3D-SARC: A Pilot Study Testing the Use of a 3D Augmented-Reality Model with Conventional Imaging as a Preoperative Assessment Tool for Surgical Resection of Retroperitoneal Sarcoma.

BACKGROUND: Retroperitoneal sarcomas (RPSs) present a surgical challenge, with complex anatomic relationships to organs and vascular structures. This pilot study investigated the role of three-dimensional (3D) augmented reality (3DAR) compared with standard imaging in preoperative planning and resection strategies. METHODS: For the study, 13 patients who underwent surgical resection of their RPS were selected based on the location of their tumor (right, left, pelvis). From the patients' preoperative computed tomography (CT) scans, 3DAR models were created using a D2P program and projected by an augmented-reality (AR) glass (Hololens). The 3DAR models were evaluated by three experienced sarcoma surgeons and compared with the baseline two-dimensional (2D) contrast-enhanced CT scans. RESULTS: Three members of the surgical team evaluated 13 models of retroperitoneal sarcomas, resulting in a total of 26 responses. When the surgical team was asked to evaluate whether the 3DAR better prepared the surgeon for planned surgical resection, 10 responses favored the 3DAR, 5 favored the 2D CT scans and 11 showed no difference (p = 0.074). According to 15 (57.6 %) of the 26 responses, the 3DAR offered additional value over standard imaging in the preoperative planning (median score of 4; range, 1-5). The median stated likelihood that the surgeons would consult the 3DAR was 5 (range, 2-5) for the preoperative setting and 3 (range, 1-5) for the intraoperative setting. CONCLUSIONS: This pilot study suggests that the use of 3DAR may provide additional value over current standard imaging in the preoperative planning for surgical resection of RPS, and the technology merits further study.

Resection of Recurrent Pelvic Soft Tissue Sarcoma: Is the Risk Worth the Reward?

INTRODUCTION: Soft tissue sarcomas (STS) of the pelvis present a surgical and oncological challenge. We investigated the outcomes of patients undergoing resection of pelvic sarcomas. METHODS: A retrospective analysis of all patients who underwent surgical resection for STS between 2014 and 2021 at a tertiary academic referral center (n = 172). Included all patients with primary or recurrent STS which originated or extended to the pelvic cavity (n = 29). RESULTS: The cohort was divided into primary pelvic sarcomas (n = 18) and recurrent pelvic sarcomas (rPS, n = 11). Complete R0/R1 resection was achieved in 26 patients (89.6%). The postoperative complication rate was 48.3%. The rate of major complications was 27.5%. The median time of follow-up from surgery was 12.3 months (range, 0.6-60.3 months). Disease-free survival was superior in the primary pelvic sarcomas group compared to the rPS group (P = 0.002). However, there was no significant difference in overall survival, (P = 0.52). Univariant and multivariant analyses identified rPS group (Hazard Ratio 8.68, P = 0.006) and resection margins (Hazard Ratio 6.29, P = 0.004) to be independently associated with disease-free survival. CONCLUSIONS: We have demonstrated that achieving R0/R1 resection is feasible. Oncological outcomes are favorable for primary tumors, whereas recurrent tumors exhibit early recurrences. Consideration of resection of recurrent pelvic STS should involve a careful multidisciplinary evaluation.

Natural History and Management of Small-Bowel Obstruction in Patients After Cytoreductive Surgery and Intraperitoneal Chemotherapy.

BACKGROUND: Small-bowel obstruction (SBO) after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is a common complication associated with re-admission that may alter patients' outcomes. Our aim was to characterize and investigate the impact of bowel obstruction on patients' prognosis. METHODS: This was a retrospective analysis of patients with SBO after CRS/HIPEC (n = 392). We analyzed patients' demographics, operative and perioperative details, SBO re-admission data, and long-term oncological outcomes. RESULTS: Out of 366 patients, 73 (19.9%) were re-admitted with SBO. The cause was adhesive in 42 (57.5%) and malignant (MBO) in 31 (42.5%). The median time to obstruction was 7.7 months (range, 0.5-60.9). Surgical intervention was required in 21/73 (28.7%) patients. Obstruction eventually resolved (spontaneous or by surgical intervention) in 56/73 (76.7%) patients. Univariant analysis identified intraperitoneal chemotherapy agents: mitomycin C (MMC) (HR 3.2, p = 0.003), cisplatin (HR 0.3, p = 0.03), and doxorubicin (HR 0.25, p = 0.018) to be associated with obstruction-free survival (OFS). Postoperative complications such as surgical site infection (SSI), (HR 2.2, p = 0.001) and collection (HR 2.07, p = 0.015) were associated with worse OFS. Multivariate analysis maintained MMC (HR 2.9, p = 0.006), SSI (HR 1.19, p = 0.001), and intra-abdominal collection (HR 2.19, p = 0.009) as independently associated with OFS. While disease-free survival was similar between the groups, overall survival (OS) was better in the non-obstruction group compared with the obstruction group (p = 0.03). CONCLUSIONS: SBO after CRS/HIPEC is common and complex in management. Although conservative management was successful in most patients, surgery was required more frequently in patients with MBO. Patients with SBO demonstrate decreased survival.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Elderly is Safe and Effective.

INTRODUCTION: An increasing proportion of elderly patients (EP) are undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC). They have increased comorbidities and perioperative risk. Current literature is deficient in describing the outcomes of EP undergoing CRS/HIPEC. MATERIALS AND METHODS: A retrospective review of our prospectively maintained CRS/HIPEC database analyzed perioperative and oncological outcomes of EP (>70 y) compared to younger patients (YP) (<60 y). RESULTS: Of 500 CRS/HIPEC patients, 62 EP and 210 YP were included. Median age was 73 y in EP and 46 y in YP. Demographic, clinical, operative, and perioperative outcomes were similar between groups. American Society of Anesthesiologists > 3 was more prevalent in the EP with 88.2% versus 54.8% in the YP (P < 0.001). Comorbidities were higher in the EP with 87.1% versus 39.0% in the YP (P < 0.001). Peritoneal Cancer Index score was similar with a median of 9. All postoperative and severe complications were similar with 55.2% and 17.1% in the YP and 64.5% and 21.0% in the EP (P = 0.242; P = 0.448). Postoperative mortality was similar with 1.5% in the YP and 5.0% in the EP (P = 0.134). In colorectal primary patients, median overall and disease-free survival was 61.8 and 12.9 mo in the YP and 64.6 and 11.3 mo in the EP (P = 0.363; P = 0.845). CONCLUSIONS: Despite a significant age difference, increased comorbidities, worse American Society of Anesthesiologists, and similar Peritoneal Cancer Index burden, we found no significant differences in perioperative complications or oncological benefit in elderly CRS/HIPEC patients. EP appear to have similar perioperative and oncological outcomes as YP.

Perioperative and Oncological Outcomes of Combined Hepatectomy with Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Metastatic Colorectal Cancer.

BACKGROUND: Synchronous peritoneal and liver metastasis in colorectal cancer is a relative contraindication for curative surgery. We aimed to evaluate the safety and oncological outcomes of combined treatment of peritoneal and liver metastasis. METHODS: We conducted a retrospective analysis of metastatic colorectal cancer patients from two prospective databases: peritoneal surface malignancy (n = 536) and hepatobiliary (n = 286). We compared 60 patients treated with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) and hepatectomy; 80 patients treated with cytoreduction and HIPEC only; and 63 patients treated with hepatectomy alone. RESULTS: No differences in demographics were observed between the groups. Median hospital and intensive care unit (ICU) stay was shorter in group C (7 and 1 days, respectively) versus groups A and B (13 and 1 days, and 12 and 1 days, respectively; p < 0.001). Postoperative complications were not significantly different. Median follow-up was 18.6, 23.1, and 30.6 months for groups A, B, and C, respectively. Estimated 5-year overall survival (OS) was 48.8% (group A), 55.4% (group B), and 60.2% (group C) [p = 0.043 for group A vs. group C], and estimated 5-year disease-free survival (DFS) was 14.2% (group A), 23.0% (group B), and 18.6% (group C). Five-year OS was superior in group C compared with group A (p = 0.043), and DFS was superior in group C compared with groups A and B (p = 0.043 and 0.03, respectively). The peritoneum was the site of first recurrence in groups A and B (23.3% and 32.5%, respectively), and the liver was the site of first recurrence in group C (44.4%). CONCLUSIONS: We report favorable perioperative and oncological outcomes in combined cytoreduction/HIPEC and hepatectomy for patients with peritoneal and liver metastasis. Surgical intervention after multidisciplinary discussion should be considered in patients with both peritoneal and hepatic lesions when complete cytoreduction is feasible.

Ratio of Pathological Response to Preoperative Chemotherapy in Patients Undergoing Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Metastatic Colorectal Cancer Correlates with Survival.

BACKGROUND: Pathological response of colorectal peritoneal metastasis (CRPM) may affect prognosis. We investigated the relationship between oncological outcomes and pathological response to chemotherapy of CRPM following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: We conducted a retrospective analysis of a prospectively maintained Peritoneal Surface Malignancies database between 2015 and 2020. Analysis included patients with CRPM who underwent a CRS/HIPEC procedure (n = 178). The cohort was divided into three groups according to the response ratio (ratio of tumor-positive specimens to the total number of specimens resected): Group A, complete response; Group B, high response ratio, and Group C, low response ratio. RESULTS: The group demographics were similar, but the overall complication rate was higher in Group C (65.2%) compared with Groups A (55%) and B (42.8%) [p = 0.03]. Survival correlated to response ratio; the estimated median disease-free survival of Group C was 9.1 months (5.97-12.23), 14.9 months (4.72-25.08) for Group B, and was not reached in Group A (p = 0.001). The estimated median overall survival in Group C was 35 months (26.69-43.31), and was not reached in Groups A and B (p = 0.001). CONCLUSIONS: The pathological response ratio to systemic therapy correlates with survival in patients undergoing CRS/HIPEC. This study supports the utilization of preoperative therapy for better patient selection, with a potential impact on survival.

The location of premalignant colorectal polyps under age 50: a further rationale for screening sigmoidoscopy.

PURPOSE: The incidence of colorectal cancer (CRC) among young adults has been dramatically rising, with guidelines for screening recently adjusted to start at age 45. However, knowledge of the precursor lesions is limited. We recently reported that 83% of CRC diagnosed under age 50 are left sided. Our aim was to analyze the location and histology of benign colorectal lesions found in a cohort of patients younger than 50, documenting the presence of advanced histology. METHODS: We used the database in the Department of Pathology to retrospectively review the location and histology of all benign colorectal neoplasms in patients under age 50 submitted to pathology examination during 2006-2016. RESULTS: A total of 8364 lesions were examined from 4773 patients, and 3534 (65.5%) of the patients had only one polyp and the rest had multiple. Mean age was 41.9 years (range 16-49) while 3843 (72.8%) of the patients were between the ages of 40 and 49. In total, 4570/8364 lesions (54.6%) were distal to the splenic flexure. The most common pathology was tubular adenoma (63.7%), then hyperplastic polyps (16.6%), sessile serrated lesions (SSLs) (13.1%), and tubulovillous adenomas (6.3%). Tubulovillous adenomas, villous lesions, advanced adenomas, and adenomas with high-grade dysplasia were all predominantly left sided (left colon and rectum = 77.6%, 85%, 78.3%, and 87.6% respectively). Of the SSLs, 71.5% were in the right colon while 16.6% of hyperplastic lesions were right sided. CONCLUSIONS: High-risk advanced adenomas are predominantly left sided. This focuses attention on the rectum and left colon where carcinogenesis is strong in the young.

Pax6 regulates gene expression in the vertebrate lens through miR-204.

During development, tissue-specific transcription factors regulate both protein-coding and non-coding genes to control differentiation. Recent studies have established a dual role for the transcription factor Pax6 as both an activator and repressor of gene expression in the eye, central nervous system, and pancreas. However, the molecular mechanism underlying the inhibitory activity of Pax6 is not fully understood. Here, we reveal that Trpm3 and the intronic microRNA gene miR-204 are co-regulated by Pax6 during eye development. miR-204 is probably the best known microRNA to function as a negative modulator of gene expression during eye development in vertebrates. Analysis of genes altered in mouse Pax6 mutants during lens development revealed significant over-representation of miR-204 targets among the genes up-regulated in the Pax6 mutant lens. A number of new targets of miR-204 were revealed, among them Sox11, a member of the SoxC family of pro-neuronal transcription factors, and an important regulator of eye development. Expression of Trpm/miR-204 and a few of its targets are also Pax6-dependent in medaka fish eyes. Collectively, this study identifies a novel evolutionarily conserved mechanism by which Pax6 controls the down-regulation of multiple genes through direct up-regulation of miR-204.

Systematic identification of edited microRNAs in the human brain.

Adenosine-to-inosine (A-to-I) editing modifies RNA transcripts from their genomic blueprint. A prerequisite for this process is a double-stranded RNA (dsRNA) structure. Such dsRNAs are formed as part of the microRNA (miRNA) maturation process, and it is therefore expected that miRNAs are affected by A-to-I editing. Editing of miRNAs has the potential to add another layer of complexity to gene regulation pathways, especially if editing occurs within the miRNA-mRNA recognition site. Thus, it is of interest to study the extent of this phenomenon. Current reports in the literature disagree on its extent; while some reports claim that it may be widespread, others deem the reported events as rare. Utilizing a next-generation sequencing (NGS) approach supplemented by an extensive bioinformatic analysis, we were able to systematically identify A-to-I editing events in mature miRNAs derived from human brain tissues. Our algorithm successfully identified many of the known editing sites in mature miRNAs and revealed 17 novel human sites, 12 of which are in the recognition sites of the miRNAs. We confirmed most of the editing events using in vitro ADAR overexpression assays. The editing efficiency of most sites identified is very low. Similar results are obtained for publicly available data sets of mouse brain-regions tissues. Thus, we find that A-to-I editing does alter several miRNAs, but it is not widespread.

Species-specific microRNA regulation influences phenotypic variability: perspectives on species-specific microRNA regulation.

Phenotypic divergence among animal species may be due in part to species-specific (SS) regulation of gene expression by small, non-coding regulatory RNAs termed "microRNAs". This phenomenon can be modulated by several variables. First, microRNA genes vary by their level of conservation, many of them being SS, or unique to a particular evolutionary lineage. Second, microRNA expression levels vary spatially and temporally in different species. Lastly, while microRNAs bind the 3'UTR of target genes in order to silence their expression, the binding sites themselves are often non-conserved. The variability of the miRNA-target paradigm between different species is thus multifactorial, and this paradigm has only just started to gain attention from researchers in various fields. Here we present and discuss recent findings regarding the characteristics and implications of SS microRNA regulation.

Roles for Dicer1 in the patterning and differentiation of the optic cup neuroepithelium.

The embryonic ocular neuroepithilium generates a myriad of cell types, including the neuroretina, the pigmented epithelium, the ciliary and iris epithelia, and the iris smooth muscles. As in other regions of the developing nervous system, the generation of these various cell types requires a coordinated sequence of patterning, specification and differentiation events. We investigated the roles of microRNAs (miRNAs) in the development of optic cup (OC)-derived structures. We inactivated Dicer1, a key mediator of miRNA biosynthesis, within the OC in overlapping yet distinct spatiotemporal patterns. Ablation of Dicer1 in the inner layer of the OC resulted in patterning alteration, particularly at the most distal margins. Following loss of Dicer1, this region generated a cryptic population of cells with a mixed phenotype of neuronal and ciliary body (CB) progenitors. Notably, inactivation of Dicer1 in the retinal progenitors further resulted in abrogated neurogenesis, with prolongation of ganglion cell birth and arrested differentiation of other neuronal subtypes, including amacrine and photoreceptor cells. These alterations were accompanied by changes in the expression of Notch and Hedgehog signaling components, indicating the sensitivity of the pathways to miRNA activity. Moreover, this study revealed the requirement of miRNAs for morphogenesis of the iris and for the regulation of CB cell type proliferation and differentiation. Together, analysis of the three genetic models revealed novel, stage-dependent roles for miRNAs in the development of the ocular sub-organs, which are all essential for normal vision.

MicroRNA-34a is dispensable for p53 function as teratogenesis inducer.

The tumor suppressor protein p53 is a powerful regulator of the embryo's susceptibility to diverse teratogenic stimuli, functioning both as a teratogenesis inducer and suppressor. However, the targets that p53 engages to fulfill its functions remain largely undefined. We asked whether the microRNA (miRNA) miR-34 family, identified as one of the main targets of p53, mediates its function as a teratogenesis inducer. For this, pregnant ICR-, p53- and miR-34a-deficient mice, as well as rats, were exposed to 5-aza-2'-deoxycytidine (5-aza), a teratogen inducing limb reduction anomalies (LRA) of the hindlimbs in mice and either the hindlimbs or forelimbs in rats. Using hind- and forelimb buds of 5-aza-exposed embryos, we identified that the miR-34 family members are the most upregulated miRNAs in mouse and rat limb buds, with their increase level being significantly higher in limb buds destined for LRA. We showed that p53 mediates the 5-aza-induced miR-34 transcription followed by met proto-oncogene and growth-arrest-specific 1 target suppression in embryonic limb buds. We demonstrated that p53 regulates the teratogenic response to 5-aza acting as a teratogenesis inducer albeit miR-34a deletion does not affect the susceptibility of mice to 5-aza. Overall, our study thoroughly characterizes the expression and regulation of miR-34 family in teratogen-resistant and teratogen-sensitive embryonic structures and discusses the involvement of epigenetic miRNA-mediated pathway(s) in induced teratogenesis.

Pleomorphic dermal sarcoma of the scalp - A single-centre experience.

BACKGROUND: Pleomorphic dermal sarcoma (PDS) of the scalp is a rare tumour which is usually slow growing, but occasionally displays rapid growth and has a low rate of local recurrence. Surgical resection is the mainstay of treatment, with or without radiotherapy. The aim of this study is to describe the surgical approach and the additional benefit of radiotherapy to the treatment of these patients. METHODS: Retrospective, single-centre analysis of patients with PDS of the scalp that underwent surgical resection between 2007 and 2021 (n = 24). Treatment variables including depth of resection (superficial or deep to the galea aponeurotica) and adjuvant radiotherapy were investigated. RESULTS: Twenty-four patients were included in this study. Median age was 80 (range, 52-95), with a median ASA score of 3 (2-3). Sixteen (66.6 %) patients underwent surgical resection including the galea, while the rest (n = 8) did not or was not known. Radiotherapy was given in 7 (29 %) patients in which only 3 (12.5 %) were in the galeal resection group. Reasons for radiotherapy administration were concomitant SCC found at the same area of resection and close margins. In a median follow-up of was 26.2 months (range, 13.6-102.5) there was only one recurrence event. CONCLUSIONS: PDS of the scalp can be safely managed with a surgical resection if clear surgical margins are achieved without radiotherapy with good oncological outcomes.

International Expert Consensus on Defining Textbook Oncologic Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastasis.

BACKGROUND: Textbook oncologic outcome (TOO) is a composite metric shown to correlate with improved survival after curative intent oncologic procedures. Despite increasing use among disciplines in surgical oncology, no consensus exists for its definition in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). STUDY DESIGN: An international consensus-based study employed a Delphi methodology to achieve agreement. Fifty-four senior surgeons from the peritoneal surface malignancies field received a questionnaire comprising TOO parameters divided into 3 surgical domains: operative, short-term, and long-term postoperative outcomes. Two online meetings with participants defined the new criteria. Consensus was achieved when 75% of agreement rate was reached. Clinical data of patients who underwent CRS and HIPEC for colorectal peritoneal metastasis between 2010 and 2022 from 1 designated center (Sheba Medical Center) were collected, the consensus definition applied and outcomes analyzed. RESULTS: Thirty-eight surgeons (70%) participated. Expert consensus TOO parameters for colorectal peritoneal metastasis CRS and HIPEC included the absence of unplanned reoperations during 30 days postoperation, absence of severe postoperative complications (Clavien-Dindo ≥III), absence of unplanned readmissions during 30 days postoperation, 90-day postoperative mortality, and absence of contraindications for chemotherapy within 12 weeks from operation, and included the achievement of complete cytoreduction (CC0). The study cohort consisted of 251 patients, and 151 (60%) met TOO criteria. Patients who achieved TOO had significantly better overall survival (median 67.5 months, 95% CI) vs patients who did not achieve TOO (median 44.6 months, 95% CI, p < 0.001) and significantly improved disease-free survival (median, 12 months, 95% CI, vs 9 months, 95% CI, p = 0.01). CONCLUSIONS: Achievement of TOO as defined by consensus statement is associated with improved survival.

MicroRNA-382 expression is elevated in the olfactory neuroepithelium of schizophrenia patients.

Schizophrenia is a common neuropsychiatric disorder that has a strong genetic component. MicroRNAs (miRNAs) have been implicated in neurodevelopmental and psychiatric disorders including schizophrenia, as indicated by their dysregulation in post-mortem brain tissues and in peripheral blood of schizophrenia patients. The olfactory epithelium (OE) is one of the few accessible neural tissues that contain neurons and their stem cells. Previous studies showed that OE-derived tissues and cells can be safely and easily collected from live human subjects and may provide a "window" into neuronal processes involved in disorders such as schizophrenia, while avoiding the limitations of using postmortem brain samples or non-neuronal tissues. In this study, we found that the brain-enriched miR-382 (miR-382-5p) expression was elevated in in vitro cultured olfactory cells, in a cohort of seven schizophrenia patients compared with seven non-schizophrenic controls. MiR-382 elevation was further confirmed in laser-capture microdissected OE neuronal tissue (LCM-OE), enriched for mature olfactory neurons, in a cohort of 18 schizophrenia patients and 18 non-schizophrenic controls. In sharp contrast, miR-382 expression could not be detected in lymphoblastoid cell lines generated from schizophrenic or non-schizophrenic individuals. We further found that miR-382 directly regulates the expression of two genes, FGFR1 and SPRY4, which are downregulated in both the cultured olfactory cells and LCM-OE derived from schizophrenia patients. These genes are involved in the fibroblast growth factor (FGF) signaling pathway, while impairment of this pathway may underlie abnormal brain development and function associated with schizophrenia. Our data suggest that miR-382 elevation detected in patients' OE-derived samples might serve to strengthen current biomarker studies in schizophrenia. This study also illustrates the potential utility of OE-derived tissues and cells as surrogate samples for the brain.