Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2(+) γδ T cell cytotoxicity in a perforin-dependent manner.

Vδ2(+) T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2(+) T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2(+) T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C-C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2(+) T cell cytotoxicity. Vδ2(+) T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive-at least in part-to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2(+) T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy

ESMO Guidance for Reporting Oncology real-World evidence (GROW)

Clinical epidemiolog

Safety of topical estrogen therapy during adjuvant endocrine treatment among patients with breast cancer: A meta-analysis based expert panel discussion

Importance Endocrine treatments, such as Tamoxifen (TAM) and/or Aromatase inhibitors (AI), are the adjuvant therapy of choice for hormone-receptor positive breast cancer. These agents are associated with menopausal symptoms, adversely affecting drug compliance. Topical estrogen (TE) has been proposed for symptom management, given its' local application and presumed reduced bioavailability, however its oncological safety remains uncertain. Objective The present systematic review, meta-analysis and expert panel review aimed to evaluate the strength of the available evidence on the risk of recurrence and mortality when TE is utilised in congruence with TAM or AI treatment, among BC survivors. Data sources Six databases and two prospective registers, were interrogated from inception to January 3rd, 2024. Search terms were Breast cancer AND Hormone replacement therapy AND topical/vaginal oestrogen AND recurrence/mortality. Study selection All study designs reporting the use vs. non-use of TE in breast cancer survivors receiving adjuvant endocrine treatment were included. Six observational studies were deemed eligible for inclusion. Data extraction and synthesis Sources of heterogeneity were explored using subgroup analysis by risk of bias, median follow-up period, node positivity and menopausal status. Trial sequential analysis was performed to quantify outcome reliability. A global expert panel was called to deliberate on the data, pinpoint areas of limited understanding, and determine the most important areas for future research. Main outcomes and measures Risk ratio effect sizes (RR) and corresponding 95 % Confidence Intervals (CI) of breast cancer recurrence and mortality in survivors on endocrine treatment (TAM and/or AI) exposed to TE were reported. Expert panel appraisal of meta-analysis evidence with definition of current knowledge gaps and future research aims. Results In 38 050 female patients receiving adjuvant endocrine treatment, of whom 1805 had been exposed to TE, TE exposure of those on AI, did not increase all-cause mortality (RR 0.99 [95 %CI 0.58, 1.69], I$^{2}$ = 81 %, P = 0.96; moderate GRADE certainty). However, such exposure may convey an increased risk of recurrence (RR 2.51 [95 % CI 1.10, 5.72], I$^{2}$ = 9 %, P = 0.03; low-GRADE certainty). Exposure to TE during TAM did not increase either recurrence risk or all-cause mortality. Clinical factors such as lymph node positivity at the time of diagnosis and menopausal status and follow-up time appeared to be significant confounders. Conclusions and relevance The use of TE does not appear to increase either recurrence or mortality risk among BC survivors treated with TAM. An increased recurrence risk, without an increase in mortality, cannot be ruled out when TE is used during AI

Synthesis of Recommendations From 25 Countries and 31 Oncology Societies: How to Navigate Through Covid-19 Labyrinth

IntroductionPandemic COVID-19 is an unexpected challenge for the oncological community, indicating potential detrimental effects on cancer patients. Our aim was to summarize the converging key points providing a general guidance in order to support decision making, pertaining to the oncologic care in the middle of a global outbreak.MethodsWe did an international online search in twenty five countries that have managed a surge in cancer patient numbers. We collected the recommendations from thirty one medical oncology societies.ResultsBy synthesizing guidelines for a) oncology service delivery adjustments, b) general and specific treatment adaptations, and c) discrepancies from guidelines comparison, we present a clinical synopsis with the forty more crucial statements. A Covid-19 risk stratification base was also created in order to obtain a quick, objective patient assessment and a risk-benefit evaluation on a case-by-case basis.ConclusionsIn an attempt to face these complex needs and due to limited understanding of COVID-19, a variability of recommendations based on general epidemiological and infectious disease principles rather than definite cancer-related evidence has evolved. Additionally, the absence of an effective treatment or vaccine requires the development of cancer management guidance, capitalizing on comprehensive COVID-19 oncology experience globally.</jats:sec

Time-trend of melanoma screening practice by primary care physicians: A meta-regression analysis

Objective. To assess whether the proportion of primary care physicians implementing full body skin examination (FBSE) to screen for melanoma changed over time. Methods. Meta-regression analyses of available data. Data Sources: MEDLINE, ISI, Cochrane Central Register of Controlled Trials. Results. Fifteen studies surveying 10,336 physicians were included in the analyses. Overall, 15%\u201382% of them reported to perform FBSE to screen for melanoma. The proportion of physicians using FBSE screening tended to decrease by 1.72% per year (P =0.086). Corresponding annual changes in European, North American, and Australian settings were 120.68% (P =0.494), 122.02% (P =0.044), and +2.59% (P =0.010), respectively. Changes were not influenced by national guide-lines. Conclusions. Considering the increasing incidence of melanoma and other skin malignancies, as well as their relative potential consequences, the FBSE implementation time-trend we retrieved should be considered a worrisome phenomenon

Synthesis of Recommendations From 25 Countries and 31 Oncology Societies: How to Navigate Through Covid-19 Labyrinth

Introduction: Pandemic COVID-19 is an unexpected challenge for the oncological community, indicating potential detrimental effects on cancer patients. Our aim was to summarize the converging key points providing a general guidance in order to support decision making, pertaining to the oncologic care in the middle of a global outbreak. Methods: We did an international online search in twenty five countries that have managed a surge in cancer patient numbers. We collected the recommendations from thirty one medical oncology societies. Results: By synthesizing guidelines for a) oncology service delivery adjustments, b) general and specific treatment adaptations, and c) discrepancies from guidelines comparison, we present a clinical synopsis with the forty more crucial statements. A Covid-19 risk stratification base was also created in order to obtain a quick, objective patient assessment and a risk-benefit evaluation on a case-by-case basis. Conclusions: In an attempt to face these complex needs and due to limited understanding of COVID-19, a variability of recommendations based on general epidemiological and infectious disease principles rather than definite cancer-related evidence has evolved. Additionally, the absence of an effective treatment or vaccine requires the development of cancer management guidance, capitalizing on comprehensive COVID-19 oncology experience globally