Apoptotic caspases have long been studied for their roles in programmed cell death and tumor suppression. With recent discoveries, however, it is becoming apparent these cell death executioners are involved in additional biological pathways beyond killing cells. In some cases, apoptotic cells secrete growth signals to stimulate proliferation of neighboring cells. This pathway functions to regenerate tissues in multiple organisms, but it also poses problems in tumor resistance to chemo- and radiotherapy. Additionally, it was found that activation of caspases does not irreversibly lead to cell death, contrary to the established paradigm. Sub-lethal activation of caspases is evident in cell differentiation and epigenetic reprogramming. Furthermore, evidence indicates spontaneous, unprovoked activation of caspases in many cancer cells, which plays pivotal roles in maintaining their tumorigenicity and metastasis. These unexpected findings challenge current cancer therapy approaches aimed at activation of the apoptotic pathway. At the same time, the newly discovered functions of caspases suggest new treatment approaches for cancer and other pathological conditions in the future.

CD90 has been identi ed as a candidate marker of cancer stem cells (CSCs) for HCC, whereas it also has been considered as a marker for tumor-associated broblasts (CAFs). OCT4, as a key transcription factor required to maintain pluripotency of human embryonic stem cell and cancer cells, has been characterized to be involved in malignant transformation and tumorigenesis of various cancers. is study aimed to examine expression patterns of CD90 in HCC and investigate whether combination of both CD90 and OCT4 could provide a more powerful predictor for prognosis of HCC than either one alone.CD90 and OCT4 were examined by immunohistochemistry. e relationship between CD90/OCT4 expression and clinicopathologic characteristics was analyzed. e correlation between CD90/OCT4 expression and overall survival and disease-free survival was determined with Kaplan-Meier analysis.CD90 was found mainly expressed in tumor-associated CAFs and OCT4 was mainly expressed in tumor cells. e expression of CD90 and OCT4 in HCC was signi cantly higher than in adjacent non-tumor and normal liver tissues. CD90 expression was correlated with pathological grade, satellite lesion, PVTT and recurrence. OCT4 expression was correlated with pathological grade, tumor size and recurrence. Data demonstrated no correlation between CD90 and OCT4. High expression of CD90 or OCT4 predicts a poor prognosis. Furthermore, combination of both CD90 and OCT4 provides a more sensitive predictor for prognosis of HCC than either marker alone.CD90 and OCT4 are both independent and reliable biomarker for predicting prognosis of HCC patients a er hepatic resection. Our results indicated the accuracy of prediction can be enhanced by their combination.

Background: Revision procedures address contour irregularities and aesthetic concerns following autologous breast reconstruction. Mental health diagnoses are known to influence patient satisfaction with reconstruction. The authors aimed to identify oncologic, reconstructive, and demographic factors, including mental health diagnoses, associated with the number of revisions after autologous breast reconstruction. Methods: The medical records of all adult women undergoing abdominal free flap–based breast reconstruction at a major academic institution between 2011 and 2016 were reviewed. Multivariate logistic regression was used to identify factors associated with receipt of revisions. Negative binomial regression was used to identify characteristics associated with number of revisions received. Results: Of 272 patients identified, 55.2 percent received one revision, 23.2 percent received two revisions, and 10.3 percent received three or more revisions after autologous breast reconstruction (median, one; range, zero to five). After adjustment on multivariate analysis, anxiety (OR, 4.34; p = 0.016) and bilateral reconstruction (OR, 3.10; p = 0.017) were associated with receipt of any revisions; other oncologic and reconstructive factors including breast cancer stage, receipt of radiation therapy, and type or timing of free flap reconstruction were not associated with revisions. Using univariate negative binomial regression, anxiety (incidence rate ratio, 1.34; p = 0.006), Caucasian race (incidence rate ratio, 1.24; p = 0.02), and bilateral reconstruction (incidence rate ratio, 1.39; p = 0.04) were predictive of increased numbers of revisions received. After stepwise selection on multivariate analysis, anxiety remained the only significant predictor of increased numbers of revisions. Conclusions: Preoperative anxiety significantly influences the number of revisions after autologous breast reconstruction. Further research is necessary to better understand the interplay among mental health, patient preference, and outcomes in breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

ATM is a well-known master regulator of double strand break (DSB) DNA repair and the defective DNA repair has been therapeutically exploited to develop PARP inhibitors based on the synthetic lethality strategy. ATM mutation is found with increased prevalence in advanced metastatic castration resistant prostate cancer (mCRPC). However, the molecular mechanisms underlying ATM mutation-driving disease progression are still largely unknown. Here we report that ATM mutation contributes to the CRPC progression through a metabolic rather than DNA repair mechanism. We showed that ATM deficiency generated by CRISPR/Cas9 editing promoted CRPC cell proliferation and xenograft tumor growth. ATM deficiency altered cellular metabolism and enhanced Warburg effect in CRPC cells. We demonstrated that ATM deficiency shunted the glucose flux to aerobic glycolysis by upregulating LDHA expression, which generated more lactate and produced less mitochondrial ROS to promote CRPC cell growth. Inhibition of LDHA by siRNA or inhibitor FX11 generated less lactate and accumulated more ROS in ATM-deficient CRPC cells and therefore potentiated the cell death of ATM-deficient CRPC cells. These findings suggest a new therapeutic strategy for ATM-mutant CRPC patients by targeting LDHA-mediated glycolysis metabolism, which might be effective for the PARP inhibitor resistant mCRPC tumors.

INTRODUCTION: The tumor microenvironment within the breast is rich in adipose elements. The interaction between adipose cells and breast cancer is poorly understood, particularly as it pertains to patients with genetic susceptibility to breast cancer. Our study focuses on the phenotype of human adipose-derived stem cells (ASCs) with the BRCA1 mutation and the effect they may have on breast cancer cell behavior. METHODS: CRISPR/Cas9 was used to generate de novo BRCA1-knockdown human ASCs (BRCA1-KD). The effect of the BRCA1 knockdown on the ASC phenotype was compared to wild type ASCs and patient derived breast ASCs with known BRCA 1 mutations. Interactions between ASCs and the MDA-MB-231 breast cancer cell line were evaluated. RESULTS: BRCA1-KD ASCs stimulated MDA-MB-231 proliferation (1.4-fold increase on day4, P=0.0074) and invasion (2.3-fold increase on day2. P=0.0171) compared to wild type ASCs. Immunofluorescence staining revealed higher levels of phosphorylated ATM activation in BRCA1-KD ASCs (72.9±5.32% vs 42.9±4.97%. P=0.0147), indicating higher levels of DNA damage. Beta-galactosidase staining demonstrated a significantly higher level of senescence in BRCA1-KD ASCs compared to wild type ASCs (7.9±0.25% vs 0.17±0.17%, P<0.0001). Using quantitative ELISA to evaluate conditioned media, we found significantly higher levels of IL-8 in BRCA1-KD ASCs (2.57±0.32-fold, P=0.0049). CONCLUSION: We have shown here for the first time that the BRCA1 mutation affects the ASC phenotype. Moreover, CRISPR/Cas9 generated BRCA1-KD ASCs stimulate a more aggressive behavior in breast cancer cells than wild type ASCs. This appears to be related to increased inflammatory cytokine production via a DNA damage-mediated cell senescence pathway.

Background Breast implant placement is the most common method for postmastectomy reconstruction. For patients who develop complications associated with implant-based reconstruction, additional surgeries may be challenging. This study examined implant-based reconstruction failure in patients undergoing salvage with abdominal free tissue transfer. Methods We conducted an Institutional Review Board approved, multicenter retrospective study of patients with implant-based primary breast reconstruction followed by implant removal and subsequent abdominal free tissue transfer between 2006 and 2016. Patient demographics, treatment details, and complications were evaluated. Severity of implant failure was graded as either (1) not severe (delayed salvage reconstruction) or (2) severe (immediate salvage reconstruction). Results Between 2006 and 2016, 115 patients with 180 mastectomy defects underwent primary implant-based reconstruction with subsequent implant removal and abdominally based free tissue reconstruction. Of these, 68 were delayed and 47 were immediate salvage reconstruction. Factors leading to elective removal were capsular contracture, asymmetry, and implant malposition. Factors leading to obligatory removal were infection, delayed wound healing, and implant extrusion. Postmastectomy radiation was significantly associated with immediate salvage reconstruction (p < 0.001, odds ratio = 3.9) as were large volume implants (p = 0.06). Deep inferior epigastric perforator flaps comprised 78.3% of all abdominally based free tissue reconstructions, while muscle-sparing transverse rectus abdominus myocutaneous flaps comprised 18.3%. Overall flap failure rate was 2.6% (2.94% delayed and 2.13% immediate salvage reconstruction; p = 1.0). Conclusion Our findings suggest that abdominal free tissue transfer remains a safe and effective salvage modality for implant-based breast reconstruction failure. Patients with severe implant failure were more likely to have received radiation. Surgeons should remain cognizant of this during care of patients.

Our study suggests that pre-existing CT scans represent a viable and economical alternative for perforator mapping before abdominal-based free flap breast reconstruction.

Background Unplanned returns to the operating room (OR) may be necessary at times to salvage a compromised free flap. The aim of this study was to assess the influence of attending surgeon continuity on free flap outcomes following a return to the OR. Methods We retrospectively reviewed patients who underwent free flap reconstruction and experienced an unplanned return to the OR within 30 days from 2002 to 2017. Logistic regression modeling was used to determine factors that predict unplanned returns to the OR. Results Of the 1,177 patients were identified, 267 (22.5%) had an unplanned return to the OR. Of these, 69 (5.9%) patients experienced total flap loss. Overall, 216 take-back procedures were performed by the primary surgeons (80.2%), while 50 were performed by covering surgeons (18.8%). Flap loss occurred more frequently during a weekend procedure (p = 0.013). Additionally, when the take-back procedure was performed within 5 days of the original surgery by the primary as opposed to a covering surgeon, patients experienced lower estimated blood loss (75cc vs. 150cc, p = 0.04). Overall, there was a significantly lower incidence of flap loss when the take-back procedure was performed by the primary, as opposed to the covering, surgeon (20 vs. 47%, p = 0.0001). Conclusion Higher rates of flap loss occur when a covering surgeon performs a take-back procedure in comparison to the primary surgeon. It is important to ensure the availability of the primary surgeon in the first few postoperative days following free flap reconstruction. When transfer of care is necessary, photographic or video documentation of the microvascular anastomosis may be helpful in addition to a verbal sign out.