Recommendations for the optimal management of peritoneal metastases in patients with colorectal cancer: a TTD and GECOP-SEOQ expert consensus statement

Peritoneal metastases (PM) occur when cancer cells spread inside the abdominal cavity and entail an advanced stage of colorectal cancer (CRC). Prognosis, which is poor, correlates highly with tumour burden, as measured by the peritoneal cancer index (PCI). Cytoreductive surgery (CRS) in specialized centres should be offered especially to patients with a low to moderate PCI when complete resection is expected. The presence of resectable metastatic disease in other organs is not a contraindication in well-selected patients. Although several retrospective and small prospective studies have suggested a survival benefit of adding hyperthermic intraperitoneal chemotherapy (HIPEC) to CRS, the recently published phase III studies PRODIGE-7 in CRC patients with PM, and COLOPEC and PROPHYLOCHIP in resected CRC with high-risk of PM, failed to show any survival advantage of this strategy using oxaliplatin in a 30-min perfusion. Final results from ongoing randomized phase III trials testing CRS plus HIPEC based on mitomycin C (MMC) are awaited with interest. In this article, a group of experts selected by the Spanish Group for the Treatment of Digestive Tumours (TTD) and the Spanish Group of Peritoneal Oncologic Surgery (GECOP), which is part of the Spanish Society of Surgical Oncology (SEOQ), reviewed the role of HIPEC plus CRS in CRC patients with PM. As a result, a series of recommendations to optimize the management of these patients is proposed (AU)

Single-cell RNA sequencing reveals the lineage of malignant epithelial cells and upregulation of TAGLN2 promotes peritoneal metastasis in gastric cancer

Background Peritoneal metastasis (PM) is an important factor contributing to poor prognosis in patients with gastric cancer (GC). Transcriptomic sequencing has been used to explore the molecular changes in metastatic cancers, but comparing the bulk RNA-sequencing data between primary tumors and metastases in PM studies is unreasonable due to the small proportion of tumor cells in PM tissues. Methods We performed single-cell RNA-sequencing analysis on four gastric adenocarcinoma specimens, including one primary tumor sample (PT), one adjacent nontumoral sample (PN), one peritoneal metastatic sample (MT) and one normal peritoneum sample (MN), from the same patient. Pseudotime trajectory analysis was used to display the process by which nonmalignant epithelial cells transform into tumor cells and then metastasize to the peritoneum. Finally, in vitro and in vivo assays were used to validate one of the selected genes that promote peritoneal metastasis. Results Single-cell RNA sequencing showed that a development curve was found from normal mucosa to tumor tissues and then into metastatic sites on peritoneum. TAGLN2 was found to trigger this metastasis process. The migration and invasion capability of GC cells were changed by downregulating and upregulating TAGLN2 expression. Mechanistically, TAGLN2 might modulate tumor metastasis via alterations in cell morphology and several signaling pathways, thus promoting epithelial–mesenchymal transition (EMT). Conclusions In summary, we identified and validated TAGLN2 as a novel gene involved in GC peritoneal metastasis. This study provided valuable insight into the mechanisms of GC metastasis and developed a potential therapeutic target to prevent GC cell dissemination (AU)

Morbimortality after 1321 consecutive CRS+HIPEC procedures: seeking excellence in surgery for peritoneal surface malignancy

Purpose Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) treatment has classically presented a percentage of associated complications that have limited its expansion. The aim of this study is to describe the morbimortality results obtained from a referral center implemented with the support of a governmental health agency and directed by a surgical team experienced in CRS for Peritoneal Surface Malignancies (PSM). Methods Data from the Peritoneal Carcinomatosis Program of Catalonia (PCPC) prospective database, including patients who underwent CRS + HIPEC between September 2006 and January 2021, were analyzed. Results A total of 1151 consecutive patients underwent 1321 CRS + HIPEC procedures. Colonic origin of peritoneal metastasis was the most frequent (47.3%). Median PCI was 7 and most patients had CC0-1 (96.1%). Multivisceral resection was performed in 44% of all patients, 57% required digestive anastomosis. Median hospital stay was 11 days (range 6–144 days). High-grade complications occurred in 20% of all patient, most of them surgical complications. Anastomotic leak occurred in 0.6% of all cases. The overall in-stay and 30-day mortality rate was 0.4%. The low-rate of complications and the high rate of complete CRS were achieved from the beginning of the PCPC. Median overall survival was 54.7 months, with a 5-year survival rate of 47.5%. Conclusions Implementation of a CRS + HIPEC referral program for the treatment of PSM with preferably an experienced surgical team enables acceptable rates of severe morbidity (20%) and mortality (< 1%) (AU)

Mesotelioma papilar bien diferenciado: descripción de tres casos y revisión bibliográfica / Well differentiated papillary mesothelioma: description of three case reports and review of the literature

El mesotelioma papilar bien diferenciado (MPBD) es una neoplasia muy infrecuente que afecta fundamentalmente a mujeres en edad reproductiva. La localización más habitual es el peritoneo y se trata de un hallazgo incidental, con un pronóstico generalmente favorable. Presentamos tres casos diagnosticados de manera incidental, en el trascurso de una intervención quirúrgica de causas diversas, que se presentaron como lesiones exofíticas peritoneales no detectadas en el estudio de imagen prequirúrgico. Es importante tener presente esta entidad para diferenciarla de otras neoplasias de pronóstico y evolución desfavorable, como el mesotelioma maligno o carcinomas primarios y metastásicos. Estudios recientes le confieren al MPBD un perfil inmunohistoquímico y molecular específico que permiten una mayor precisión diagnóstica de la entidad.(AU)

Well Differentiated Papillary Mesothelioma (MPBD) is a very rare neoplasm that mainly affects women of reproductive age. The most common location is the peritoneum and it is an incidental finding, with a generally favorable prognosis. We present three cases diagnosed incidentally, in the course of a surgical intervention of various causes, which presented as peritoneal exophytic lesions not detected in the pre-surgical imaging study. It is important to keep this entity in mind, to differentiate it from other neoplasms with an unfavorable prognosis and evolution, such as Malignant Mesothelioma or primary and metastatic carcinomas. Recent studies give the MPBD a specific immunohistochemical and molecular profile that allow a greater diagnostic precision of the entity.(AU)

Carcinomatosis peritoneal tras nefrectomía parcial laparoscópica en carcinoma de células renales: nuestra experiencia y revisión de la literatura / Peritoneal carcinomatosis after partial nephrectomy for renal cell carcinoma: Our experience and literature review

Objetivo: La carcinomatosis peritoneal asociada al carcinoma de células renales es una entidad infrecuente, normalmente asociada a grandes masas renales, siendo muy rara su presentación tras la cirugía de tumores renales localizados. Nuestro objetivo es revisar la literatura y analizar los factores implicados en el desarrollo de carcinomatosis peritoneal tras nefrectomía parcial laparoscópica en tumores localizados.Material y métodos: Presentamos nuestra experiencia con 2 casos de carcinomatosis peritoneal tras cirugía parcial laparoscópica. Realizamos revisión de la literatura y analizamos los factores asociados al desarrollo de carcinomatosis peritoneal tras cirugía parcial laparoscópica en carcinoma de células renales.Resultados: Entre 2005-2018 en nuestro servicio fueron sometidos a nefrectomía parcial laparoscópica 225 pacientes por neoplasia renal localizada. Dos pacientes desarrollaron carcinomatosis peritoneal en el seguimiento, uno al año y medio de la cirugía y un segundo caso a los 7 años. Pocos casos de carcinomatosis peritoneal tras cirugías de neoplasia renal han sido descritos en la literatura, estando más frecuentemente asociados a grandes masas renales, con múltiples metástasis al diagnóstico, siendo el pronóstico infausto. Entre los factores implicados en su desarrollo pueden estar la diseminación de células tumorales durante la cirugía, la extensión tumoral directa o la metástasis por vía hematógena.Conclusiones: La carcinomatosis peritoneal tras nefrectomía parcial laparoscópica constituye un evento muy raro, pero que debe ser tenido en cuenta y, dado que es el único factor en el que podemos influir, extremar al máximo las precauciones durante el acto quirúrgico, siguiendo los principios oncológicos. (AU)

Objective: Peritoneal carcinomatosis associated with renal cell carcinoma is an infrequent entity, usually associated with large renal masses, and with a very rare presentation after surgery of localized renal tumors. Our objective is to review the literature and analyze the factors involved in the development of peritoneal carcinomatosis after laparoscopic partial nephrectomy in localized tumors.Material and methods: We present our experience with two cases of peritoneal carcinomatosis after laparoscopic partial nephrectomy. We reviewed the literature and analyzed the factors associated with the development of peritoneal carcinomatosis after laparoscopic partial surgery in renal cell carcinoma.Results: Between 2005-2018, 225 patients underwent laparoscopic partial nephrectomy for localized renal neoplasia in our service. Two patients developed peritoneal carcinomatosis during follow-up, at 1.5 and 7 years after surgery. Few cases of postoperative peritoneal carcinomatosis for renal neoplasia have been described in the literature, being more frequently associated with large renal masses, with multiple metastases at diagnosis, with a poor prognosis. The dissemination of tumor cells during surgery, direct tumor extension or metastasis by hematogenous route, are among the factors involved in the development of this condition.Conclusions: Peritoneal carcinomatosis after laparoscopic partial nephrectomy constitutes a very rare event. However, it should be taken into consideration, and, since it is the only factor we can influence, we must maximize precautions during the surgical act, following oncological principles. (AU)

Interval cytoredutive surgery and HIPEC in advanced ovarian cancer with small-bowel disease: results and reflections

Introduction: Small-bowel involvement in patients with ovarian cancer has been strongly correlated with the possibility of cytoreduction and thus with survival. The main objective of this study was to evaluate the prognostic significance of small-bowel involvement in patients undergoing optimal-complete interval cytoreductive surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).Methods: We included a series of patients diagnosed with stage IIIC-IVA (pleural effusion) high-grade serous epithelial ovarian cancer and in whom CRS + HIPEC was indicated after neoadjuvant systemic chemotherapy (NACT). The study period extended from January 2008 to January 2020, with a minimum follow-up of 12 months from the inclusion of the last patient. A multivariate analysis using Cox regression allowed us to identify the variables that were independently related to disease-free survival.Results: A total of 144 patients were selected, 13 (9%) of whom were excluded from the analysis, because their disease was considered unresectable. The study included a series of 131 patients with a median age of 62 years (34-79 years) and a median Peritoneal Cancer Index (PCI) calculated during surgery of 9 (1-35). The median PCI of bowel areas 9-12 (SB-PCI) was 3 (1-10). Performance of a CC-1 cytoreduction (HR: 1.93, 95% CI: 1.02-3.64, p = 0.042) and SB-PCI greater than 3 (HR: 2.25, 95%CI: 1.13-4.48, p = 0.21) were independent factors associated with shorter disease-free survival.Conclusion: Small-bowel involvement, even in patients with a macroscopically complete resection, showed a correlation with worse prognostic outcomes and could be considered as a variable in the postoperative management of these patients. (AU)

Extended intraoperative peritoneal lavage as prophylactic peritoneal recurrence for locally advanced gastric cancer: a prospective randomized trial

Background To demonstrate whether extensive intraoperative peritoneal lavage (EIPL) could yield better results in overall survival and less recurrence, regardless of peritoneal cytology, compared to standard peritoneal lavage (SPL). Methods A prospective randomised multicenter study including 94 patients (47 per arm) to detect a 20% difference in 3-year overall survival in patients with locally advanced tumours without peritoneal carcinomatosis. Three samples of peritoneal fluid were obtained (at the beginning, the end of procedure and after the assigned peritoneal lavage). Clinicopathological and surgical data were analysed by group. Postoperative complications, location of recurrence and surgical approach were evaluated. Overall survival was calculated by the Kaplan–Meier method and the uni/multivariate analysis for prognostic factors was carried out using Cox regression analysis. Results A total of 86 patients were analysed (4 excluded per group). No statistical differences were observed in clinicopathological or surgical data between groups, considering both groups well-balanced for analysis. Overall survival at 3 years was 64.3% for SPL vs. 62.3% for EIPL (p 0.421). Only three patients had at least one positive peritoneal cytology (1:2). There were no differences regarding postoperative complications (SPL: 37.2% vs. EIPL: 32.5%, p 0.65) or between location of recurrence and number of recurrences. The number of recurrences did not differ between surgical approaches, but locoregional and peritoneal recurrences were fewer with the laparoscopic approach (p 0.048). Conclusions The regular use of extensive peritoneal lavage in patients with locally advanced gastric cancer, regardless of peritoneal cytology, has not been effective as prophylaxis of peritoneal recurrence or better survival (AU)

10 ns PEFs induce a histological response linked to cell death and cytotoxic T-lymphocytes in an immunocompetent mouse model of peritoneal metastasis

Purpose The application of nanosecond pulsed electric fields (nsPEFs) could be an effective therapeutic strategy for peritoneal metastasis (PM) from colorectal cancer (CRC). The aim of this study was to evaluate in vitro the sensitivity of CT-26 CRC cells to nsPEFs in combination with chemotherapeutic agents, and to observe the subsequent in vivo histologic response. Methods In vitro cellular assays were performed to assess the effects of exposure to 1, 10, 100, 500 and 1000 10 ns pulses in a cuvette or bi-electrode system at 10 and 200 Hz. nsPEF treatment was applied alone or in combination with oxaliplatin and mitomycin. Cell death was detected by flow cytometry, and permeabilization and intracellular calcium levels by fluorescent confocal microscopy after treatment. A mouse model of PM was used to investigate the effects of in vivo exposure to pulses delivered using a bi-electrode system; morphological changes in mitochondria were assessed by electron microscopy. Fibrosis was measured by multiphoton microscopy, while the histological response (HR; hematoxylin–eosin–safran stain), proliferation (KI67, DAPI), and expression of immunological factors (CD3, CD4, CD8) were evaluated by classic histology. Results 10 ns PEFs exerted a dose-dependent effect on CT-26 cells in vitro and in vivo, by inducing cell death and altering mitochondrial morphology after plasma membrane permeabilization. In vivo results indicated a specific CD8+ T cell immune response, together with a strong HR according to the Peritoneal Regression Grading Score (PRGS). Conclusions The effects of nsPEFs on CT-26 were confirmed in a mouse model of CRC with PM (AU)

Experiencia inicial del tratamiento de la carcinomatosis peritoneal irresecable con PIPAC / Initial Single-center Experience of PIPAC in Patients With Unresectable Peritoneal Metastasis

Introducción: La carcinomatosis peritoneal se asocia a un mal pronóstico y las opciones terapéuticas son limitadas. El desarrollo de la quimioterapia intraperitoneal presurizada en aerosol (PIPAC) ofrece una alternativa de tratamiento paliativo para estos pacientes con una baja tasa de morbimortalidad. Nuestro objetivo es evaluar la implantación y la experiencia inicial de PIPAC para el tratamiento de la carcinomatosis peritoneal irresecable en nuestro centro. Material y métodos: Realizamos un estudio prospectivo incluyendo todos los pacientes a los que se les realizó PIPAC entre enero de 2019 y febrero de 2020 en nuestro hospital. Se recogieron: el origen del tumor primario, el volumen de ascitis, la extensión de la carcinomatosis peritoneal, el régimen de quimioterapia aplicada, el tiempo quirúrgico, las complicaciones postoperatorias, la estancia hospitalaria y la mortalidad. Resultados: Analizamos 9 PIPAC realizadas en 5pacientes con carcinomatosis peritoneal de origen gástrico, ovárico y neoplasia mucinosa apendicular. La tasa de acceso a la cavidad peritoneal fue del 100%. El PCI medio fue 27,6 (24-35). El tiempo quirúrgico medio fue de 93min (70-125). En nuestra serie solo hubo una complicación Clavien-DindoII (1/9 procedimientos). La estancia hospitalaria media fue de 2días (1-4). La mortalidad fue del 0%. Conclusión: La implantación de PIPAC en nuestro centro se ha llevado a cabo con seguridad, pudiendo afirmar que es una técnica reproducible y con una baja tasa de morbimortalidad en nuestra experiencia inicial. (AU)

Introduction: Peritoneal carcinomatosis remains a condition with poor prognosis and limited therapeutic options. Pressurized Intrapertioneal Aerosol Chemotherapy (PIPAC) has been developed as a new tool for delivering intraperitoneal chemotherapy with low morbidity. The aim of this study was to evaluate the initial experience of PIPAC in patients with peritoneal carcinomatosis at our hospital. Methods: A prospective study between January 2019 and February 2020 was carried at a tertiary public hospital. Primary tumor, ascites volume, PCI, chemotherapy regimen, operative time, morbidity, length of hospital stay and mortality were recorded for analysis. Results: We analyzed 9 PIPAC procedures performed in 5patients. Median PCI was 27.6 (24-35). Median surgical time was 93minutes (70-125). Only one adverse event occurred out of 9 procedures (Clavien-DindoII). Median length of hospital stay was 2days (1-4). Mortality was 0%. Conclusion: PIPAC seems to be a feasible and safe procedure to treat peritoneal carcinomatosis, with low morbidity and short hospital stay. (AU)

Fundamentos de mejora de la calidad de vida en citorreducción quirúrgica por carcinomatosis peritoneal / Principles on quality of life improvement in cytoreductive surgery for peritoneal carcinomatosis

Introducción. El abordaje multidisciplinar de la carcinomatosis peritoneal ha permitido un aumento relevante de la supervivencia con una morbimortalidad aceptable. Sin embargo, se dispone de muy poca información sobre el impacto del tratamiento en la calidad de vida de estos pacientes. Una valoración detallada de la calidad de vida perioperatoria debería ser un instrumento de gran valor para conocer sus expectativas y promover estrategias de mejora. Pacientes y método. Estudio retrospectivo de 79 pacientescon indicación de citorreducción quirúrgica entre 2007 y 2019 a los que se realizó un cuestionario adaptado sobre calidad de vida, según el modelo EORTC QLQ-C30 (versión 3.0), al diagnóstico y a los seis meses de finalizar el tratamiento. Se han considerado factores epidemiológicos y clinicoquirúrgicos para determinar su influencia en la valoración realizada. Resultados. La puntuaciónmedia del QLQ-C30 fue de 52.8±6.1 al diagnóstico con influencia notable de la sintomatología tumoral y 64.6±6.3 postratamiento a costa de una limitación funcional y pobre percepción de salud. Un perfil de paciente mujer menor de 65 años es más susceptible de puntuaciones más altas. El estado nutricional parece afectar a la percepción de calidad de vida (p=0.004). El grado de citorreducción (p=0.048) y la influencia de complicaciones postoperatorias mayores (p=0.041) también podrían contribuir en la opinión del paciente. Conclusiones. La escala EORTC QLQ-C30 nos aproxima a la percepción subjetiva del paciente intervenido por carcinomatosis peritoneal pero carece de una estandarización, quizás por influencia de factores socioculturales propios del área geográfica donde se desarrolla la enfermedad. (AU)

Background. Peritoneal carcinomatosis muldisciplinar approach has allowed an outstanding increase in survival with acceptable morbidity and mortality. Nonetheless, there is very little available information on the quality of life treatment impact for these patients. A perioperative quality of life detailed assessment should be a valuable instrument to know their expectations and promote improvement strategies. Patients and method. Retrospective study of 79 patients with an indication for cytoreductive surgery between 2007 and 2019 who filled out an adapted quality of life questionnaire, according to the EORTC QLQ-C30 (version 3.0), at diagnosis and six months post-treatment. Epidemiological, clinical and surgical factors have been taken into account on the assessment performed. Results. QLQ-C30 mean score was 52.8±6.1 at diagnosis with a remarkable influence of tumour symptoms and 64.6±6.3 after treatment at the expense of functional limitation and poor perception of health. Female-patient profile under 65 years of age is more susceptible to higher scores. Nutritional status seems to affect to the quality of life perception (p=0.004). Cytoreduction degree (p=0.048) in association with major postoperative complications (p=0.041) could also influence patient’s opinion. Conclusions. EORTC QLQ-C30 is bringing closer to patient subjective perception operated on peritoneal carcinomatosis, although lacking standard model, maybe due to the influence of sociocultural factors in the geographic area where the disease is happening. Association existing between survival and best possible quality of life, together with influence of these new variables, could explain their inclusion in this type of questionnaires during cancer treatment assessment and provide strategies for following actions. (AU)

Rendimiento de los marcadores tumorales séricos en la recaída peritoneal por cáncer colorrectal / Serum tumor markers efficiency for colorectal cancer peritoneal relapse

El cáncer colorrectal es una de las formas más habituales de neoplasia a nivel mundial y el peritoneo representa su tercera localización metastásica más frecuente. La resección quirúrgica continua siendo la primera opción de tratamiento curativo en asociación con una terapia citostática. El antígeno carcinoembrionario (CEA) representa el marcador sérico más estudiado en el cáncer colorrectal. En los últimos años, se ha sumado el análisis de otros biomarcadores tumorales a modo de contribución predictiva de recaída peritoneal en pacientes intervenidos. Su evaluación sérica preoperatoria está afianzándose como indicador de recurrencia y localización de la misma. No obstante, existen muy pocos estudios que evalúen su valor pronóstico en el postoperatorio de la enfermedad, especialmente cuando se carece de alguna determinación previa a la cirugía. Ofrecemos una interpretación del significado predictivo del CEA y del antígeno carbohidrato (Ca 19.9) séricos obtenidos en el postoperatorio de estos pacientes cuando son contextualizados de una forma individualizada con otros factores de riesgo clínico para recaída peritoneal. (AU)

Colorectal cancer is one of the most common worldwide neoplasia and peritoneum represents its third metastatic site. Surgicalresection remains to be the first curative treatment option in association with cytostatic therapy. Carcinoembryonic antigen (CEA)appears to be the most studied serum marker in colorectal cancer. In present years, other tumor biomarkers analysis has been added as a predictive contribution of peritoneal relapse in operated patients. A preoperative serum assessement of them is becoming established as an indicator of recurrence and location. Nevertheless, there are very few studies that evaluate its prognostic value during the postoperative follow-up of disease, especially when there is no determination prior to surgery. We reflect on the predictivesignificance of serum both CEA and carbohydrate antigen (Ca19.9) that were taken in the postoperative follow-up of these patients, establishing an individualized relationship of their value with other clinical risk factors for peritoneal relapse. (AU)

Carcinomatosis peritoneal secundaria a cáncer de mama ductal infiltrante sincrónico a adenocarcinoma de sigma. Revisión bibliográfica a propósito de un caso tratado en nuestro hospital / Peritoneal carcinomatosis secondary to invasive ductal carcinoma synchronous to sigmoid adenocarcinoma. Literature review and report of a case treated in our hospital

OBJETIVO: Revisión bibliográfica del diagnóstico, tratamiento y supervivencia del carcinoma de mama metastásico que cursa con carcinomatosis peritoneal. PACIENTES Y MÉTODOS: Presentamos el caso de una paciente en tratamiento en nuestro hospital comentándose los aspectos clínicos, diagnósticos y terapéuticos de interés. CONCLUSIÓN: Las metástasis del tracto gastrointestinal extra-hepáticas secundarias a tumor de mama son poco comunes (8-10%). La carcinomatosis peritoneal presenta una baja incidencia, habiéndose descrito pocos casos en la literatura, siendo la mayoría de tipo lobulillar infiltrante. Nuestro caso tratado de carcinomatosis peritoneal de origen mamario ductal infiltrante lo hace aún más infrecuente

AIM: We provide a literature review of the diagnosis, treatment and survival of metastatic breast cancer with peritoneal carcinomatosis. PATIENTS AND METHODS: We present a case treated in our institution and discuss relevant clinical, diagnostic, and therapeutic features. CONCLUSION: Extra-hepatic gastrointestinal metastasis from breast cancer is infrequent (8%-10%). The incidence of peritoneal carcinomatosis is low, with few cases reported in the literature, mostly from invasive lobular carcinoma. Our case of invasive ductal carcinoma is even less frequent