Association of Surgical Approaches and Outcomes in Total Mesorectal Excision and Margin Status for Rectal Cancer.

INTRODUCTION: Despite being a key metric with a significant correlation with the outcomes of patients with rectal cancer, the optimal surgical approach for total mesorectal excision (TME) has not yet been identified. The aim of this study was to assess the association of the surgical approach on the quality of TME and surgical margins and to characterize the surgical and long-term oncologic outcomes in patients undergoing robotic, laparoscopic, and open TME for rectal cancer. METHODS: Patients with primary, nonmetastatic rectal adenocarcinoma who underwent either lower anterior resection or abdominoperineal resection via robotic (Rob), laparoscopic (Lap), or open approaches were selected from the US Rectal Cancer Consortium database (2007-2017). Quasi-Poisson regression analysis with backward selection was used to investigate the relationship between the surgical approach and outcomes of interest. RESULTS: Among the 664 patients included in the study, the distribution of surgical approaches was as follows: 351 (52.9%) underwent TME via the open approach, 159 (23.9%) via the robotic approach, and 154 (23.2%) via the laparoscopic approach. There were no significant differences in baseline demographics among the three cohorts. The laparoscopic cohort had fewer patients with low rectal cancer (<6 cm from the anal verge) than the robotic and open cohorts (Lap 28.6% versus Rob 59.1% versus Open 45.6%, P = 0.015). Patients who underwent Rob and Lap TME had lower intraoperative blood loss compared with the Open approach (Rob 200 mL [Q1, Q3: 100.0, 300.0] versus Lap 150 mL [Q1, Q3: 75.0, 250.0] versus Open 300 mL [Q1, Q3: 150.0, 600.0], P < 0.001). There was no difference in the operative time (Rob 243 min [Q1, Q3: 203.8, 300.2] versus Lap 241 min [Q1, Q3: 186, 336] versus Open 226 min [Q1, Q3: 178, 315.8], P = 0.309) between the three approaches. Postoperative length of stay was shorter with robotic and laparoscopic approach compared to open approach (Rob 5.0 d [Q1, Q3: 4, 8.2] versus Lap 5 d [Q1, Q3: 4, 8] versus Open 7.0 d [Q1, Q3: 5, 9], P < 0.001). There was no statistically significant difference in the quality of TME between the robotic, laparoscopic, and open approaches (79.2%, 64.9%, and 64.7%, respectively; P = 0.46). The margin positivity rate, a composite of circumferential margin and distal margin, was higher with the robotic and open approaches than with the laparoscopic approach (Rob 8.2% versus Open 6.6% versus Lap 1.9%, P = 0.17), Rob versus Lap (odds ratio 0.21; 95% confidence interval 0.05, 0.83) and Rob versus Open (odds ratio 0.5; 95% confidence interval 0.22, 1.12). There was no difference in long-term survival, including overall survival and recurrence-free survival, between patients who underwent robotic, laparoscopic, or open TME (Figure 1). CONCLUSIONS: In patients undergoing surgery with curative intent for rectal cancer, we did not observe a difference in the quality of TME between the robotic, laparoscopic, or open approaches. Robotic and open TME compared to laparoscopic TME were associated with higher margin positivity rates in our study. This was likely due to the higher percentage of low rectal cancers in the robotic and open cohorts. We also reported no significant differences in overall survival and recurrence-free survival between the aforementioned surgical techniques.

Chemoprophylactic Anticoagulation After Spine Surgery Does Not Increase Epidural Hematoma Risk: A Propensity-matched Analysis.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: To calculate the magnitude of any increased risk of epidural hematoma (EDH) associated with chemoprophylactic anticoagulation (chemoprophylaxis), if any. SUMMARY OF BACKGROUND DATA: Chemoprophylaxis for the prevention of venous thromboembolic events may be associated with an increased risk of EDH after spine surgery. MATERIALS AND METHODS: A total of 6869 consecutive spine surgeries performed at our institution were identified, and clinical and demographic data were collected. We identified cases in which symptomatic EDHs were evacuated within 30 days postoperatively. Patients receiving chemoprophylaxis and controls were matched using K-nearest neighbor propensity score matching to calculate the effect of anticoagulation on the rate of postoperative EDH. RESULTS: After propensity score matching, 1071 patients who received chemoprophylaxis were matched to 1585 controls. Propensity scores were well balanced between populations (Rubin B=20.6, Rubin R=1.05), and an 89.6% reduction in bias was achieved, with a remaining mean bias of 3.2%. The effect of chemoprophylaxis on EDH was insignificant ( P =0.294). Symptomatic EDH was independently associated with having a transfusion [odds ratio (OR)=7.30 (1.15, 46.20), P =0.035], having thoracic-level surgery [OR=41.19 (3.75, 452.4), P =0.002], and increasing body mass index [OR=1.44 (1.04, 1.98), P =0.028] but was not associated with chemoprophylaxis. Five out of 13 patients who developed EDH (38.5%) were receiving some form of anticoagulation, including 1 patient on therapeutic anticoagulation, 1 concurrently on aspirin and chemoprophylaxis, and 2 who were also found to have developed thrombocytopenia postoperatively. The median time on anticoagulation before EDH was 8.1 days. A higher proportion of patients who developed EDH also developed venous thromboembolic events than the general population [38.5% vs. 2.4%, OR=25.34 (9.226, 79.68), P <0.0001], and 1 EDH patient died from pulmonary embolism while off chemoprophylaxis. CONCLUSIONS: Chemoprophylactic anticoagulation did not cause an increase in the rate of spinal EDH in our patient population.

Epinephrine inhibits PI3Kα via the Hippo kinases.

The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.

Multiscale protein networks systematically identify aberrant protein interactions and oncogenic regulators in seven cancer types.

Global proteomic data generated by advanced mass spectrometry (MS) technologies can help bridge the gap between genome/transcriptome and functions and hold great potential in elucidating unbiased functional models of pro-tumorigenic pathways. To this end, we collected the high-throughput, whole-genome MS data and conducted integrative proteomic network analyses of 687 cases across 7 cancer types including breast carcinoma (115 tumor samples; 10,438 genes), clear cell renal carcinoma (100 tumor samples; 9,910 genes), colorectal cancer (91 tumor samples; 7,362 genes), hepatocellular carcinoma (101 tumor samples; 6,478 genes), lung adenocarcinoma (104 tumor samples; 10,967 genes), stomach adenocarcinoma (80 tumor samples; 9,268 genes), and uterine corpus endometrial carcinoma UCEC (96 tumor samples; 10,768 genes). Through the protein co-expression network analysis, we identified co-expressed protein modules enriched for differentially expressed proteins in tumor as disease-associated pathways. Comparison with the respective transcriptome network models revealed proteome-specific cancer subnetworks associated with heme metabolism, DNA repair, spliceosome, oxidative phosphorylation and several oncogenic signaling pathways. Cross-cancer comparison identified highly preserved protein modules showing robust pan-cancer interactions and identified endoplasmic reticulum-associated degradation (ERAD) and N-acetyltransferase activity as the central functional axes. We further utilized these network models to predict pan-cancer protein regulators of disease-associated pathways. The top predicted pan-cancer regulators including RSL1D1, DDX21 and SMC2, were experimentally validated in lung, colon, breast cancer and fetal kidney cells. In summary, this study has developed interpretable network models of cancer proteomes, showcasing their potential in unveiling novel oncogenic regulators, elucidating underlying mechanisms, and identifying new therapeutic targets.

Using machine learning and big data for the prediction of venous thromboembolic events after spine surgery: A single-center retrospective analysis of multiple models on a cohort of 6869 patients.

Objective: Venous thromboembolic event (VTE) after spine surgery is a rare but potentially devastating complication. With the advent of machine learning, an opportunity exists for more accurate prediction of such events to aid in prevention and treatment. Methods: Seven models were screened using 108 database variables and 62 preoperative variables. These models included deep neural network (DNN), DNN with synthetic minority oversampling technique (SMOTE), logistic regression, ridge regression, lasso regression, simple linear regression, and gradient boosting classifier. Relevant metrics were compared between each model. The top four models were selected based on area under the receiver operator curve; these models included DNN with SMOTE, linear regression, lasso regression, and ridge regression. Separate random sampling of each model was performed 1000 additional independent times using a randomly generated training/testing distribution. Variable weights and magnitudes were analyzed after sampling. Results: Using all patient-related variables, DNN using SMOTE was the top-performing model in predicting postoperative VTE after spinal surgery (area under the curve [AUC] =0.904), followed by lasso regression (AUC = 0.894), ridge regression (AUC = 0.873), and linear regression (AUC = 0.864). When analyzing a subset of only preoperative variables, the top-performing models were lasso regression (AUC = 0.865) and DNN with SMOTE (AUC = 0.864), both of which outperform any currently published models. Main model contributions relied heavily on variables associated with history of thromboembolic events, length of surgical/anesthetic time, and use of postoperative chemoprophylaxis. Conclusions: The current study provides promise toward machine learning methods geared toward predicting postoperative complications after spine surgery. Further study is needed in order to best quantify and model real-world risk for such events.

Outpatient telemedicine in neurosurgery: 15,677 consecutive encounters in a comparative analysis of its effectiveness and impact on the surgical conversion rate.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has necessitated the use of telehealth visits (THVs). The effects on neurosurgical practice have not been well characterized, especially concerning new-patient THVs. Therefore, the authors of this study reviewed their institution's experience with outpatient clinic visits and THVs from before the COVID-19 pandemic to the present to focus on clinical metrics, rates of surgery, and the effects of implementing THVs in order to better understand their implications for clinical practice as more data emerge over time. METHODS: The authors reviewed 15,677 consecutive new outpatient in-person visits (IPVs), THVs, and neurosurgical procedures/cases proceeding from their institution between 2018 and 2022 for trends and associations related to THVs. RESULTS: Among spine patients, there was no difference in the proportion of encounters that led to surgery (surgical conversion rate) between THVs and IPVs (p = 0.49). Among cranial patients, THVs were negatively associated with conversion (OR 0.73, p = 0.03). On average, patients using THVs lived further from the hospital (p < 0.001); however, the patient catchment area appeared unchanged. The median distance to the hospital among THV patients was counterbalanced by a decreased distance for spine patients pursing IPVs (p < 0.001), with no significant change to case volume. There was no change in distance to the hospital among cranial patients. For both cranial and spine patients, surgical conversion was more likely among those who lived a great distance from the hospital if their initial encounter was an IPV (p = 0.007 and < 0.001, respectively). However, there was no relationship between distance from the hospital and surgical conversion among THV patients (p = 0.565). The availability of THVs did not significantly affect follow-up time (p = 0.837). For new patients at IPVs, there was no difference in time to the operating room between cranial and spine cases; for new patients at THVs, however, time to the operating room was significantly faster for cranial cases than for spine cases (p = 0.0018). CONCLUSIONS: Compared to IPVs, THVs lead to decreased surgical conversion for cranial patients but not spine patients. THVs do not appear to increase the catchment area. For patients who live far from the hospital, an IPV is associated with surgical conversion. Surgical conversion is faster following cranial THVs than after spine THVs. THVs did not increase the duration of follow-up.

Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2.

Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.

Chemoprophylactic Anticoagulation Following Lumbar Surgery Significantly Reduces Thromboembolic Events After Instrumented Fusions, Not Decompressions.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To quantify any reduction in venous thromboembolic events (VTEs) caused by chemoprophylaxis among lumbar surgery patients. SUMMARY OF BACKGROUND DATA: Chemoprophylactic anticoagulation (chemoprophylaxis) is used to prevent VTE after lumbar surgery. However, the treatment effect of chemoprophylaxis has not been reported among spine surgery patients, as conventional statistical methods preclude such inferences. MATERIALS AND METHODS: A total of 1243 consecutive lumbar fusions and 1433 noninstrumented lumbar decompressions performed at our institution over a six-year period were identified, and clinical and demographic data were collected, including on VTE events within 30 days postoperatively. Instrumented lumbar fusions and noninstrumented lumbar surgeries were analyzed separately. Patients who were given chemoprophylaxis (treatment) and controls were matched according to known VTE risk factors, including age, body mass index, sex, diabetes, chronic kidney disease, history of VTE, estimated blood loss, length of surgery, transfusion, whether surgery was staged, and whether surgery used an anterior approach. K-nearest neighbor propensity score matching was performed, and the treatment effect of chemoprophylaxis was calculated. RESULTS: Unadjusted, there was no difference in the rate of VTE between treatment and controls in either population. Baseline clinical and demographic characteristics differed significantly between treatment and control groups. In all, 575 lumbar fusion patients and 435 noninstrumented lumbar decompression patients were successfully propensity score matched, yielding balanced models (Rubin B <25, 0.560% reduction in known bias for both populations. The treatment effect of chemoprophylaxis after lumbar fusion in our patient population was a reduction in VTE incidence from 9.4% to 4.2% ( P <0.05), and propensity score adjusted regression confirmed a reduced odds of VTE with chemoprophylaxis (odds ratio=0.37, P =0.035). The treatment effect was not significant for noninstrumented lumbar decompression patients. CONCLUSION: Among patients undergoing instrumented lumbar fusions, chemoprophylactic anticoagulation causes a significant reduction in VTE, but causes no significant reduction among patients undergoing noninstrumented lumbar decompression.

Anterior approach lumbar fusions cause a marked increase in thromboembolic events: Causal inferences from a propensity-matched analysis of 1147 patients.

OBJECTIVE: Anterior lumbar fusions are thought to be associated with elevated venous thromboembolic event (VTE) rates, but the magnitude of this increase in VTE is not well described. The objective of this study was to quantify any increase in VTE caused by anterior approach lumbar fusion. METHODS: 1147 consecutive lumbar fusions performed at our institution over a six-year period were identified, and clinical and demographic data were collected. K-nearest neighbor propensity score matching and propensity score adjusted regression were performed. Patients undergoing anterior versus posterior approach lumbar fusions were matched according to age, body mass index, sex, VTE history, estimated blood loss, length of surgery, transfusion, selection for postoperative intensive care unit (ICU) admission, comorbid disease burden, and use of chemoprophylactic anticoagulation. RESULTS: Anterior approach surgery (OR=4.29, p < 0.001), a history of VTE (OR=8.67, p < 0.001), age (OR=1.53, p = 0.014), length of surgery (OR=1.16, p = 0.044), and selection for postoperative ICU admission (OR=4.60, p = 0.005) were independently associated with VTE on multivariable regression. 1058 anterior or posterior approach fusion patients were matched. After matching, overall bias was reduced by 71.0 %, no covariates remained significantly different between groups, and propensity scores were well balanced between populations (Rubin's B≤0.25, 0.5 ≤Rubin's R≤2.0). Significantly more patients in the anterior group underwent lower extremity duplex ultrasonography (LED) (36.9 % vs. 14.8 %, OR=3.36 [2.38, 4.76], p < 0.0001), and a statistically insignificantly higher proportion of LEDs were positive among patients in the anterior group (23.2 % vs. 13.2 %, OR=1.99 [0.92, 4.25], p = 0.108). After matching, the rate of VTE was 8.6 % for the anterior group and 1.3 % for the posterior group, with anterior approach surgery causing an increase in VTE by 7.2 % (95 % CI [2.28 %, 12.16 %], p = 0.004). CONCLUSION: Among patients undergoing lumbar fusions, anterior approach surgery causes an increase in VTE by 7.2%, which is a multifold increase in the proportion of patients with thromboembolic complications.

A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma.

Tumors exhibit enhancer reprogramming compared to normal tissue. The etiology is largely attributed to cell-intrinsic genomic alterations. Here, using freshly resected primary CRC tumors and patient-matched adjacent normal colon, we find divergent epigenetic landscapes between CRC tumors and cell lines. Intriguingly, this phenomenon extends to highly recurrent aberrant super-enhancers gained in CRC over normal. We find one such super-enhancer activated in epithelial cancer cells due to surrounding inflammation in the tumor microenvironment. We restore this super-enhancer and its expressed gene, PDZK1IP1, following treatment with cytokines or xenotransplantation into nude mice, thus demonstrating cell-extrinsic etiology. We demonstrate mechanistically that PDZK1IP1 enhances the reductive capacity CRC cancer cells via the pentose phosphate pathway. We show this activation enables efficient growth under oxidative conditions, challenging the previous notion that PDZK1IP1 acts as a tumor suppressor in CRC. Collectively, these observations highlight the significance of epigenomic profiling on primary specimens.

Low-molecular-weight Heparin (enoxaparin) versus unfractionated heparin for venous thromboembolism prophylaxis in patients undergoing craniotomy.

OBJECTIVE: To explore the difference in post-operative DVT, PE, and ICH complications following administration of prophylactic UFH or enoxaparin in patients undergoing craniotomy. METHODS: A retrospective chart review was conducted for 542 patients at our institution receiving either 5000units/0.5 mL UFH (BID or TID; 180 patients) or single daily 40 mg/0.4 mL enoxaparin (362 patients) following craniotomy. Multivariate linear regression models were developed comparing rates of postoperative DVT, PE, and reoperation for bleeding in patients given enoxaparin versus UFH prophylaxis while controlling for age at surgery, history of VTE, surgery duration, number of post-operative hospital days, reoperation, post-operative infections, and reason for surgery (tumor type, genetics, etc.). Mann Whitney U tests were subsequently performed comparing rates of postoperative DVT, PE, and ICH for each group. RESULTS: Patients receiving prophylactic enoxaparin, when compared to UFH, exhibited similar rates of postoperative DVT (22 % vs 20.6 %, p = 0.86), PE (9.7 % vs 8.9 %, p = 0.86), and reoperation for bleeding (0.4 % vs 0.2 %, p = 0.58), while controlling for the factors described above. CONCLUSION: In patients undergoing craniotomy, rates for DVT, PE, and ICH were similar between patients treated with either prophylactic enoxaparin or UFH. Further studies are needed to understand whether a certain subset of patients demonstrate improved benefit from either prophylactic anticoagulant.

Surgical Site Infection in the Intensive Care Setting After Posterior Spinal Fusion: A Case Series Highlighting the Microbial Profile, Risk Factors, and the Importance of Comorbid Disease Burden.

BACKGROUND: Most posterior spinal fusion (PSF) patients do not require admission to an intensive care unit (ICU), and those who do may represent an underinvestigated, high-risk subpopulation. OBJECTIVE: To identify the microbial profile of and risk factors for surgical site infection (SSI) in PSF patients admitted to the ICU postoperatively. METHODS: We examined 3965 consecutive PSF patients treated at our institution between 2000 and 2015 and collected demographic, clinical, and procedural data. Comorbid disease burden was quantified using the Charlson Comorbidity Index (CCI). We performed multivariable logistic regression to identify risk factors for SSI, readmission, and reoperation. RESULTS: Anemia, more levels fused, cervical surgery, and cerebrospinal fluid leak were positively associated with ICU admission, and minimally invasive surgery was negatively associated. The median time to infection was equivalent for ICU patients and non-ICU patients, and microbial culture results were similar between groups. Higher CCI and undergoing a staged procedure were associated with readmission, reoperation, and SSI. When stratified by CCI into quintiles, SSI rates show a strong linear correlation with CCI ( P = .0171, R = 0.941), with a 3-fold higher odds of SSI in the highest risk group than the lowest (odds ratio = 3.15 [1.19, 8.07], P = .032). CONCLUSION: Procedural characteristics drive the decision to admit to the ICU postoperatively. Patients admitted to the ICU have higher rates of SSI but no difference in the timing of or microorganisms that lead to those infections. Comorbid disease burden drives SSI in this population, with a 3-fold greater odds of SSI for high-risk patients than low-risk patients.

PI3K drives the de novo synthesis of coenzyme A from vitamin B5.

In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth, governing cellular nutrient uptake, energy generation, reducing cofactor production and macromolecule biosynthesis1. Many of the driver mutations in cancer with the highest recurrence, including in receptor tyrosine kinases, Ras, PTEN and PI3K, pathologically activate PI3K signalling2,3. However, our understanding of the core metabolic program controlled by PI3K is almost certainly incomplete. Here, using mass-spectrometry-based metabolomics and isotope tracing, we show that PI3K signalling stimulates the de novo synthesis of one of the most pivotal metabolic cofactors: coenzyme A (CoA). CoA is the major carrier of activated acyl groups in cells4,5 and is synthesized from cysteine, ATP and the essential nutrient vitamin B5 (also known as pantothenate)6,7. We identify pantothenate kinase 2 (PANK2) and PANK4 as substrates of the PI3K effector kinase AKT8. Although PANK2 is known to catalyse the rate-determining first step of CoA synthesis, we find that the minimally characterized but highly conserved PANK49 is a rate-limiting suppressor of CoA synthesis through its metabolite phosphatase activity. Phosphorylation of PANK4 by AKT relieves this suppression. Ultimately, the PI3K-PANK4 axis regulates the abundance of acetyl-CoA and other acyl-CoAs, CoA-dependent processes such as lipid metabolism and proliferation. We propose that these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone/growth-factor-driven or oncogene-driven metabolism and growth.

PI3King the Environment for Growth: PI3K Activation Drives Transcriptome Changes That Support Oncogenic Growth.

PI3K signaling plays an integral role in cells, coordinating the necessary alterations in cellular metabolism and programs to support survival and proliferation. In the first genome-wide analysis of alternative splicing in PIK3CA-mutant breast cancer, Ladewig and colleagues show that activating mutations in PIK3CA alter the use of known exons and splice junctions, leading to changes in gene expression and transcription factor activity that promote an oncogenic phenotype. Their work reveals a novel mechanism underlying the functional impact of PI3K signal activation in the context of breast cancer, where PIK3CA mutations are common and PI3K inhibitors are part of the standard of care. Their studies uncover a feedforward mechanism by which PI3K signaling enables a shift in the spectrum of translated splice variants as another method through which the PI3K pathway has evolved to regulate its own activity, thereby modifying the cellular response to upstream activation based on the signaling that has come before. These findings have profound implications for understanding the evolution of the PI3K pathway and the rewiring of cells in response to prolonged or repeated signal activation. See related article by Ladewig et al., p. 2269.

Circling back to PTEN: Fumarate inhibits canonical tumor suppressor.

Ge et al. (2022) describes an inhibitory, post-translational modification of PTEN at C211 by fumarate, which offers new insight into the integration of PI3K signaling and metabolism via a potential feedforward regulatory mechanism involving a PI3K-glucose-fumarate-PTEN axis.

Patient-Derived In Vitro and In Vivo Models of Cancer.

Over the last two decades, cancer researchers have taken the promise offered by the Human Genome Project and have expanded its capacity to use sequencing to identify the genomic alterations that give rise to and sustain individual tumors. This expansion has allowed researchers to identify and target highly recurrent alterations in specific cancer contexts, such as EGFR mutations in non-small cell lung cancer (Lynch et al, N Engl J Med 350:2129-2139, 2004; Sharifnia et al., Proc Natl Acad Sci U S A 111:18661-18666, 2014), BCR-ABL translocations in chronic myeloid leukemia (Deininger, Pharmacol Rev 55:401-423. https://doi.org/10.1124/pr.55.3.4 , 2003; Druker et al, N Engl J Med 344. 1038-1042, 2001; Druker et al, N Engl J Med 344:1031-1037. https://doi.org/10.1056/NEJM200104053441401 , 2001), or HER2 amplifications in breast cancer (Slamon et al, N Engl J Med 344:783-792. https://doi.org/10.1056/NEJM200103153441101 , 2001; Solca et al, Beyond trastuzumab: second-generation targeted therapies for HER-2-positive breast cancer. In: Sibilia M, Zielinski CC, Bartsch R, Grunt TW (eds) Drugs for HER-2-positive breast cancer. Springer, Basel, pp 91-107, 2011). Despite these advances in our capacity to identify the genetic alterations that drive tumor initiation, survival, and proliferation, our ability to target these alterations to provide effective treatment options for patients in need, particularly those with rare or advanced cancers, remains limited (Gould et al, Nat Med 21:431-439. https://doi.org/10.1038/nm.3853 , 2015). Patient-derived models of cancer offer one potential mechanism to overcome this barrier between the bench and bedside. Through the development and testing of patient-derived models of cancer, functional genomics efforts can identify tumor-specific drug sensitivities and thereby provide a connection between tumor genetics and effective therapeutics for patients in need of treatment options.Recognizing that cancer is a multifaceted set of disease states, the development of personalized models of cancer that can be used to compare treatment options, identify tumor-specific vulnerabilities, and guide clinical decision-making has tremendous potential for improving patient outcomes. This chapter will describe a representative set of patient-derived models of cancer, reviewing each of their strengths and weaknesses and highlighting how selecting a model to suit a specific question or context is critical. Each model comes with a unique set of pros and cons, making them more or less appropriate for each specific research or clinical question. As each model can be leveraged to gain new insights into cancer biology, the key to their deployment is to identify the most appropriate model for a specific context, while carefully considering the strengths and limitations of the selected model. When used appropriately, patient-derived models may prove to be the missing link needed to bring the promise of personalized oncology to fruition in the clinic.

The role of preoperative embolization in the treatment of spinal metastases from renal cell carcinoma.

BACKGROUND: One strategy to reduce extensive intraoperative bleeding for patients undergoing surgery for metastatic renal cell carcinoma (RCC) to the spine is preoperative embolization. Prior studies have shown mixed results. The objective of this study is to evaluate the efficacy of preoperative embolization in patients undergoing spine surgery for metastatic RCC with consideration of multiple confounders. We aim to assess blood loss and other outcomes reflective of functional status and postoperative complications. METHODS: A retrospective chart review was conducted for 43 patients that underwent surgery for metastatic spinal RCC and either received preoperative embolization (n = 29) or did not (n = 14). Mann Whitney tests were run for initial analyses. Multivariate regression models were then used to predict outcomes while controlling for multiple demographic and preoperative variables. RESULTS: Mann Whitney tests revealed a significant difference between the mean age of patients undergoing preoperative embolization in comparison to those that did not (59.2 years versus 52.4 years; p = 0.044). We found that preoperative embolization was not significantly associated with decreased blood loss (2257 mL versus 2000 mL; p = 0.97). There were also no significant differences between groups in post-procedural complications (34.5% versus 14.3%; p = 0.097), last follow-up Nurick score (ß = 0.72, p = 0.18; 2.1 versus 1.6) or operative duration (ß = 28, p = 0.66; 408 min versus 353 min). The female gender was found to be significantly associated with higher last follow-up Nurick scores (ß = 1.24, p = 0.033). CONCLUSION: We observed no differences in blood loss or other outcomes between patients undergoing preoperative embolization and those that did not.

A Functional Precision Oncology Approach to Identify Treatment Strategies for Myxofibrosarcoma Patients.

In this era of precision medicine, numerous workflows for the targeting of high-recurrent mutations in common tumor types have been developed, leaving patients with rare diseases with few options. Here, we implement a functional precision oncology approach utilizing comprehensive genomic profiling in combination with high-throughput drug screening, to identify tumor-specific drug sensitivities for patients with rare tumor types such as myxofibrosarcoma. From a patient with a high-grade myxofibrosarcoma, who was enrolled in the Englander Institute for Precision Medicine (EIPM) program, we established patient-derived 3D sarco-spheres and xenograft models for functional testing. In the absence of a large cohort of clinically similar cases, high-throughput drug screening was performed on the patient-derived cells, and compared with two other myxofibrosarcoma lines and a benign fibroblast line to functionally identify tumor-specific drug sensitivities. The addition of functional drug sensitivity testing to complement genomic profiling identified multiple therapeutic options that were further validated in patient derived xenograft models. Genomic analyses detected the frequently known codeletion of the tumor suppressors CDKN2A/B together with the methylthioadenosine phosphorylase (MTAP) and a TP53 E286fs*50 mutation. High-throughput drug screening demonstrated tumor-specific sensitivity to compounds targeting the cell cycle. Based on genomic analysis and high-throughput drug screening, we show that targeting the cell cycle in these tumors is a powerful approach. IMPLICATIONS: This study demonstrates the potential of functional testing to aid clinical decision making for patients with rare or molecularly complex malignancies when combined with comprehensive genomic profiling.

Targeting Cullin-RING E3 Ubiquitin Ligase 4 by Small Molecule Modulators.

Cullin-RING E3 ubiquitin ligase 4 (CRL4) plays an essential role in cell cycle progression. Recent efforts using high throughput screening and follow up hit-to-lead studies have led to identification of small molecules 33-11 and KH-4-43 that inhibit E3 CRL4's core ligase complex and exhibit anticancer potential. This review provides: 1) an updated perspective of E3 CRL4, including structural organization, major substrate targets and role in cancer; 2) a discussion of the challenges and strategies for finding the CRL inhibitor; and 3) a summary of the properties of the identified CRL4 inhibitors as well as a perspective on their potential utility to probe CRL4 biology and act as therapeutic agents.