Endometriosis: Etiology, pathobiology, and therapeutic prospects.

Endometriosis is a common condition associated with infertility that causes chronic pain in many, but not all, women. It is defined by the presence of endometrial-like tissue outside the uterus. Although the cause and natural history of the disorder remain uncertain, hormonal, neurological, and immunological factors are all implicated in the mechanisms contributing to development of symptoms. Because definitive diagnosis requires surgery, there is often a long diagnostic delay after onset of symptoms. Current interventions for endometriosis have limited efficacy and unacceptable side effects/risks and are associated with high rates of symptom recurrence. Here, we review recent advances in our understanding of the etiology of endometriosis, discuss current diagnostic and treatment strategies, highlight current clinical trials, and consider how recent results offer new avenues for the identification of endometriosis biomarkers and the development of effective non-surgical therapies that are fertility-sparing.

Gut-Brain Cross-Talk in Metabolic Control.

Because human energy metabolism evolved to favor adiposity over leanness, the availability of palatable, easily attainable, and calorically dense foods has led to unprecedented levels of obesity and its associated metabolic co-morbidities that appear resistant to traditional lifestyle interventions. However, recent progress identifying the molecular signaling pathways through which the brain and the gastrointestinal system communicate to govern energy homeostasis, combined with emerging insights on the molecular mechanisms underlying successful bariatric surgery, gives reason to be optimistic that novel precision medicines that mimic, enhance, and/or modulate gut-brain signaling can have unprecedented potential for stopping the obesity and type 2 diabetes pandemics.

The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future.

Peritoneal metastasis (PM) is often regarded as a less frequent pattern of spread; however, collectively across all spectra of primary tumors, the consequences of PM impact a large population of patients annually. Unlike other modes of metastasis, symptoms at presentation or during the treatment course are common, representing an additional challenge in the management of PM. Early efforts with chemotherapy and incomplete surgical interventions transiently improved symptoms, but durable symptom control and survival extension were rare, which established a perspective of treatment futility for PM through most of the 20th century. Notably, the continued development of better systemic therapy combinations, optimization of cytoreductive surgery (CRS), and rigorous investigation of combining regional therapy-specifically hyperthermic intraperitoneal chemotherapy-with CRS, have resulted in more effective multimodal treatment options for patients with PM. In this article, the authors provide a comprehensive review of the data establishing the contemporary approach for tumors with a high frequency of PM, including appendix, colorectal, mesothelioma, and gastric cancers. The authors also explore the emerging role of adding hyperthermic intraperitoneal chemotherapy to the well established paradigm of CRS and systemic therapy for advanced ovarian cancer, as well as the recent clinical trials identifying the efficacy of poly(adenosine diphosphate ribose) polymerase maintenance therapy. Finally, recent data are included that explore the role of precision medicine technology in PM management that, in the future, may help further improve patient selection, identify the best systemic therapy regimens, detect actionable mutations, and identify new targets for drug development.

Current treatment and future directions in the management of anal cancer.

Although rare, the rate of squamous cell carcinoma of the anus (SCCA) is rising globally. Most patients present with nonmetastatic disease and are curable with appropriate treatment, which has evolved significantly over the last several decades. Before the 1970s, SCCA was managed with radical surgery, resulting in a permanent colostomy. Researchers found that preoperative treatment with chemotherapy and concurrent radiation could achieve a pathologic complete response. After this observation, definitive therapy shifted from radical surgery to sphincter-preserving chemoradiation. Investigations into the necessity of chemotherapy and the optimal regimen found that chemotherapy with mitomycin-C and 5-fluorouracil is required for cure. Further studies evaluating the addition of induction or maintenance chemotherapy, monoclonal antibody therapy, or higher radiation doses have demonstrated no significant benefit to disease control. Advanced radiation delivery with intensity-modulated radiotherapy techniques is now considered the standard of care because of its prospectively determined, favorable acute toxicity profile compared with 3-dimensional conformal radiation. It is important to note that chemoradiation treatment response may be slow (up to 26 weeks) and should be assessed through serial clinical examinations. Today, surgical management of SCCA is reserved only for the lowest risk, early stage tumors or for recurrent/persistent disease. Current studies are evaluating radiation dose de-escalation in early stage disease and radiation dose escalation and the addition of immune checkpoint inhibitors in locally advanced cancers. In reviewing how and why modern-day treatment of SCCA was established, the objective of this report is to reenforce adherence to current treatment paradigms to assure the best possible outcomes for patients.

Management of glioblastoma: State of the art and future directions.

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

Intratumor injected gold molecular clusters for NIR-II imaging and cancer therapy.

Surgical resections of solid tumors guided by visual inspection of tumor margins have been performed for over a century to treat cancer. Near-infrared (NIR) fluorescence labeling/imaging of tumor in the NIR-I (800 to 900 nm) range with systemically administrated fluorophore/tumor-targeting antibody conjugates have been introduced to improve tumor margin delineation, tumor removal accuracy, and patient survival. Here, we show Au25 molecular clusters functionalized with phosphorylcholine ligands (AuPC, ~2 nm in size) as a preclinical intratumorally injectable agent for NIR-II/SWIR (1,000 to 3,000 nm) fluorescence imaging-guided tumor resection. The AuPC clusters were found to be uniformly distributed in the 4T1 murine breast cancer tumor upon intratumor (i.t.) injection. The phosphocholine coating afforded highly stealth clusters, allowing a high percentage of AuPC to fill the tumor interstitial fluid space homogeneously. Intra-operative surgical navigation guided by imaging of the NIR-II fluorescence of AuPC allowed for complete and non-excessive tumor resection. The AuPC in tumors were also employed as a photothermal therapy (PTT) agent to uniformly heat up and eradicate tumors. Further, we performed in vivo NIR-IIb (1,500 to 1,700 nm) molecular imaging of the treated tumor using a quantum dot-Annexin V (QD-P3-Anx V) conjugate, revealing cancer cell apoptosis following PTT. The therapeutic functionalities of AuPC clusters combined with rapid renal excretion, high biocompatibility, and safety make them promising for clinical translation.

An endoscopically compatible fast-gelation powder forms Janus-adhesive hydrogel barrier to prevent postoperative adhesions.

Postoperative adhesions occur widely in various tissues, bringing the risk of secondary surgery and increased medical burden. Hydrogel barriers with Janus-adhesive ability can achieve physical isolation of adjacent tissues and are therefore considered an ideal solution. However, integrating endoscopic delivery convenience and viscoelastic Janus hydrogel formation remains a great challenge. Here, we present a report of the in situ formation of Janus-adhesive hydrogel barrier using a sprayable fast-Janus-gelation (FJG) powder. We first methacrylate the polysaccharide macromolecules to break the intermolecular hydrogen bonds and impart the ability of rapid hydration. FJG powder can rapidly absorb interfacial water and crosslink through borate ester bonds, forming a toughly adhesive viscoelastic hydrogel. The Janus barrier can be simply formed by further hydrating the upper powder with cationic solution. We construct rat models to demonstrate the antiadhesions efficiency of viscoelastic FJG hydrogels in organs with different motion modalities (e.g., intestine, heart, liver). We also developed a low-cost delivery device with a standardized surgical procedure and further validated the feasibility and effectiveness of FJG powder in minimally invasive surgery using a preclinical translational porcine model. Considering the advantages in terms of therapeutic efficacy, clinical convenience, and commercialization, our results reveal the great potential of Janus-gelation powder materials as a next-generation antiadhesions barrier.

Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest Trial (GOT ICE): A Randomized Clinical Trial Comparing Outcomes After Aortic Arch Surgery.

BACKGROUND: Deep hypothermia has been the standard for hypothermic circulatory arrest (HCA) during aortic arch surgery. However, centers worldwide have shifted toward lesser hypothermia with antegrade cerebral perfusion. This has been supported by retrospective data, but there has yet to be a multicenter, prospective randomized study comparing deep versus moderate hypothermia during HCA. METHODS: This was a randomized single-blind trial (GOT ICE [Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest]) of patients undergoing arch surgery with HCA plus antegrade cerebral perfusion at 4 US referral aortic centers (August 2016-December 2021). Patients were randomized to 1 of 3 hypothermia groups: DP, deep (≤20.0 °C); LM, low-moderate (20.1-24.0 °C); and HM, high-moderate (24.1-28.0 °C). The primary outcome was composite global cognitive change score between baseline and 4 weeks postoperatively. Analysis followed the intention-to-treat principle to evaluate if: (1) LM noninferior to DP on global cognitive change score; (2) DP superior to HM. The secondary outcomes were domain-specific cognitive change scores, neuroimaging findings, quality of life, and adverse events. RESULTS: A total of 308 patients consented; 282 met inclusion and were randomized. A total of 273 completed surgery, and 251 completed the 4-week follow-up (DP, 85 [34%]; LM, 80 [34%]; HM, 86 [34%]). Mean global cognitive change score from baseline to 4 weeks in the LM group was noninferior to the DP group; likewise, no significant difference was observed between DP and HM. Noninferiority of LM versus DP, and lack of difference between DP and HM, remained for domain-specific cognitive change scores, except structured verbal memory, with noninferiority of LM versus DP not established and structured verbal memory better preserved in DP versus HM (P = 0.036). There were no significant differences in structural or functional magnetic resonance imaging brain imaging between groups postoperatively. Regardless of temperature, patients who underwent HCA demonstrated significant reductions in cerebral gray matter volume, cortical thickness, and regional brain functional connectivity. Thirty-day in-hospital mortality, major morbidity, and quality of life were not different between groups. CONCLUSIONS: This randomized multicenter study evaluating arch surgery HCA temperature strategies found low-moderate hypothermia noninferior to traditional deep hypothermia on global cognitive change 4 weeks after surgery, although in secondary analysis, structured verbal memory was better preserved in the deep group. The verbal memory differences in the low- and high-moderate groups and structural and functional connectivity reductions from baseline merit further investigation and suggest opportunities to further optimize brain perfusion during HCA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02834065.

Addressing Barriers to Entry and Retention of Women in Interventional Vascular Specialties With Proposed Solutions: A Scientific Statement From the American Heart Association.

Representation of women in interventional vascular fields (interventional cardiology, interventional radiology, and vascular surgery) lags behind that in other specialties. With women representing half of all medical school graduates, encouraging parity of women in these fields needs to start in medical school. Barriers to pursuing careers in vascular intervention include insufficient exposure during core clerkships, early mentorship, visibility of women in the field, length of training, lifestyle considerations, work culture and environment, and concerns about radiation exposure. This scientific statement highlights potential solutions for both the real and perceived barriers that women may face in pursuing careers in vascular intervention, including streamlining of training (as both interventional radiology and vascular surgery have done with a resultant increase in percentage of women trainees), standardization of institutional promotion of women in leadership, and professional and industry partnerships for the retention and advancement of women.

2024 AHA/ACC/ACS/ASNC/HRS/SCA/SCCT/SCMR/SVM Guideline for Perioperative Cardiovascular Management for Noncardiac Surgery: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 AHA/ACC/ACS/ASNC/HRS/SCA/SCCT/SCMR/SVM Guideline for Perioperative Cardiovascular Management for Noncardiac Surgery" provides recommendations to guide clinicians in the perioperative cardiovascular evaluation and management of adult patients undergoing noncardiac surgery. METHODS: A comprehensive literature search was conducted from August 2022 to March 2023 to identify clinical studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: Recommendations from the "2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery" have been updated with new evidence consolidated to guide clinicians; clinicians should be advised this guideline supersedes the previously published 2014 guideline. In addition, evidence-based management strategies, including pharmacological therapies, perioperative monitoring, and devices, for cardiovascular disease and associated medical conditions, have been developed.

2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

Colorectal cancer: a comprehensive review of carcinogenesis, diagnosis, and novel strategies for classified treatments.

Colorectal cancer is the third most common and the second deadliest cancer worldwide. To date, colorectal cancer becomes one of the most important challenges of the health system in many countries. Since the clinical symptoms of this cancer appear in the final stages of the disease and there is a significant golden time between the formation of polyps and the onset of cancer, early diagnosis can play a significant role in reducing mortality. Today, in addition to colonoscopy, minimally invasive methods such as liquid biopsy have received much attention. The treatment of this complex disease has been mostly based on traditional treatments including surgery, radiotherapy, and chemotherapy; the high mortality rate indicates a lack of success for current treatment methods. Moreover, disease recurrence is another problem of traditional treatments. Recently, new approaches such as targeted therapy, immunotherapy, and nanomedicine have opened new doors for cancer treatment, some of which have already entered the market, and many methods have shown promising results in clinical trials. The success of immunotherapy in the treatment of refractory disease, the introduction of these methods into neoadjuvant therapy, and the successful results in tumor shrinkage without surgery have made immunotherapy a tough competitor for conventional treatments. It seems that the combination of those methods with such targeted therapies will go through promising changes in the future of colorectal cancer treatment.

Early Initiation of Biologics and Disease Outcomes in Adults and Children With Inflammatory Bowel Diseases: Results From the Epidemiology Group of the Nationwide Israeli Inflammatory Bowel Disease Research Nucleus Cohort.

BACKGROUND & AIMS: In this nationwide study, we explored whether early initiation of biologics is associated with improved outcomes in children and adults with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: All patients diagnosed with CD or UC in Israel (2005-2020) were included in the Epidemiology Group of the Israeli Inflammatory Bowel Disease Research Nucleus cohort, encompassing 98% of the population. We compared disease duration at biologics initiation (ie, 0-3 months, >3-12 months, >1-2 years, and >2-3 years) using the cloning, censoring, and weighting by inverse probabilities method to emulate a target trial, adjusting for time-varying confounders and selection bias. RESULTS: Of the 34,375 included patients (of whom 5240 [15%] were children), 7452 of 19,264 (39%) with CD and 2235 of 15,111 (15%) with UC received biologics. In CD, by 10 years postdiagnosis, the probability of CD-related surgery decreased gradually but modestly with earlier initiation of biologics; a significant difference was noted between >2-3 years (31%) and 0-3 months (18%; P = .02; number needed to treat, 7.7), whereas there was no difference between the 0-3-month and >3-12-month periods. The 10-year probability of steroid dependency for the 0-3-month period (19%) differed both from the >2-3-year (31%; P < .001) and 1-2-year periods (37%; P < .001). In UC, no significant differences in colectomy or steroid dependency rates were observed between the treatment initiation periods. Similar trends were noted in the pediatric population. CONCLUSIONS: Very early initiation of biologics was not associated with some outcomes except for a modest risk reduction of surgery and steroid dependency for CD, which requires confirmation in future studies. In UC, early introduction of biologics was not associated with reduced risk of colectomy or steroid dependency.

Perioperative systemic IL-6 and immune-adipose- metabolism transcription in tumour and tumour adjacent breast cancer.

Surgical resection is the primary treatment approach for patients with breast cancer. Despite optimal multimodal treatment, metastatic recurrence remains a risk. Surgery-mediated systemic inflammation and local tissue inflammation generate an immunosuppressive and wound-healing environment that may accelerate cancer recurrence and metastasis post-operatively. Investigating the impact of surgery on local and systemic inflammation may provide knowledge for improvement of patient prognosis and treatment opportunities. Systemic cytokines were quantified in the blood plasma of patients with breast cancer pre-operatively, early post-operatively, and late post-operatively. Early post-operative levels of IL-6 were significantly elevated in patients who underwent mastectomy compared with wide local excision. Post-operative IL-6 levels correlate with clinicopathological features (age and BMI). The transcriptomes of local matched tumour and normal tumour adjacent (normal) breast tissue, from patients with breast cancer, were analysed by RNA-Seq. Elevated gene expressions of IL6, ADIPOQ, FABP4, LPL, PPARG, and CD36 in normal tissue were associated with worse overall survival of patients with ER-positive breast cancer. In tissue with higher expression of IL6 and ADIPOQ, a higher abundance of M2-like macrophage gene expression was identified. This study revealed perioperative systemic dynamics of inflammatory mediators and identified local immune-adipose-metabolism gene expression in tumour-adjacent tissue associated with pro-tumour function.

Medical Microrobots.

Scientists around the world have long aimed to produce miniature robots that can be controlled inside the human body to aid doctors in identifying and treating diseases. Such microrobots hold the potential to access hard-to-reach areas of the body through the natural lumina. Wireless access has the potential to overcome drawbacks of systemic therapy, as well as to enable completely new minimally invasive procedures. The aim of this review is fourfold: first, to provide a collection of valuable anatomical and physiological information on the target working environments together with engineering tools for the design of medical microrobots; second, to provide a comprehensive updated survey of the technological state of the art in relevant classes of medical microrobots; third, to analyze currently available tracking and closed-loop control strategies compatible with the in-body environment; and fourth, to explore the challenges still in place, to steer and inspire future research.

Histotripsy: A Method for Mechanical Tissue Ablation with Ultrasound.

Histotripsy is a relatively new therapeutic ultrasound technology to mechanically liquefy tissue into subcellular debris using high-amplitude focused ultrasound pulses. In contrast to conventional high-intensity focused ultrasound thermal therapy, histotripsy has specific clinical advantages: the capacity for real-time monitoring using ultrasound imaging, diminished heat sink effects resulting in lesions with sharp margins, effective removal of the treated tissue, a tissue-selective feature to preserve crucial structures, and immunostimulation. The technology is being evaluated in small and large animal models for treating cancer, thrombosis, hematomas, abscesses, and biofilms; enhancing tumor-specific immune response; and neurological applications. Histotripsy has been recently approved by the US Food and Drug Administration to treat liver tumors, with clinical trials undertaken for benign prostatic hyperplasia and renal tumors. This review outlines the physical principles of various types of histotripsy; presents major parameters of the technology and corresponding hardware and software, imaging methods, and bioeffects; and discusses the most promising preclinical and clinical applications.

Contemporary Perioperative Nutritional Care.

Over the last decades, surgical complication rates have fallen drastically. With the introduction of new surgical techniques coupled with specific evidence-based perioperative care protocols, patients today run half the risk of complications compared with traditional care. Many patients who in previous years needed weeks of hospital care now recover and can leave in days. These remarkable improvements are achieved by using nutritional stress-reducing care elements for the surgical patient that reduce metabolic stress and allow for the return of gut function. This new approach to nutritional care and how it is delivered as an integral part of enhancing recovery after surgery are outlined in this review. We also summarize the new and increased understanding of the effects of the routes of delivering nutrition and the role of the gut, as well as the current recommendations for artificial nutritional support.

Nutritional Challenges and Treatment After Bariatric Surgery.

Bariatric surgery is an important weight loss tool in individuals with severe obesity. It is currently the most effective long-term weight loss treatment that lowers obesity-related comorbidities. It also has significant physiological and nutritional consequences that can result in gastrointestinal complications and micronutrient deficiencies. After gastric bypass, clinical events that negatively affect nutritional status include malabsorption, dumping syndrome, kidney stones, altered intestinal bile acid availability, bowel obstruction, ulcers, gastroesophageal reflux, and bacterial overgrowth. Risk factors for poor nutritional status and excessive loss of lean body mass and bone include reduced dietary quality and inadequate intake, altered nutrient absorption, and poor patient compliance with nutrient supplementation. There are unique concerns in adolescents, older individuals, and individuals who become pregnant postoperatively. With careful management, health-care professionals can assist with long-term weight loss success and minimize the risk of acute and long-term nutrition complications after bariatric surgery.

Androgenic steroids induce pathologic scarring in a preclinical porcine model via dysfunctional extracellular matrix deposition.

Hypertrophic scarring is a major source of morbidity. Sex hormones are not classically considered modulators of scarring. However, based on increased frequency of hypertrophic scarring in patients on testosterone, we hypothesized that androgenic steroids induce abnormal scarring and developed a preclinical porcine model to explore these effects. Mini-swine underwent castration, received no testosterone (noT) or biweekly testosterone therapy (+T), and underwent excisional wounding. To create a delayed wound healing model, a subset of wounds were re-excised at 2 weeks. Scars from postoperative day 42 (POD42) and delayed wounds (POD28) were harvested 6 weeks after initial wounding for analysis via histology, bulk RNA-seq, and mechanical testing. Histologic analysis of scars from +T animals showed increased mean fibrosis area (16 mm2noT, 28 mm2+T; p = .007) and thickness (0.246 mm2noT, 0.406 mm2+T; p < .001) compared to noT. XX+T and XY+T scars had greater tensile burst strength (p = .024 and p = .013, respectively) compared to noT swine. Color deconvolution analysis revealed greater deposition of type I and type III collagen as well as increased collagen type I:III ratio in +T scars. Dermatopathologist histology scoring showed that +T exposure was associated with worse overall scarring (p < .05). Gene ontology analysis found that testosterone exposure was associated with upregulation of cellular metabolism and immune response gene sets, while testosterone upregulated pathways related to keratinization and laminin formation on pathway analysis. In conclusion, we developed a preclinical porcine model to study the effects of the sex hormone testosterone on scarring. Testosterone induces increased scar tissue deposition and appears to increase physical strength of scars via supraphysiologic deposition of collagen and other ECM factors. The increased burst strength seen in both XX and XY animals suggests that hormone administration has a strong influence on scar mechanical properties independent of chromosomal sex. Anti-androgen topical therapies may be a promising future area of research.

Mapping interictal discharges using intracranial EEG-fMRI to predict postsurgical outcomes.

Various subjective and objective methods have been proposed to identify which interictal epileptiform discharge (IED)-related EEG-fMRI results are more likely to delineate seizure generating tissue in patients with drug-resistant focal epilepsy for the purposes of surgical planning. In this intracranial EEG-fMRI study, we evaluated the utility of these methods to localize clinically relevant regions pre-operatively and compared the extent of resection of these areas to post-operative outcome. Seventy patients admitted for intracranial video-EEG monitoring were recruited for a simultaneous intracranial EEG-fMRI study. For all analyses of blood oxygen level-dependent responses associated with IEDs, an experienced epileptologist identified the most Clinically Relevant brain activation cluster using available clinical information. The Maximum cluster (the cluster with the highest z-score) was also identified for all analyses and assigned to one of three confidence levels (low, medium, or high) based on the difference of the peak z-scores between the Maximum and Second Maximum cluster (the cluster with the second highest peak z-value). The distance was measured and compared between the peak voxel of the aforementioned clusters and the electrode contacts where the interictal discharge and seizure onset were recorded. In patients who subsequently underwent epilepsy surgery, the spatial concordance between the aforementioned clusters and the area of resection was determined and compared to post-operative outcome. We evaluated 106 different IEDs in 70 patients. Both subjective (identification of the Clinically Relevant cluster) and objective (Maximum cluster much more significant than the second maximum cluster) methods of culling non-localizing EEG-fMRI activation maps increased the spatial concordance between these clusters and the corresponding IED or seizure onset zone contacts. However, only the objective methods of identifying medium and high confidence maps resulted in a significant association between resection of the peak voxel of the Maximum cluster and post-operative outcome. Resection of this area was associated with good post-operative outcomes but was not sufficient for seizure freedom. On the other hand, we found that failure to resect the medium and high confidence Maximum clusters was associated with a poor post-surgical outcome (negative predictive value = 1.0, sensitivity = 1.0). Objective methods to identify higher confidence EEG-fMRI results are needed to localize areas necessary for good post-operative outcomes. However, resection of the peak voxel within higher confidence Maximum clusters is not sufficient for good outcomes. Conversely, failure to resect the peak voxel in these clusters is associated with a poor post-surgical outcome.