Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status.

BACKGROUND: Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. METHODS: We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients' outcomes were compared using Cox regression and competing risk models. RESULTS: Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18-3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78-0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9-100%). Conversely, among the 61 patients with gBRCA1m and < 50% sTILs, we observed poor 15-year OS (50.8%; 95% CI, 39.7-65.0%). Furthermore, gBRCA1m was associated with higher (adjusted subdistribution HR, 4.04; 95% CI, 2.29-7.13) and tumor BRCA1-PM with lower (adjusted subdistribution HR, 0.42; 95% CI, 0.19-0.95) incidence of second primary tumors, compared to BRCA1-non-alteration. CONCLUSIONS: Although both gBRCA1m and tumor BRCA1-PM alter BRCA1 gene transcription, they are associated with different outcomes in young, node-negative, chemotherapy-naïve TNBC patients. By combining sTILs and BRCA1 status for risk classification, we were able to identify potential subgroups in this population to intensify and optimize adjuvant treatment.

Multiscale deep learning framework captures systemic immune features in lymph nodes predictive of triple negative breast cancer outcome in large-scale studies.

The suggestion that the systemic immune response in lymph nodes (LNs) conveys prognostic value for triple-negative breast cancer (TNBC) patients has not previously been investigated in large cohorts. We used a deep learning (DL) framework to quantify morphological features in haematoxylin and eosin-stained LNs on digitised whole slide images. From 345 breast cancer patients, 5,228 axillary LNs, cancer-free and involved, were assessed. Generalisable multiscale DL frameworks were developed to capture and quantify germinal centres (GCs) and sinuses. Cox regression proportional hazard models tested the association between smuLymphNet-captured GC and sinus quantifications and distant metastasis-free survival (DMFS). smuLymphNet achieved a Dice coefficient of 0.86 and 0.74 for capturing GCs and sinuses, respectively, and was comparable to an interpathologist Dice coefficient of 0.66 (GC) and 0.60 (sinus). smuLymphNet-captured sinuses were increased in LNs harbouring GCs (p < 0.001). smuLymphNet-captured GCs retained clinical relevance in LN-positive TNBC patients whose cancer-free LNs had on average ≥2 GCs, had longer DMFS (hazard ratio [HR] = 0.28, p = 0.02) and extended GCs' prognostic value to LN-negative TNBC patients (HR = 0.14, p = 0.002). Enlarged smuLymphNet-captured sinuses in involved LNs were associated with superior DMFS in LN-positive TNBC patients in a cohort from Guy's Hospital (multivariate HR = 0.39, p = 0.039) and with distant recurrence-free survival in 95 LN-positive TNBC patients of the Dutch-N4plus trial (HR = 0.44, p = 0.024). Heuristic scoring of subcapsular sinuses in LNs of LN-positive Tianjin TNBC patients (n = 85) cross-validated the association of enlarged sinuses with shorter DMFS (involved LNs: HR = 0.33, p = 0.029 and cancer-free LNs: HR = 0.21 p = 0.01). Morphological LN features reflective of cancer-associated responses are robustly quantifiable by smuLymphNet. Our findings further strengthen the value of assessment of LN properties beyond the detection of metastatic deposits for prognostication of TNBC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Muscularity of older trauma patients at intensive care unit admission, association with functional outcomes, and relationship with frailty: A retrospective observational study.

BACKGROUND: Older individuals are at an increased risk of delayed recovery following a traumatic injury. Measurement of muscularity and frailty at hospital admission may aid with prognostication and risk stratification. OBJECTIVE: This study aimed to describe muscularity at intensive care unit (ICU) admission in patients admitted following trauma and assess the relationship between muscularity and clinical, long-term functional outcomes and frailty at ICU admission. METHODS: This retrospective study utilised data from a prospective observational study investigating frailty in patients aged ≥50 years, admitted to the ICU following trauma. Patients were eligible if they had a Computed Tomography (CT) scan including the third lumbar vertebra at ICU admission. Specialist software was used to quantify CT-derived skeletal muscle cross-sectional area. Muscularity status was classified as normal or low using published sex-specific cut-points. Demographic data, frailty, clinical, and long-term functional outcomes (Glasgow Outcome Scale-Extended and EQ-5DL-5L Visual analogue scale and utility score) were extracted from the original study. RESULTS: One hundred patients were screened; 71 patients had a CT scan on admission with 66 scans suitable for muscle assessment. Patients with low muscularity (n = 25, 38%) were older and had a higher Acute Physiology and Chronic Health Evaluation II score and lower body mass index than patients with normal muscularity. Low muscularity was associated with frailty at admission (32% vs 5%, p = 0.005) but not with long term outcomes at 6 or 12 months. As a continuous variable, lower muscle cross-sectional area was associated with a poorer outcome on the Glasgow Outcome Scale-Extended at 6 months (mean [standard deviation]: 150 [43] and 180 [44], respectively; p = 0.014), no association was observed after adjustment for age p = 0.43). CONCLUSION: In a population of older adults hospitalised following trauma, low muscularity at ICU admission was prevalent. Low muscularity was associated with frailty but not long-term functional outcomes. Larger studies are warranted to better understand the relationship between muscularity and long-term functional outcomes.

In Vivo Reversal of P-Glycoprotein-Mediated Drug Resistance in a Breast Cancer Xenograft and in Leukemia Models Using a Novel, Potent, and Nontoxic Epicatechin EC31.

The modulation of P-glycoprotein (P-gp, ABCB1) can reverse multidrug resistance (MDR) and potentiate the efficacy of anticancer drugs. Tea polyphenols, such as epigallocatechin gallate (EGCG), have low P-gp-modulating activity, with an EC50 over 10 µM. In this study, we optimized a series of tea polyphenol derivatives and demonstrated that epicatechin EC31 was a potent and nontoxic P-gp inhibitor. Its EC50 for reversing paclitaxel, doxorubicin, and vincristine resistance in three P-gp-overexpressing cell lines ranged from 37 to 249 nM. Mechanistic studies revealed that EC31 restored intracellular drug accumulation by inhibiting P-gp-mediated drug efflux. It did not downregulate the plasma membrane P-gp level nor inhibit P-gp ATPase. It was not a transport substrate of P-gp. A pharmacokinetic study revealed that the intraperitoneal administration of 30 mg/kg of EC31 could achieve a plasma concentration above its in vitro EC50 (94 nM) for more than 18 h. It did not affect the pharmacokinetic profile of coadministered paclitaxel. In the xenograft model of the P-gp-overexpressing LCC6MDR cell line, EC31 reversed P-gp-mediated paclitaxel resistance and inhibited tumor growth by 27.4 to 36.1% (p < 0.001). Moreover, it also increased the intratumor paclitaxel level in the LCC6MDR xenograft by 6 fold (p < 0.001). In both murine leukemia P388ADR and human leukemia K562/P-gp mice models, the cotreatment of EC31 and doxorubicin significantly prolonged the survival of the mice (p < 0.001 and p < 0.01) as compared to the doxorubicin alone group, respectively. Our results suggested that EC31 was a promising candidate for further investigation on combination therapy for treating P-gp-overexpressing cancers.

Prevalence, recovery, and factors associated with dysphagia in an older critically ill trauma cohort: A cross-sectional study.

BACKGROUND: Patients admitted to the intensive care unit (ICU) following trauma often have multiple injuries, which can lead to disordered swallowing, dysphagia. The prevalence of dysphagia in trauma populations ranges between 4.2% and 86%; however, clinical and associated longitudinal health outcomes and patient-reported quality of life are unknown. OBJECTIVES: The objective of this study was to compare hospital and clinical outcomes for older critically ill trauma patients diagnosed with and without dysphagia up to 12 months after hospital admission. Secondary outcomes include characteristics of dysphagia assessment and recovery during indexed hospital admission. METHODS: Post hoc analysis of an observational study. All patients were recruited from a tertiary ICU trauma unit, all were aged above 50 years, with an expected ICU length of stay of >24 h. Criteria of dysphagia diagnosis were determined via presence of International Classification of Diseases (ICD-10) code (R13). Hospital, clinical, and health-reported quality-of-life data were collected. RESULTS: Ninety-eight patients were included with 79 (81%) being male, overall median injury severity scale: 21.5 (interquartile range: 14-29); 38 (38.8%) with spinal injury, 37 (37.8%) with multitrauma excluding head injury, and 23 (23.5%) with multitrauma including head injury. Prevalence of dysphagia was 29%, with patients diagnosed with dysphagia more likely to have required invasive mechanical ventilation (odds ratio [OR]: 4.0, 95% confidence interval [CI]: 1.25-12.78), for an increased duration (OR: 2.6, 95% CI: 0.27-4.92) and required longer ICU admission (OR: 2.98, 95% CI: 0.28-5.69). Recovery of swallow function was protracted beyond the indexed hospital admission, with only 18% of those diagnosed with dysphagia returning to a normal, unrestricted, oral diet by hospital discharge. At 6 and 12 months, functional disabilities were reported across the cohort with no significant differences between groups. CONCLUSIONS: In older critically ill trauma patients, dysphagia is common. Use and duration of invasive mechanical ventilation and increased ICU length of stay for survivors were significantly increased for those with dysphagia. Management of swallowing is required across the continuum of care commencing in and beyond ICU to optimise recovery and outcomes.

The impact of frailty in critically ill patients after trauma: A prospective observational study.

BACKGROUND: As our population ages, older adults are increasingly exposed to trauma. Frailty could be a useful measure to identify patients at risk of a poor outcome. This study aimed to determine the impact of frailty in an Australian trauma intensive care unit (ICU) population. METHODS: A prospective observational study of critically ill trauma patients ≥50 years of age. Frailty was determined on admission to the ICU using the frailty phenotype. Demographic and hospital data were collected, and patients were followed up at 6 and 12 months. The primary outcome was 12-month mortality, and multiple regression was used to determine associated factors. RESULTS: One hundred thirty-eight patients were included, whose mean age was 68 years; 78.2% (108/138) were classified as major trauma (Injury Severity Score >12). Twenty-two percent (30/138) of patients were identified as frail. Patients with frailty were significantly older: however, they were less severely injured and required lower rates of surgical interventions and mechanical ventilation. Frailty was independently associated with mortality at 6 and 12 months (odds ratio: 5.9, 95% confidence interval: 1.9-18.1 and odds ratio: 7.3, 95% confidence interval: 2.5-21.9, respectively). Patients with frailty had lower measures of global functioning (Glasgow Outcome Scale-Extended frail 3 [1-5] vs nonfrail 6 [(5-7], p = 0.002) and health status (Euro Qol 5Q-5D-5L utility score 0.6 [0.5-0.7] vs 0.7 [0.6-0.9], p = 0.02) at 12 months than patients without frailty. CONCLUSION: Frailty is a useful predictor of poor outcomes in critically ill trauma patients. REGISTRATION OF PROTOCOL NUMBER: ACTRN12615000039583.

Mitigating drought impacts in remote island atolls with traditional water usage behaviors and modern technology.

Adaptation to drought is particularly challenging on remote island atolls, such as those found in the Republic of the Marshall Islands (RMI), a nation of 58,000 populating 29 low-lying coral atolls spread over >2 million km2. Exposure to consecutive atmospheric hazards, such as meteorological floods and droughts diminish scarce water resources and erode the resilience of island communities. Drought impact mitigation measures must supply emergency drinking water to stricken communities, while simultaneously conserving natural sources in order to reduce their vulnerability to subsequent events. Household surveys (n = 298) and focus group discussions (n = 16) in eight RMI communities revealed that 86% of households have experienced drought and 88% reported using multiple water sources to meet normal household needs. With no surface water and a thin freshwater lens (FWL), rainwater collected from rooftops is the most common household water source. The traditional use of carved hollows in the base of coconut trees to collect rainwater ("Mammaks") appears to have been displaced by large rainwater tanks. However, rationing of rainwater for consumption only during drought was widely reported, with private wells supporting non-consumptive uses. Reverse osmosis (RO) desalination units have provided relief during drought emergencies but concerns have been raised around dependency, maintenance challenges, and loss of traditional water practices. Most notably, RO use has the potential to change the anthroposhpere by adversely affecting the FWL; 86% of RO units were installed at island-centre where excessive pumping can cause upconing, making the FWL brackish. Balancing the introduction of desalination technology to mitigate water shortages with maintenance of traditional water conservation practices to preserve the quantity and quality of the FWL is a promising strategy on island atolls that requires further investigation.

Frailty in Patients With Trauma Who Are Critically Ill: A Prospective Observational Study to Determine Feasibility, Concordance, and Construct and Predictive Validity of 2 Frailty Measures.

BACKGROUND: As the older population increases, more older people are exposed to trauma. Frailty can be used to highlight patients at risk of a poorer outcome. OBJECTIVE: The objectives of this study were to compare 2 frailty measures with regard to concordance, floor and ceiling effects, and construct and predictive validity and to determine which is more valid and clinically applicable in a critically ill trauma population. DESIGN: This was a prospective observational study. METHODS: Patients were included if admitted to an intensive care unit (ICU) under a trauma medical unit and ≥ 50 years old. Frailty was determined using 2 frailty measures, the Frailty Phenotype (FP) and Clinical Frailty Scale (CFS). RESULTS: One hundred people were enrolled; their mean age was 69.2 years (SD = 10.4) and 81% had major trauma (as determined with the Injury Severity Score). Frailty was identified with the FP in 22 participants and with the CFS in 13 participants. The 2 frailty measures had an excellent correlation (Spearman rank correlation coefficient = 0.77; 95% confidence interval = 0.66-0.85). Both the FP and the CFS had large floor effects but no ceiling effects. The FP and CFS showed construct validity, with frailty being significantly associated with increasing age, requiring an aid to mobilize, and more falls and hospital admissions. Frailty on the FP was predictive of ICU and hospital mortality, whereas frailty on the CFS was predictive of hospital mortality. LIMITATIONS: The limitations of this study include the use of a single site, small sample size, and collection of frailty measures retrospectively. CONCLUSIONS: Measuring frailty in a trauma ICU population was feasible, with excellent correlation between the 2 frailty measures. Both showed aspects of construct and predictive validity; however, the FP identified frailty in more participants and was associated with more comorbidities and higher mortality at ICU discharge. Therefore, the FP might be more clinically relevant in this population.

Use of dong quai (Angelica sinensis) to treat peri- or postmenopausal symptoms in women with breast cancer: is it appropriate?

OBJECTIVE: Regarding the growing use of alternative therapies for peri- or postmenopausal symptoms, we evaluated the effect of a water extract of Angelica sinensis (dong quai), used for peri- or postmenopausal relief, on the proliferation of estrogen receptor-positive (MCF-7) and negative (BT-20) breast cancer cells in vitro. DESIGN: The present study was designed to investigate the growth-modulating effect of dong quai water extract, alone or in the presence of 17beta-estradiol and 4-hydroxytamoxifen, on MCF-7 and BT-20 cell cultures using MTT proliferation assay. RESULTS: The water extract of dong quai dose-dependently and significantly stimulated the proliferation of MCF-7 cells with a weak estrogen-agonistic activity in the presence of 17beta-estradiol, as evidenced by the significant suppression by 4-hydroxytamoxifen. Meanwhile, the extract significantly exerted a growth-stimulating effect on BT-20 in a dose-dependent manner with or without 17beta-estradiol. No obvious difference was found in the growth of BT-20 cells treated with the extract in the presence of 17beta-estradiol or 4-hydroxytamoxifen. CONCLUSIONS: The water extract of dong quai stimulated the growth of MCF-7 cells, possibly dependent of weak estrogen-agonistic activity, and augmented the BT-20 cell proliferation independent of estrogen receptor-mediated pathway. The present study provides data regarding the estrogen-like activity of dong quai, which might assist in decision making on herbal therapy use by women at risk for both estrogen-sensitive and insensitive breast cancer. Because of the lack of clinical data demonstrating the potential side effects of dong quai, its use in herbal preparations for the treatment of peri- or postmenopausal symptoms, especially in women with breast cancer, warrants caution pending further study.