Macroscopic Disease Research Articles

A review of robotic surgery in the management of recurrent ovarian carcinoma: indication and techniques

Background: Treatment of recurrent ovarian cancer may consist of salvage chemother-apy or secondary cytoreductive surgery. Retrospective studies suggest that radical secondary cytoreduction resulting in no macroscopic disease (R0) after completion of surgery benefits patients and prolongs survival. The role of robotic-assisted secondary cytoreductive surgery (RASCS) is in its infancy. The aim of this manuscript is to review the literature regarding the role, the indication, and the techniques of RASCS and to summarize the published perioperative, postoperative, and oncologic outcomes of RASCS. Methods: A comprehensive systemic review was conducted in the PubMed, MEDLINE, EMBASE, and Google Scholar databases from 1 January 1980 through 31 December 2021. Keywords searched were “ovarian cancer”, “recurrence”, “robotic-assisted secondary debulking/cytoreductive surgery”, “morbidity and mortality of secondary cytoreductive surgery”, “indications for secondary cytoreductive”, and combinations of these terms. Studies selected and analyzed included randomized controlled trials (RCTs) as well as prospective and retrospective anlayses and case series. RASCS procedures and techniques are described. Results: Several retrospectives, meta-analyses and prospective randomized trials suggest that optimal secondary cytoreductive surgery is associated with extended progression-free and overall survival. Preoperative selection criteria, such as Memorial Sloan Kettering (MSK) criteria and AGO (Arbeitsgemeinschaft Gynaekologische Onkologie) scores demonstrate that clinical-pathological factors can predict optimal secondary cytoreductive surgery and correlate with improved progression-free survival and overall survival. The surgical procedures that are required in secondary cytoreductive surgery can be complex. Limited retrospective studies have demonstrated that secondary cytoreductive surgery utilizing a robotic surgical platform can achieve the same rate of optimal cytoreductive surgery as open laparotomy with decreased morbidity. The effect of RASCS on progression-free and overall survival has not been established. Conclusions: Early literature reports indicate that RASCS, in selected patients, can be applied for surgical treatment of recurrent ovarian cancer without compromising morbidity; long-term studies are warranted to determine the effect on progression-free and overall survival.

DNA Methylation Profiles of Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10-4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P < 10-6). DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.

Including Surgical Resection in the Multimodal Management of Very Locally Advanced Sinonasal Cancer.

Sinonasal cancer often presents as locoregionally advanced disease. National guidelines recommend management of stage T4b tumors with systemic therapy and radiotherapy, but recent studies suggest that including surgical resection in the multimodal treatment of these tumors may improve local control and survival. We queried the National Cancer Database to examine patterns of care and outcomes in T4b sinonasal squamous cell carcinoma (SCC). Prospectively gathered data. National Cancer Database. Patients with T4b N0-3 M0 sinonasal squamous cell carcinoma diagnosed in 2004 to 2016 were stratified between those who received chemoradiotherapy and those who underwent surgical resection with neoadjuvant or adjuvant treatment. The overall survival of each cohort was assessed via Kaplan-Meier analysis and Cox proportional hazard models, with repeat analysis after reweighting of data via inverse probability of treatment weighting. Among 805 patients included in analysis, 2-year overall survival for patients undergoing surgical resection was 60.8% (95% CI, 56.1%-65.9%), while for patients undergoing chemoradiotherapy it was 46.7% (95% CI, 41.9%-52.0%). On Cox regression analysis, the inclusion of surgery in management was associated with improved survival in univariate analysis (hazard ratio [HR], 0.723 [95% CI, 0.606-0.862]; P < .001) and multivariate analysis (HR, 0.739 [95% CI, 0.618-0.885]; P = .001). Results with reweighted data were consistent in univariate analysis (HR, 0.765 [95% CI, 0.636-0.920]; P = .004]). Surgical treatment with neoadjuvant or adjuvant treatment for stage T4b sinonasal SCC was associated with promising survival outcomes, suggesting a role for incorporating surgery in treatment of select T4b SCC, particularly when removal of all macroscopic disease is feasible.

The impact of BMI on interval cytoreduction and survival for advanced ovarian cancer

To evaluate the survival impact of high body mass index (BMI) after interval cytoreduction for advanced epithelial ovarian cancer (EOC) and to assess the association among BMI, route of cytoreductive surgery, and rate of complete removal of macroscopic disease (R0 resection) in this cohort of patients.

Peritoneal metastases found in routinely resected specimens after cytoreductive surgery and heated intraperitoneal chemotherapy

IntroductionPeritoneal metastases (PM) originating from colorectal cancer (CRC) and pseudomyxoma peritonei (PMP) can be treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Certain sites in the peritoneal cavity are prone to contain PM and are, therefore, routinely resected. The aim of this study is to investigate the frequency of disease in CRS specimens routinely resected. Secondly, to investigate if the risk of finding PM in routinely resected specimen is associated with involvement of anatomic related peritoneal areas. Materials and methodsThis study investigated 433 patients diagnosed with PMP (n = 119) or PM from CRC (n = 314) and operated with CRS + HIPEC between June 2006 and November 2020 at a national center. Baseline data were prospectively registered. Pathology reports were reviewed for the presence of metastases in the routinely resected umbilicus, ligamentum teres hepatis, ovaries and greater omentum. Tumor extent was estimated using the Dutch region count. ResultsPM was found in 14.7% of umbilical resections, in 17.4% of the resected ligamentum teres hepatis, in 48.2% of the resected ovaries and in 49.5% of the greater omentum specimens. We found an association between macroscopic disease involvement of the nearest region and risk of PM found in the related resections. Seven of 31 women with no macroscopically visible disease in the pelvis had PM diagnosed in the resected ovaries. ConclusionsA substantial proportion of routine resections held histologic verified PM. Our results may advocate for a routinely performed resection of the umbilicus, ligamentum teres hepatis, ovaries and greater omentum.

Postoperative external beam radiotherapy for locoregional control in iodine refractory differentiated thyroid cancer.

BackgroundThe role of postoperative external beam radiotherapy (EBRT) in patients with residual iodine refractory-differentiated thyroid cancer (IR-DTC) is still inconclusive. The aim of this retrospective study was to evaluate locoregional control (LRC) and overall survival (OS), and potential side effects after postoperative EBRT for both microscopic and macroscopic non-radically resected, locally advanced IR-DTC.MethodsBetween 1990 and 2016, 49 patients with locally advanced IR-DTC received EBRT for microscopic (R1; n = 28) or macroscopic (R2; n = 21) locoregional residual disease. For more insight into the added effect of EBRT, we performed an intrapatient sub-analysis in 32 patients who had undergone more than 1 surgical intervention, comparing LRC after primary, curative-intended surgery with LRC after repeated surgery plus EBRT. To estimate LRC and OS, we used Kaplan–Meier curves. From 2007 onward, we prospectively recorded toxicity data in our head and neck cancer database (n = 10).ResultsLRC rates 5 years after EBRT were higher for R1 (84.3%) than for R2 (44.9%) residual disease (P = 0.016). The 5-year OS rate after EBRT was 72.1% for R1 and 33.1% for R2 disease (P = 0.003). In the intrapatient analysis (n = 32), LRC rates were 6.3% 5 years after only initial surgery and 77.9% after repeated surgery with EBRT (P < 0.001). Acute toxicity was limited to grade I and II xerostomia, mucositis, and hoarseness; only one patient developed late grade III dysphagia.ConclusionsPostoperative EBRT is associated with long-lasting LRC and OS with acceptable toxicity in patients with locally advanced IR-DTC, especially in microscopic residual disease.

The role of factor XIII in surgery for advanced stage of epithelial ovarian cancer.

Hereditary factor (F) XIII-deficiency is a known risk factor for postoperative complications, but data of acquired FXIII-deficiency in malignancies are limited. Therefore, we evaluated the role of acquired FXIII-deficiency in surgery for advanced epithelial ovarian cancer (EOC). We performed a retrospective analysis of patients with known serum FXIII status and treatment between 2011 and 2018 at our center. We defined cohorts according to FXIII with values > 75% as normal (group A), 55-75% as reduced (group B) and < 55% as low (group C). Complications were classified according to the Clavien-Dindo Classification, class III-V complications were defined as severe. 347 patients with EOC were identified. 180 patients (51.2%) were in group A, 82 patients (23.6%) in group B, and 85 patients (24.4%) in group C. Lower levels of FXIII were associated with higher amount of ascites, FIGO IV, high grade serous histology, low albumin, and higher CA-125 levels. Regarding intraoperative variables, low FXIII was associated with longer duration of surgery, higher blood loss, higher surgical complexity score/number of bowel anastomosis and a higher probability for macroscopic residual disease. The risk of severe complications in group A was 12.2%, 24.4% in group B, and 31.8% in group C. In a multivariate model, low FXIII (OR 2.8), > 1 bowel anastomosis (OR 2.7), age-adjusted Charlson comorbidity index ≥ 4 (OR 3.6) and a longer duration of surgery (> 285min.) were significant predictive factors for severe complications. FXIII is associated with tumor and treatment burden. A low level of FXIII is associated with postoperative complications. The knowledge about the presurgical serum FXIII-level might be helpful to plan the treatment strategy.

Extended Pleurectomy/Decortication for Malignant Pleural Mesothelioma: Humanitas's Experience.

Background: We analysed a series of malignant pleural mesothelioma (MPM) patients who consecutively underwent extended Pleurectomy/Decortication (eP/D) in a centre with a high level of thoracic surgery experience (IRCCS Humanitas Research Hospital) to explore postoperative morbidity and mortality, pattern of recurrence and survival. Methods: A retrospective analysis was performed on MPM patients underwent eP/D in our centre from 2010 to 2021. All patients were identified from our departmental database. Postoperative complications were scored according to Clavien–Dindo criteria. Survival analysis was performed by the Kaplan–Meier methods and Cox multivariable analysis. Results: Eighty-five patients underwent extended pleurectomy decortication (eP/D) during study period. Macroscopical residual disease (R2) was reported in one case. A neoadjuvant chemotherapy regiment was administrated in 88% of the surgical cohort. A complete trimodality treatment including induction with platinum agents and pemetrexed, radical cytoreductive surgery and volumetric modulated arc therapy technology (VMAT) could be administered in 63 patients (74%). Postoperative morbidity rate was 54.11%, major complications (defined as Clavien–Dindo ≥ 3) were reported in 11 patients (12.9%). Thirty-day mortality and 90-day mortality were, respectively, 2.35% and 3.53%. Median disease-free and overall survival were, respectively, 13.7 and 25.5 months. The occurrence of major complications (Clavien–Dindo ≥ 3), operative time, pT3–T4, pathological node involvement (pN+) were prognostic factors associated with worse survival. Conclusions: In our experience, eP/D is a well-tolerated procedure with acceptable mortality and morbidity, allowing for the administration of trimodality regimens in most patients. eP/D offered in a multimodality treatment setting have satisfactory long term oncological results. To obtain best oncological results the goal of surgery should be macroscopic complete resection in carefully selected patients (clinical N0).

Isolated Tumor Cells and Micrometastatic Nodal Disease in Breast Cancer Patients After Neoadjuvant Chemotherapy: Is Post Mastectomy Radiation Therapy Indicated?

<h3>Purpose/Objective(s)</h3> The prognostic and treatment implications of isolated tumor cells (ypN0i+) and micrometastatic (ypN1mi) nodal disease after neoadjuvant chemotherapy (NACT) is not well-studied. These patients are excluded from the ongoing NSABP B-51 trial which only includes patients with macroscopic nodal disease after NACT. We evaluate the long-term outcomes and the role of post-mastectomy radiation therapy (PMRT) in breast cancer patients with ypN0i+ and ypN1mi disease after NACT and mastectomy (MX). <h3>Materials/Methods</h3> Using the National Cancer Database (NCDB), we identified patients (≥ 18 year old) with breast cancer who were treated with NACT and MX diagnosed between 2004 and 2016. Patients with cT4 or metastatic disease were excluded. Chi-square testing was used to evaluate clinicopathological parameters of those treated with and without PMRT. Kaplan-Meier analysis was used to evaluate the effect of PMRT on overall survival (OS). Univariate and multivariate Cox proportional hazard models with and without inverse probability treatment weighting (IPTW) were used to identify prognostic factors associated with OS. <h3>Results</h3> Our final cohort consisted of 3,253 patients (34.0% ypN0i+, 66.0% ypN1mi) with a median age at diagnosis of 49 years (29 – 74 years). PMRT was utilized in 60.4% of the entire cohort, 51.8% of ypN0i+ patients and in 64.9% of ypN1mi patients. There was an increase in use of PMRT throughout the study period (56.2% in 2004-2011 vs. 61.9% in 2012-2016). With a median follow up of 36.8 months, the 5-year OS was 84.3% and 79.9% for ypN0i+ and ypN1mi patients, respectively (HR 1.23 [0.97-1.55], <i>P</i> = 0.092). Without accounting for covariates, there was no significant effect of PMRT on OS in ypN0i+ patients, ypN1mi patients, or in the entire cohort. In IPTW-MVA, PMRT had no significant effect on OS (HR 0.93 [0.74-1.18], <i>P</i> = 0.565]. Factors that were significant for worse OS on IPTW-MVA were higher comorbidity score, higher grade, hormone-receptor negative subtype, higher ypT stage, presence of lymphovascular invasion, Asian/Pacific Islander race, and more recent year of diagnosis. HER-2 positive subtype, receipt of hormone therapy, and private insurance were associated with improved OS. <h3>Conclusion</h3> Patients with ypN1mi disease had a trend towards worse OS in comparison to patients with ypN0i+ disease. The majority of patients with ypN0i+ and ypN1mi are receiving PMRT with higher rates of PMRT in ypN1mi vs. ypN0i+. PMRT rates are increasing with time. There is no association of PMRT with improved OS. Prospective randomized controlled data is needed to further evaluate the role of PMRT in these patients who were excluded from the ongoing NSABP B-51.

Total Colectomy as a Part of Ultra-Radical Surgery for Ovarian Cancer-Short- and Long-Term Outcomes.

(1) Background: The aim of this study was to assess the outcomes for patients who underwent total colectomy (TC) as a part of surgery for ovarian cancer (OC). (2) Methods: We performed a retrospective analysis of 1636 OC patients. Residual disease (RD) was reported using Sugarbaker’s completeness of cytoreduction score. (3) Results: Forty-two patients underwent TC during primary debulking surgery (PDS), and four and ten patients underwent TC during the interval debulking surgery (IDS) and secondary cytoreduction, respectively. The median overall survival (mOS) in OC patients following the PDS was 45.1 months in those with CC-0 (21%) resection, 11.1 months in those with CC-1 (45%) resection and 20.0 months in those with CC-2 (33%) resection (p = 0.28). Severe adverse events were reported in 18 patients (43%). In the IDS group, two patients survived more than 2 years after IDS and one patient died after 28.6 months. In the recurrent OC group, the mOS was 6.9 months. Patient age above 65 years was associated with a shortened overall survival (OS) and the presence of adverse events. (4) Conclusions: TC as a part of ultra-radical surgery for advanced OC results in high rates of optimal debulking. However, survival benefits were observed only in patients with no macroscopic disease.

Novel Technique of Pelvic Autonomic Nerve-Sparing with Near-Infrared Fluorescence Technology and ICG during Deep Endometriosis Surgery

<h3>Study Objective</h3> To describe the anatomical and technical highlights of a novel nerve-sparing surgery for deep endometriosis (DE) using near-infrared (NIR) fluorescence technology and indocyanine green (ICG). <h3>Design</h3> Stepwise demonstration of a technique. <h3>Setting</h3> An urban general hospital. ICG is a fluorescent dye that allows accurate, intraoperative, real-time assessment of tissue vascularization, once excited with light of a specific wavelength in the near-infrared spectrum. NIR fluorescence technology and ICG have been confirmed as feasible, safe, and useful tools to guide surgery in several settings, including colorectal and urologic surgeries. However, no reports have discussed pelvic autonomic nerve-sparing surgery using this tool in the gynecological field. <h3>Patients or Participants</h3> Stage IV endometriosis patients with parametrial involvement. <h3>Interventions</h3> An intravenous injection of 0.25mg/kg body weight of ICG for intraoperative NIR fluorescence imaging. Pelvic autonomic nerves were highlighted by ICG because these nerves are surrounded by many capillaries. <h3>Measurements and Main Results</h3> Evaluation of blood perfusion of DE nodules and achieving better visualization of anatomical relationship to the pelvic autonomic nerves. We could easily identify ischemic nodules which included DE and fibrosis under NIR fluorescence imaging, beyond the limits of macroscopic disease. Endometriosis or fibrosis was confirmed pathologically from all resected tissues, and resection margins of these tissues were negative for disease. These results suggest that this technique might be feasible for objectively identifying the border between DE lesions and healthy tissue. Furthermore, the hypogastric nerve and inferior hypogastric plexus were strongly highlighted by ICG and objectively preserved with assessment of perfusion. The patients developed no perioperative complications, including postoperative bladder or rectal dysfunction after surgery. <h3>Conclusion</h3> Application of ICG with NIR fluorescence appears potentially useful, not only to remove DE, but also to improve nerve-sparing. To our knowledge, this is the first reported use of ICG during pelvic autonomic nerve-sparing surgery for gynecologic disease.

Gastrointestinal: Autoimmune enteropathy associated with thymoma.

A 50-year-old gentleman presented with 4 months of chronic watery, non-bloody diarrhea up to 10 times a day, and weight loss. He had a history of a thymoma first diagnosed 7 years earlier, which was resected with positive histological margins. There was no macroscopic residual disease or vascular invasion. He did not receive any adjuvant treatment and developed recurrent Masaoka-Koga stage IVa thymoma with pleural, pericardial, and lung invasion requiring further treatment with resection, chemotherapy (3 cycles of cisplatin, doxorubicin, and cyclophosphamide), and radiotherapy (54 Gy in 30 fractions). There was no mediastinal lymph node involvement or evidence of distant hematogenous metastasis. Histopathology demonstrated multiple nodules of mixed WHO type B1 and B2, but predominantly type B1 thymoma. His diarrhea commenced after his thymoma recurrence. He did not have any features suggesting other autoimmune diseases associated with thymoma including myasthenia gravis. Physical examination and initial laboratory investigations were unremarkable. Stool cultures were negative for bacterial, viral, and parasitic infections. A computed tomography (CT) scan of the abdomen revealed wall thickening and fat stranding affecting the small intestine and colon (Fig. 1a). Correspondingly, mild patchy erythematous colitis in the rectum and sigmoid colon was seen on colonoscopy (Fig. 1b). Histologically, colonic biopsies showed active colitis with prominent regenerative changes. Goblet cells were noticeably absent, and there was prominent apoptosis, features typical of autoimmune enteropathy (Fig. 1c). Patient serum was incubated with frozen sections of normal small intestinal mucosa, showing strong staining by immunofluorescence for human IgA and IgG with a goblet cell distribution (Fig. 2). A diagnosis of thymoma-associated autoimmune enteropathy was made, and the patient was commenced on a weaning dose of prednisone starting at 25 mg daily leading to resolution of his symptoms. Thymomas are associated with concomitant autoimmune diseases in up to 30% of patients, possibly due to defective immune regulation. Differentials for thymoma-associated autoimmune conditions causing diarrhea include autoimmune enteropathy and Good's syndrome (thymoma-associated hypogammaglobulinemia). Thymoma-associated autoimmune enteropathy is rare with only five reported cases in the literature. Proposed diagnostic criteria include chronic diarrhea lasting over 6 weeks, malabsorption, and abnormal histology of the small bowel (villous blunting, deep crypt lymphocytosis, minimal intraepithelial lymphocytosis, and increased crypt apoptotic bodies). A spectrum of changes can be seen in the colon including increased mononuclear inflammatory infiltrate, active inflammation including neutrophilic cryptitis and microabscesses, intraepithelial lymphocytosis, and increased crypt epithelial apoptosis. Changes of chronicity including crypt architectural distortion and Paneth cell metaplasia have also been described. The presence of anti-enterocyte or anti-goblet antibodies is supportive, but the sensitivity and specificity of these markers are unknown. Steroids are the first-line management for autoimmune enteropathy; however, further immunosuppression (azathioprine, cyclosporin, tacrolimus, or infliximab) may be required in up to 90% of cases. For patients with thymoma-associated autoimmune enteropathy, resection of the thymoma may also improve symptoms.

RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

Background20–60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. Methods/designRAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART). Trial registrationISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017–002329-39, CTA #: 20363/0380/001–0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0.

Peripheral, Central, and Cross Sensitization in Endometriosis-Associated Pain and Comorbid Pain Syndromes.

Endometriosis-associated pain and the mechanisms responsible for its initiation and persistence are complex and difficult to treat. Endometriosis-associated pain is experienced as dysmenorrhea, cyclical pain related to organ function including dysuria, dyschezia and dyspareunia, and persistent pelvic pain. Pain symptomatology correlates poorly with the extent of macroscopic disease. In addition to the local effects of disease, endometriosis-associated pain develops as a product of peripheral sensitization, central sensitization and cross sensitization. Endometriosis-associated pain is further contributed to by comorbid pain conditions, such as bladder pain syndrome, irritable bowel syndrome, abdomino-pelvic myalgia and vulvodynia. This article will review endometriosis-associated pain, its mechanisms, and its comorbid pain syndromes with a view to aiding the clinician in navigating the literature and terminology of pain and pain syndromes. Limitations of our current understanding of endometriosis-associated pain will be acknowledged. Where possible, commonalities in pain mechanisms between endometriosis-associated pain and comorbid pain syndromes will be highlighted.

Gastric cancer with positive peritoneal cytology: survival benefit after induction chemotherapy and conversion to negative peritoneal cytology

BackgroundThe optimal treatment in patients with gastric cancer and peritoneal disease remains controversial. Some guidelines indicate palliative treatment only, while others consider surgical treatment in case of positive lavage cytology (CY+) or limited peritoneal disease. Here, we analyzed the role of peritoneal disease in patients with gastric cancer, and the prognostic relevance of response to neoadjuvant therapy.MethodsIn this retrospective cohort analysis, we analyzed patients with adenocarcinoma of the stomach or esophago-gastric junction from a single center operated between 2011 and 2019. According to histology and lavage cytology, patients were classified into four risk groups: (A) no peritoneal disease, (B) CY+ who converted to negative lavage cytology (CY−) after neoadjuvant chemotherapy, (C) CY+ without conversion after chemotherapy, and (D) patients with visible peritoneal metastasis.ResultsOverall, n = 172 patients were included. At initial presentation, n = 125 (73%) had no peritoneal disease, and about a third of patients (n = 47, 27%) had microscopic or macroscopic peritoneal disease. Among them, n = 14 (8%) were CY+ without visible peritoneal metastasis, n = 9 converted to CY− after chemotherapy, and in n = 5 no conversion was observed. Median overall survival was not reached in patients who had initially no peritoneal disease and in patients who converted after chemotherapy, resulting in 3-year survival rates of 65% and 53%. In contrast, median overall survival was reduced to 13 months (95% CI 8.7–16.7) in patients without conversion and was 16 months (95% CI 12–20.5) in patients with peritoneal metastasis without difference between the two groups (p = .364). The conversion rate from CY+ to CY− was significantly higher after neoadjuvant treatment with FLOT (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel) compared to ECF (epirubicin, cisplatin, and 5-fluorouracil) (p = 0.027).ConclusionConversion of CY+ to CY− after neoadjuvant chemotherapy with FLOT is a significant prognostic factor for a better overall survival. Surgical treatment in well-selected patients should therefore be considered. However, peritoneal recurrence remains frequent despite conversion, urging for a better local control.

Clinicopathological Characteristics and Prognostic Factors in Ovarian Metastases from Right- and Left-Sided Colorectal Cancer.

Background: Secondary tumors of the ovary (STOs) account for 10–25% of all ovarian malignancies, including metastases from primary gynecological tumors. Colorectal cancer (CRC) has been recognized as one of the most common causes of STOs in Western countries. Despite it being well-known that CRC originating from the right versus left side of the colon/rectum differ substantially, there is a paucity of information regarding the effect of the primary tumor sidedness on the clinicopathological characteristics of STOs. Methods: This retrospective, observational chart review study included patients with histologically confirmed STOs of CRC origin diagnosed between January 2000 and December 2019. The clinicopathological characteristics of STOs originating from left-sided and right-sided CRC were compared. Univariable and multivariable analyses employing elastic net Cox proportional hazard models were used to evaluate potential prognostic factors. Further, the role of imaging methods in STOs diagnostics was evaluated. Results: Fifty-one patients with STOs of colorectal origin were identified. The primary tumor originated in the right and left colon/rectum in 39% and 61% of the cases, respectively. STOs originating from right-sided primary tumors were more frequently bilateral, associated with peritoneal carcinomatosis, had the ovarian surface affected by the tumor, and contained a mucinous component. The independent prognostic factors for overall survival in the whole cohort included: the presence of macroscopic residual disease after cytoreductive surgery, menopausal status, the application of systemic therapy, and the application of targeted therapy. In 54% of cases, the imaging methods failed to determine the laterality of the STOs correctly as compared to pathological reports and/or intraoperative findings. Conclusion: STOs originating from left-sided and right-sided CRC show distinct clinicopathological characteristics. Moreover, different metastatic pathways might be employed according to the primary tumor sidedness. Considering the discrepancies between radiological assessment and histopathological findings regarding the laterality of STOs, bilateral adnexectomy should be advised whenever feasible.

Impact of delay in adjuvant chemotherapy administration for patients with advanced-stage epithelial ovarian carcinoma undergoing primary debulking surgery with bowel resection

<h3>Objectives:</h3> Patients with epithelial ovarian carcinoma (EOC) undergoing primary debulking surgery (PDS) with small or large bowel resection have a higher risk of postoperative complications that could delay administration of adjuvant chemotherapy. The aim of the present study was to evaluate the impact of chemotherapy delay in the survival of patients with EOC undergoing bowel resection using a hospital-based database. <h3>Methods:</h3> The National Cancer Database (NCDB) was accessed and patients diagnosed between 2004-2015 with stage III-IV EOC without a history of another tumor who underwent PDS that included small or large bowel resection with known surgery-chemotherapy interval and at least one month of follow-up were identified. Overall survival (OS) was compared between patients who received multi-agent chemotherapy 2-6 week (group 1), 7-9 weeks (group 2) and 10-12 weeks (group 3) from surgery with the log-rank test. A Cox multivariate model was constructed to control for confounders. Impact of chemotherapy delay was also evaluated among patients who achieved complete gross resection (CGR) and those who had macroscopic disease. <h3>Results:</h3> A total of 9274 patients who met the inclusion criteria were identified; 69.8% received adjuvant chemotherapy 2-6 weeks from surgery while 24.5% and 5.7% received chemotherapy 7-9 weeks and 10-12 weeks respectively. Patients in group 2 (30.2%) and 3 (36.6%) were more likely to experience a prolonged hospital stay (>10 days) following PDS compared to those in group 1 (19.4%), p<0.001. Rates of unplanned re-admission within 30-days from surgery in group 1,2 and 3 were 7.7%, 9.2% and 11.3% respectively, p=0.002. Median OS for patients in group 1 was 44.78 months compared to 42.25 and 39.89 for those in groups 2 and 3 respectively, p=0.103. After controlling for patient age, race, presence of comorbidities insurance, tumor histology and stage, compared to patients in group 1 those in group 2 (HR: 1.04, 95% CI: 0.98, 1.10) and group 3 (HR 1.05, 95% CI: 0.94, 1.17) did not have worse survival. Status of residual disease was available for 3659 patients; 46% achieved CGR. For patients with CGR, median OS for those in group 1 and 2 was 55.46 and 52.70 months compared to 42.18 for those in group 3, p=0.015. After controlling for aforementioned variables those in group 3 had worse survival (HR: 1.37, 95% CI: 1.04, 1.82) compared to patients in group 1 while there was no difference in survival between group 2 and 1 (HR: 1.06, 95% CI: 0.90, 1.27). For patients with macroscopic residual disease, timing of chemotherapy administration was not associated with survival; median OS for patients in group 1, 2 and 3 was 41.3, 42.74 and 41.13 months respectively, p=0.82. <h3>Conclusions:</h3> For patients with advanced stage EOC undergoing PDS with bowel resection extreme delay in adjuvant chemotherapy administration over 10 weeks from surgery may be associated with a negative impact on the survival of those who achieve CGR.

The prevalence of intra-tumoral and distant thrombi, as well as tumour-cell emboli in canine neoplasia.

Macroscopic thromboembolic disease has been associated with canine neoplasia, whereas prevalence studies of concurrent microthrombi and tumour-cell emboli are lacking. This retrospective study investigated microthrombi and tumour cell emboli by reviewing pathology records of dogs diagnosed with lymphoma, sarcoma, carcinoma and mast cell tumours with a concurrent description of thrombi or emboli. Pathology reports and medical records of cases with either tumour biopsies and/or post mortems with a diagnosis of neoplasia were reviewed for the presence of microthrombi, macrothrombi and/or tumour-cell emboli and the association with tumour type. Of the 28 895 canine cases in the database, 21 252 (73.5%) were antemortem biopsy specimens and 7643 were post mortems (26.5%); 2274 solid tumours were identified, 2107 (92.7%) were antemortem biopsy diagnoses and 167 (7.3%) were post mortem diagnoses. The prevalence of solid tumour types in the database (28 895 cases) was 872 (3.0%) lymphoma, 722 (2.5%) sarcoma, 455 (1.6%) carcinoma and 225 (0.8%) mast cell tumour. The prevalence of microthrombi associated with these tumours was 58/2274 (2.6%). Intra-tumoral microthrombi were reported in 53/2274 (2.3%) cases, the majority in sarcomas (37/53, 69.8%). No macrothrombi were reported. Tumour-cell emboli were identified in 39/2274 (1.7%) cases, 31/39 (79.5%) were extra-tumoral or distant emboli, and carcinoma the most commonly associated tumour (29/39; 74.4%). Microthrombi were reported in 2.6% of cases, the majority in sarcomas and tumour-cell emboli were identified in 1.7% of cases, the majority carcinomas. Prospective investigations are necessary to explore the potential clinical and prognostic implications of microthrombi and tumour-cell emboli in canine neoplasia.

Salvage surgery for patients with residual/persistent diseases after improper or insufficient treatment of oral squamous cell carcinoma: can we rectify these mistakes?

BackgroundPatterns of failure after treatment of oral and squamous cell carcinomas (OSCC) are diversified, with recurrences being one of the common causes. A special group of patients are sometimes encountered in the outpatient clinic for improper or insufficient initial treatment with reports of positive margins, implying residual/persistent diseases. The question of whether these patients can be surgically salvaged remain unanswered.MethodsA retrospective study was performed between January 2013 and December 2017 for patients with residual or rapid recurrent (within 3 months) OSCCs, who received salvage surgeries in our institution. The patients with residual/persistent OSCCs were those with microscopic or macroscopic positive surgical margins, while those with rapid recurrent OSCCs were those with close or negative margins, but unabated painful symptoms right after treatment. Both clinicopathological and prognostic variables were analyzed. The focus was also directed towards lessons for possible initial mistakes, resulting in these residual/persistent diseases.ResultsOf 103 patients, 68 (66%) were men, with mean age of 56.3 years. The overall survival reached 60.2%. Regarding the primary OSCC status, most of our patients (n = 75, 72.8%) were diagnosed with ycT2–3 stages. Besides, most patients were found with macroscopic residual diseases (52.4%) before our salvage surgery. The sizes of the residual/persistent OSCCs were generally under 4 cm (87.3%) with minimally residual in 21 (20.4%). Among all the variables, primary T stage (p = 0.003), and residual lesion size (p < 0.001) were significantly associated with the prognosis in multivariate analysis. Though the causes for the initial surgical failure were multifactorial, most were stemmed from poor planning and unstandardized execution.ConclusionsCases with residual/persistent OSCCs were mostly due to mistakes which could have been avoided under well-round treatment plans and careful surgical practice. Salvage surgery for cases with smaller residual/persistent OSCCs is still feasible with acceptable outcomes.

Musculoskeletal manifestations of neurofibromatosis type1 (von Recklinghausen's disease) and tuberous sclerosis (Bourneville's disease)

Neurofibromatosis type1 (NF1) and tuberous sclerosis (TS) are among the most common genetic diseases. Bone and soft tissue manifestations are common disease manifestations. The standard radiological procedure is magnetic resonance imaging (MRI). All macroscopic disease manifestations can be diagnosed radiologically and observed during the course. Specific complications such as plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST) in NF1 are readily visible on MRI. Differentiation of plexiform neurofibromas and MPNST is uncertain and requires follow-up. MRI is the most important procedure for the investigation of soft tissue and bone manifestations of NF1 and TS.