CRC with low expression of MUC2 in the tumor respond better when treated with adjuvant chemotherapy. This observation supports that MUC2 is involved in resistance to fluorouracil-based adjuvant chemotherapy and might be a promising future predictive biomarker in stage II CRC patients.

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.

Metastatic lymph node ratio as a better prognostic tool than the TNM system in colorectal cancer.

Background: The minimum number of lymph nodes that should be evaluated in colon cancer to adequately categorize lymph node status is still controversial. The lymph node ratio (LNR) may be a better prognostic indicator. Materials & methods: We studied 1065 patients treated from 1 January 2000 to 31 August 2012. Results: Significant differences in survival were detected according to regional lymph nodes (pN) (p < 0.001) and LNR (p < 0.001). LRN and pN are independent prognostic factors. Spearman correlation analysis showed a significant correlation between the total number of dissected lymph nodes and pN (rs = 0.167; p < 0.001), but the total number of dissected lymph nodes is not significantly correlated with LNR (rs = -0.019; p = 0.550). Interpretation: In this study, LNR seems to demonstrate a superior prognostic value compared with the pN categories, in part due to its greater independence regarding the extent of lymphadenectomy.

Lay abstract The prognosis of colon cancer is determined by tumor dimensions, number of metastatic lymph nodes and the presence of distant metastasis. Altogether, these criteria comprise the TNM (tumor-node-metastasis) staging system. Some societies consider a minimum of 12 lymph nodes to access the prognosis, but it is not always possible to resect this number of lymph nodes during the surgery. The lymph node ratio, calculated as the division between the number of metastatic lymph nodes and the number of resected lymph nodes, seems to demonstrate a superior prognostic value because it is independent from the extent of lymphadenectomy.

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.

Current opinion about antimicrobial therapy in palliative care: an update.

PURPOSE OF REVIEW: The review englobes the latest studies published regarding the problem of antimicrobial usage with palliative intent. RECENT FINDINGS: In the advanced stages of illness like cancer, dementia, or neurodegenerative diseases, important decisions have to be made concerning the global treatment plan. Infections are very common among this kind of patients as they typically have multiple comorbidities and are incapacitated. These infections, in a majority of the cases, will be treated with antimicrobial therapy because this is a standard medical procedure. For a health professional, the decision of whether to treat, withhold, or withdraw a treatment can be difficult. In fact, in palliative care, the challenge is to balance compassionate care for people suffering from end-of-life diseases with the need for responsible antibiotic usage. Antimicrobial treatment could alleviate symptoms from an infection and make patients more comfortable, on the other hand, its overuse of it could bring a broader public health risk. SUMMARY: On the contrary, in 18 months there are few studies about this problem, what reveals no concern about the use of antimicrobians in end-of-life patients.

Angiogenic factors: role in esophageal cancer, a brief review.

Esophageal cancer has an aggressive behavior with rapid tumor mass growth and frequently poor prognosis; it is known as one of the most fatal types of cancer worldwide. The identification of potential molecular markers that can predict the response to treatment and the prognosis of this cancer has been subject of a vast investigation in the recent years. Among several molecules, various angiogenic factors that are linked to the tumor development, growth, and invasion, such as VEGF, HGF, angiopoietin-2, IL-6, and TGF-B1, were investigated. In this paper, the authors sought to review the role of these angiogenic factors in prognosis and hypothesize how they can be used as a treatment target.

Antimicrobial therapy in palliative care: an overview.

In the advanced stages of illness, patients often face challenging decisions regarding their treatment and overall medical care. Terminal ill patients are commonly affected by infections. However, in palliative care, the use of antimicrobials can be an ethical dilemma. Deciding whether to treat, withhold, or withdraw the antimicrobial treatment for an infection can be difficult. Antimicrobial administration can lead to adverse outcomes but the two main benefits, longer survival and symptom relief, are the main reasons why physicians prescribe antimicrobial when treating terminally ill patients. For the patient who has an irreversible advanced heart or lung disease, or an advanced dementia, or a metastatic cancer, it is easier the decision of withholding mechanical ventilation, tube feeding, and dialysis than antibiotherapy. To characterize infections, agents, and their treatments in palliative care, we conducted a review of the literature. We also included some tips to help health professionals to guide their clinical approach.

Bone Metastases: An Overview.

Bone is a frequent site of metastases and typically indicates a short-term prognosis in cancer patients. Once cancer has spread to the bones it can rarely be cured, but often it can still be treated to slow its growth. The majority of skeletal metastases are due to breast and prostate cancer. Bone metastasis is actually much more common than primary bone cancers, especially in adults. The diagnosis is based on signs, symptoms and imaging. New classes of drugs and new interventions are given a better quality of life to these patients and improved the expectancy of life. It is necessary a multidisciplinary approach to treat patients with bone metastasis. In this paper we review the types, clinical approach and treatment of bone metastases.

Gastric Cancer and Angiogenesis: Is VEGF a Useful Biomarker to Assess Progression and Remission?

Gastric cancer (GC) has high mortality owing to its aggressive nature. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of GC. The aim of this work was to review the angiogenic biomarkers related to the behavior of GC, documented in the literature. A search of the PubMed database was conducted with the MeSH terms: "Stomach neoplasms/blood [MeSH] or stomach neoplasms/blood supply [MeSH] and angiogenic proteins/blood [Major]". A total of 30 articles were initially collected, and 4 were subsequently excluded. Among the 26 articles collected, 16 examined the role of vascular endothelial growth factor (VEGF), 4 studied endostatin, 3 investigated angiopoietin (Ang)-2, 2 studied the Ang-like protein 2 (ANGTPL2), and 1 each examined interleukin (IL)-12, IL-8, and hypoxia inducible factor. Regarding VEGF, 6 articles concluded that the protein was related to lymph node metastasis or distant metastases. Five articles concluded that VEGF levels were elevated in the presence of GC and decreased following tumor regression, suggesting that VEGF levels could be a predictor of recurrence. Four articles concluded that high VEGF levels were correlated with poor prognosis and lower survival rates. Ang-2 and ANGTPL2 were elevated in GC and associated with more aggressive disease. Endostatin was associated with intestinal GC. VEGF is the most extensively studied angiogenic factor. It is associated with the presence of neoplastic disease and lymph node metastasis. It appears to be a good biomarker for disease progression and remission, but not for diagnosis. The data regarding other biomarkers are inconclusive.