Periventricular leukomalacia (PVL) is the most frequent cause of cerebral palsy and other intellectual disabilities, and currently there is no treatment. In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly. We have previously identified that the combination of transferrin and insulin growth factors (TSC1) promotes endogenous OL regeneration and remyelination in the postnatal and adult rodent brain. Here, we produced a periventricular white matter lesion with a single intracerebral injection of N-methyl-d-aspartate (NMDA). Comparing lesions produced by NMDA alone and those produced by NMDA + TSC1 we found that: NMDA affected survival and reduced migration of OL progenitors (OLPs). In contrast, mice injected with NMDA + TSC1 proliferated twice as much indicating that TSC1 supported regeneration of the OLP population after the insult. Olig2-mRNA expression showed 52% OLP survival in mice receiving a NMDA injection and increased to 78% when TSC1 + NMDA were injected simultaneously and ventricular size was reduced by TSC1. Furthermore, in striatal slices TSC1 reduced the inward currents induced by NMDA in medium-sized spiny neurons, demonstrating neuroprotection. Thus, white matter loss after excitotoxicity can be partially rescued as TSC1 conferred neuroprotection to preexisting OLP and regeneration via OLP proliferation. Furthermore, we showed that early TSC1 administration maximizes neuroprotection.

Purpose Tumor-infiltrating lymphocytes (TILs) have emerged as a predictor of breast cancer treatment response and patient outcomes. Current studies investigating racial/ethnic differences in TILs and immune profiles in breast cancer offer varying results. Our study provides some preliminary data in the breast cancer tumor microenvironment where there is a paucity of information, from Asian and Native Hawaiian/Pacific Islander (NHPI) racial/ethnic groups, not well represented in the literature. Methods We reviewed 183 cases of women diagnosed with early stage breast cancer who received neoadjuvant treatment at 2 large health systems in Hawaii between 2008 and 2020. We evaluated clinical and demographic information including: age at diagnosis, self-reported race/ethnicity, tumor stage, tumor subtype according to ER, PR, and HER2 receptor status, the amount of TILs and pathologic complete response (pCR). Results We found a significantly greater amount of TILs in Asians (37.7%, P = .01) and NHPI (37.2%, P = .02) patients compared to White patients on multivariate analysis. We found no significant differences in pCR among the different racial/ethnic groups. Conclusions Racial/ethnic differences in the amount of TILs in breast cancer tumors may suggest differences in the breast tumor microenvironment. This may in part contribute to known outcome disparities in these populations and should be further evaluated.

Background/Rationale: There have been increasing studies regarding the morphologic evaluation of tumor-infiltrating lymphocytes (TILs) and the tumor microenvironment. In breast cancer, TILs are more abundant in stroma (sTILs) compared to intratumoral (iTILs) areas and iTILs have been an unreliable marker due to difficulty in standardizing their evaluation. The International Immuno-Oncology Working Group published recommendations to guide the accurate assessment of TILs. TILs have relevance in the setting of neoadjuvant therapy (NAT), primarily in triple negative and HER2 positive breast cancers. Studies report that sTIL infiltration is predictive of response to NAT in these two breast cancer subtypes, but not in the estrogen positive breast cancer subtype. The presence of TILs is a good prognostic indicator and correlates with axillary lymph node negativity, lower histological grade and improved recurrence-free survival. Therefore, evaluating TILs prior to NAT can provide important predictive and prognostic information for clinicians. There are insufficient data exploring differences in sTILs among different racial/ethnic groups. Previous data showed Asians had more sTILs compared to White and African American patients, consistent with data from Asia that found substantial sTILs in their respective patient populations. Our diverse population has known racial/ethnic disparities, where Pacific Islanders have a higher mortality compared to Asian and White patients. Evaluating sTILs within this population may reveal tumor biology differences that could contribute to health disparities. Research objectives: To determine the stromal tumor infiltrating lymphocytes on core biopsy specimens and correlate them with clinical characteristics: ethnicity, age, BMI and stage To determine differences in pathologic complete response (pCR) with ethnicity, age, BMI, neoadjuvant therapy and stage Table 1. % Stromal tumor infiltrating lymphocytes (sTILs) compared to age, BMI, ethnicity, stage and pCR adjusted for breast cancer subtypeVariableValueNMeanSDPAge30838.615.140927.123.0.30501834.626.6.67601431.121.3.4570+826.822.8.30BMI< 252825.918.825-301638.521.9.07> 301337.228.0.12EthnicityAsian1636.724.2.01Pacific Islander2038.021.3.004White1818.515.9Other348.130.6.02Stage1A818.48.01B933.425.5.192A1631.923.0.172B938.620.6.113A630.823.2.313B937.225.8.10pCRno3233.019.8yes2530.825.6.72 Table 2. Pathologic complete tesponse (pCR) compared to age, BMI, neoadjuvant therapy, ethnicity and stage adjusted for breast cancer subtypeVariableValueNMeanSDPAge3080.5500.5354090.4060.527.5650180.4450.511.6360140.3030.469.2770+80.5860.518.89BMI< 25280.5260.50825-30160.2730.447.11> 30130.4530.519.65Neoadjuvant TherapyACT140.2680.469.88TC110.2370.505TCHP160.7480.479.02THP120.4280.515.41Letrozole40.3850.500.62EthnicityAsian160.4720.512.77Pacific Islander200.3890.503.85White180.4200.511other30.7060.577.36Stage1A80.2410.3541B90.4270.527.412A160.7240.479.022B90.0320.441.403A60.8220.516.023B90.2680.500.90 Results: We evaluated 57 neoadjuvant breast cancer cases for sTILs according to the International Immuno-Oncology Working Group recommendations and reviewed their clinical characteristics. We found significant % sTILs differences in ethnicity, specifically Asian (35%), Pacific Islander (38.5%) and Other (46%) category compared to White (19%) Table 1. There were no differences found in sTILs according to age, BMI or stage. We also found no significant pCR differences according to age, BMI or ethnicity, however for certain stages and neoadjuvant therapy, there is an increased rate of pCR, although these are a small number of cases, no conclusions can be made, Table 2. Future studies to evaluate the significance of sTILs in different ethnicities may be informative to delineate possible mechanisms contributing to known disparities they experience. Citation Format: Jami Fukui, Alana Taniguchi, Madison Meister, Ian Pagano, Jeffrey Killeen. Racial/ethnic differences in tumor infiltrating lymphocytes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-06-13.

PurposeTumor infiltrating lymphocytes (TILs) have emerged as a predictor of cancer treatment response and patient outcomes, including for breast cancer. Current studies investigating racial/ethnic differences in TILs and immune profiles in breast cancer offer varying results. Our study hopes to address the paucity of data in breast cancer tumor microenvironment from different racial/ethnic groups not well represented in the literature.MethodsWe reviewed 183 cases of women diagnosed with early stage breast cancer who received neoadjuvant treatment at two large health systems in Hawaii between 2008 and 2020. We evaluated clinical and demographic information including: age at diagnosis, race/ethnicity, tumor stage, tumor subtype according to ER, PR, and HER2 receptor status and compared them with obtaining a pathologic complete response (pCR) and amount of stromal TILs (sTILs).ResultsWe found a significantly greater amount of sTILs in Asians (37.7%, p=0.01) and Native Hawaiian/Pacific Islander (NHPI) (37.2%, p=0.02) patients compared to White patients on multivariate analysis. We found no significant differences in pCR among the different racial/ethnic groups.ConclusionsRacial/ethnic differences in the amount of sTILs in breast cancer tumors suggest that higher sTIL percentages alone do not predict for pCR. Increases in sTILs in Asian and NHPI patients suggest differences in immune cell profiles in the breast tumor microenvironment. This may in part contribute to known outcome disparities in these populations.