Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Treatment with the non-ionic surfactant poloxamer P188 reduces DNA fragmentation in cells from bovine chondral explants exposed to injurious unconfined compression.

Excessive mechanical loading to a joint has been linked with the development of post-traumatic osteoarthritis (OA). Among the suspected links between impact trauma to a joint and associated degeneration of articular cartilage is an acute reduction in chondrocyte viability. Recently, the non-ionic surfactant poloxamer 188 (P188) has been shown to reduce by approximately 50% the percentage of non-viable chondrocytes 24 h post-injury in chondral explants exposed to 25 MPa of unconfined compression. There is a question whether these acutely 'saved' chondrocytes will continue to degrade over time, as P188 is only thought to act by acute repair of damaged cell membranes. In order to investigate the degradation of traumatized chondrocytes in the longer term, the current study utilized TUNEL staining to document the percentage of cells suffering DNA fragmentation with and without an immediate 24 h period of exposure of the explants to P188 surfactant. In the current study, as in the previous study by this laboratory, chondral explants were excised from bovine metacarpophalangeal joints and subjected to 25 MPa of unconfined compression. TUNEL staining was performed at 1 h, 4 days, and 7 days post-impact. The current study found that P188 was effective in reducing the percentage of cells with DNA fragmentation in impacted explants by approximately 45% at 4 and 7 days post-impact. These data suggest that early P188 intervention was effective in preventing DNA fragmentation of injured chondrocytes. The current hypothesis is that this process was mitigated by the acute repair of damaged plasma membranes by the non-ionic surfactant P188, and that most repaired cells did not continue to degrade as measured by the fragmentation of their DNA.

The limitation of acute necrosis in retro-patellar cartilage after a severe blunt impact to the in vivo rabbit patello-femoral joint.

We have previously shown that surface lesions and acute necrosis of chondrocytes are produced by severe levels of blunt mechanical load, generating contact pressures greater than 25 MPa, on chondral and osteochondral explants. We have also found surface lesions and chronic degradation of retro-patellar cartilage within 3 years following a 6J impact intensity with an associated average pressure of 25 MPa in the rabbit patello-femoral joint. We now hypothesized that cellular necrosis is produced acutely in the retro-patellar cartilage in this model as a result of a 6J impact and that an early injection of the non-ionic surfactant, poloxamer 188 (P188), would significantly reduce the percentage of necrotic cells in the traumatized cartilage. Eighteen rabbits were equally divided into a 'time zero' group and two other groups carried out for 4 days. One '4 day' group was administered a 1.5 ml injection of P188 into the impacted joint immediately after trauma, while the other was injected with a placebo solution. Impact trauma produced surface lesions on retro-patellar cartilage in all groups. Approximately 15% of retro-patellar chondrocytes suffered acute necrosis in the 'time zero' and '4-day no poloxamer' groups. In contrast, significantly fewer cells (7%) suffered necrosis in the poloxamer group, most markedly in the superficial cartilage layer. The use of P188 surfactant early after severe trauma to articular cartilage may allow sufficient time for damaged cells to heal, which may in turn mitigate the potential for post-traumatic osteoarthritis. Additional studies are needed to improve the efficacy of this surfactant and to determine the long-term health of joint cartilage after P188 intervention.