Neoadjuvant Chemotherapy plus Interval Cytoreductive Surgery with or without Hyperthermic Intraperitoneal Chemotherapy (NIHIPEC) in the Treatment of Advanced Ovarian Cancer: A Multicentric Propensity Score Study.

INTRODUCTION: Epithelial ovarian cancer (EOC) is primarily confined to the peritoneal cavity. When primary complete surgery is not possible, neoadjuvant chemotherapy (NACT) is provided; however, the peritoneum-plasma barrier hinders the drug effect. The intraperitoneal administration of chemotherapy could eliminate residual microscopic peritoneal tumor cells and increase this effect by hyperthermia. Intraperitoneal hyperthermic chemotherapy (HIPEC) after interval cytoreductive surgery could improve outcomes in terms of disease-free survival (DFS) and overall survival (OS). MATERIALS AND METHODS: A multicenter, retrospective observational study of advanced EOC patients who underwent interval cytoreductive surgery alone (CRSnoH) or interval cytoreductive surgery plus HIPEC (CRSH) was carried out in Spain between 07/2012 and 12/2021. A total of 515 patients were selected. Progression-free survival (PFS) and OS analyses were performed. The series of patients who underwent CRSH or CRSnoH was balanced regarding the risk factors using a statistical analysis technique called propensity score matching. RESULTS: A total of 170 patients were included in each subgroup. The complete surgery rate was similar in both groups (79.4% vs. 84.7%). The median PFS times were 16 and 13 months in the CRSH and CRSnoH groups, respectively (Hazard ratio (HR) 0.74; 95% CI, 0.58-0.94; p = 0.031). The median OS times were 56 and 50 months in the CRSH and CRSnoH groups, respectively (HR, 0.88; 95% CI, 0.64-1.20; p = 0.44). There was no increase in complications in the CRSH group. CONCLUSION: The addition of HIPEC after interval cytoreductive surgery is safe and increases DFS in advanced EOC patients.

Textbook outcome in oncological gastric surgery: a systematic review and call for an international consensus.

BACKGROUND: Textbook outcome (TO) is a multidimensional measure used to assess the quality of surgical practice. It is a reflection of an "ideal" surgical result, based on a series of benchmarks or established reference points that may vary depending on the pathology in question. References to TO in the literature are scarce, and the few reports that are available were all published very recently. In the case of gastric surgery, there is no established consensus on the parameters that should be included in TO, a circumstance that prevents comparison between series. AIM: To present a review of the literature on TO in gastric surgery (TOGS) and to try to establish a consensus on its definition. MATERIAL AND METHODS: Following the PRISMA guide, we performed an unlimited search for articles on TOGS in the MEDLINE (PubMed), EMBASE and Cochrane, Latindex, Scielo, and Koreamed databases, without language restriction, updated on December 31, 2022. The inclusion criterion was any type of study assessing TO in adult patients after oncological gastric surgery. Selected studies were assessed, and TOGS was measured. The parameters used to assess the achievement of TOGS in selected studies were also recorded. RESULTS: Twelve articles were included, comprising a total of 44,581 patients who had undergone an oncological gastric resection. The median rate of TOGS was 38.6%. All the publications but one included mortality as a TO variable, showing statistically significant differences in favor of the group in which TOGS was achieved. All articles included the number of nodes examined in the surgical specimen, with the assessment of fewer than 15 being associated with a low rate of TOGS achievement in five studies (41.7%). The variable postoperative complications according to the Clavien-Dindo score was the most important cause of failure to achieve TOGS in four studies (33.3%). Seven articles (58.3%) found a significant increase in long-term survival in patients who obtained TO. Advanced age, elevated ASA, and Charlson score had a negative impact on obtaining TOGS. CONCLUSIONS: The standardization of TOGS is necessary to be able to establish comparable results between groups.

Suitability of the AUC Ratio as an Indicator of the Pharmacokinetic Advantage in HIPEC.

The purpose of this study was to evaluate the area under the concentration-time curve (AUC) ratio as an optimal indicator of the pharmacokinetic advantage during hyperthermic intraperitoneal perioperative chemotherapy. The impact on the AUC ratio on the variables related to the calculation of systemic drug exposure, instillation time, and peripheral drug distribution was evaluated through simulations as well as through a retrospective analysis of studies published in the literature. Both model simulations and the retrospective analysis showed that the 3 variables evaluated had an impact on the AUC ratio value if the complete systemic exposure was not fully considered. However, when that complete systemic exposure was considered, none of these variables affected the AUC ratio value. AUC ratio is not a characteristic parameter of a drug if the calculated systemic drug exposure is not complete. Thus, AUC ratio is not valid for comparing the pharmacokinetic advantage of 2 drugs, and it should not be employed to prove whether a drug can be used in hyperthermic intraperitoneal perioperative chemotherapy safely with regard to toxicity. As an alternative, the study of the absorption rate constant and the bioavailability are proposed as the true and independent parameters that reflect the amount of drug absorbed.

Cost and effectiveness of lung lobectomy by video-assisted thoracic surgery for lung cancer.

BACKGROUND: Video-assisted thoracic surgery (VATS) emerged as a minimally invasive surgery for diseases in the field of thoracic surgery. We herein reviewed our experience on thoracoscopic lobectomy for early lung cancer and evaluated Health System use. METHODS: A cost-effectiveness study was performed comparing VATS vs. open thoracic surgery (OPEN) for lung cancer patients. Demographic data, tumor localization, dynamic pulmonary function tests [forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusion capacity (DLCO) and maximal oxygen uptake (VO2max)], surgical approach, postoperative details, and complications were recorded and analyzed. RESULTS: One hundred seventeen patients underwent lung resection by VATS (n=42, 36%; age: 63±9 years old, 57% males) or OPEN (n=75, 64%; age: 61±11 years old, 73% males). Pulmonary function tests decreased just after surgery with a parallel increasing tendency during first 12 months. VATS group tended to recover FEV1 and FVC quicker with significantly less clinical and post-surgical complications (31% vs. 53%, P=0.015). Costs including surgery and associated hospital stay, complications and costs in the 12 months after surgery were significantly lower for VATS (P<0.05). CONCLUSIONS: The VATS approach surgery allowed earlier recovery at a lower cost than OPEN with a better cost-effectiveness profile.

Impact of Laparotomy and Intraperitoneal Hyperthermic Instillation (LIHI) on the oxaliplatin pharmacokinetics after intravenous administration in Wistar rats.

PURPOSE: In peritoneal metastasis condition, the fact that most of the disease is limited to the peritoneal cavity laid the foundations for a surgical treatment, including intraperitoneal hyperthermic chemotherapy (HIPEC). The aim of this study was to evaluate the impact of the surgical procedures implied in open HIPEC technique, referred to laparotomy procedures followed by an intraperitoneal hyperthermic instillation (LIHI) on oxaliplatin tissue distribution and elimination. To delimit the influence of this procedure alone, oxaliplatin was administered as an intravenous (iv) bolus in both groups. METHODS: An experimental model in Wistar rats was employed, and LIHI was evaluated as a dichotomous covariate by using a population pharmacokinetic (PK) approach. Rats were randomized in two groups receiving 1.5 mg iv oxaliplatin alone or 1.5 mg iv oxaliplatin under LIHI conditions, carrying out a hyperthermic 5% dextrose instillation. The oxaliplatin plasma concentrations were characterized by an open two-compartment PK model. RESULTS: Results concluded that surgical conditions affect the oxaliplatin elimination and distribution from blood to peripheral tissues, increasing the systemic drug exposure. Concretely, oxaliplatin peripheral volume of distribution, and clearance decreased by 48.6% and 55.3%, respectively, compared to the control group that resulted in a two-fold increase of the area under the concentration time curve. CONCLUSIONS: Comparison in clinical practice of oxaliplatin PK parameters obtained after iv administrations with those obtained after HIPEC interventions must be done carefully. This would limit the use of iv PK parameters to simulate new scenarios for oxaliplatin in HIPEC.

Outpatient treatment in uncomplicated acute diverticulitis: 5-year experience.

BACKGROUND/AIMS: Most cases of diverticular inflammation are mild and require only medical treatment with liquid diet and antibiotics. Until recently, this treatment required admission to hospitals, which consequently entailed costs. In most cases, treatment was conservative, and less than a quarter of patients admitted actually underwent surgery. In the last year, the outpatient treatment of these patients with uncomplicated diverticulitis has proven effective and safe. The aim of the present study was to describe our experience after 5 years of outpatient treatment with oral antibiotics. MATERIALS AND METHODS: We conducted a retrospective revision study between January 2010 and December 2014. We included all patients admitted to the Emergency Department of the University General Hospital of Elche with a diagnosis of uncomplicated acute diverticulitis based on medical history, physical examination and abdominopelvic computed tomography (CT) scanning. Outpatient treatment consisted of oral antibiotics for 10 days (metronidazole 500 mg/8 h and ciprofloxacin 500 mg/12 h), a liquid diet and oral analgesics (acetaminophen 1 g/6 h). RESULTS: During the period from January 2010 to December 2014, 224 patients were treated on an outpatient basis at a success rate of over 92%. Only 18 patients (8%) required admission after outpatient treatment. CONCLUSION: Outpatient treatment of uncomplicated acute diverticulitis was demonstrated to be safe and effective.

Perfilamos nuestra revista para alcanzar los objetivos / Shaping up our Journal to achieve our aims

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Dual regulation of P-glycoprotein expression by trichostatin A in cancer cell lines.

BACKGROUND: It has been reported that the histone deacetylase inhibitor (iHDAc) trichostatin A (TSA) induces an increase in MDR1 gene transcription (ABCB1). This result would compromise the use of iHDACs in combination with other cytotoxic agents that are substrates of P-glycoprotein (Pgp). It has also been reported the use of alternative promoters by the ABCB1 gene and the existence of a translational control of Pgp protein. Finally, the ABCB1 gene is located in a genetic locus with the nested gene RUNDC3B in the complementary DNA strand, raising the possibility that RUNDC3B expression could interfere with ABCB1 alternative promoter regulation. METHODS: A combination of RT-PCR, real time RT-PCR, Western blot and drug accumulation assays by flow cytometry has been used in this study. RESULTS: The iHDACs-induced increase in MDR1 mRNA levels is not followed by a subsequent increase in Pgp protein levels or activity in several pancreatic and colon carcinoma cell lines, suggesting a translational control of Pgp in these cell lines. In addition, the MDR1 mRNA produced in these cell lines is shorter in its 5' end that the Pgp mRNA produced in cell lines expressing Pgp protein. The different size of the Pgp mRNA is due to the use of alternative promoters. We also demonstrate that these promoters are differentially regulated by TSA. The translational blockade of Pgp mRNA in the pancreatic carcinoma cell lines could be related to alterations in the 5' end of the MDR1 mRNA in the Pgp protein expressing cell lines. In addition, we demonstrate that the ABCB1 nested gene RUNDC3B expression although upregulated by TSA is independent of the ABCB1 alternative promoter used. CONCLUSIONS: The results show that the increase in MDR1 mRNA expression after iHDACs treatment is clinically irrelevant since this mRNA does not render an active Pgp protein, at least in colon and pancreatic cancer cell lines. Furthermore, we demonstrate that TSA in fact, regulates differentially both ABCB1 promoters, downregulating the upstream promoter that is responsible for active P-glycoprotein expression. These results suggest that iHDACs such as TSA may in fact potentiate the effects of antitumour drugs that are substrates of Pgp. Finally, we also demonstrate that TSA upregulates RUNDC3B mRNA independently of the ABCB1 promoter in use.

Fistulotomy and sphincter reconstruction in the treatment of complex fistula-in-ano: long-term clinical and manometric results.

OBJECTIVE: To evaluate the long-term clinical and manometric results of fistulotomy and sphincter reconstruction for the treatment of complex fistula-in-ano. BACKGROUND: Complex fistula-in-ano is difficult to treat due to the occurrence of postoperative anal incontinence and the high rate of recurrence. METHODS: Seventy patients who were diagnosed with complex fistula-in-ano and underwent fistulotomy and sphincter reconstruction between October 2000 and October 2006 were analyzed in the present study. Preoperative assessment included physical examination, anorectal manometry, and anal endosonography. Appointments were scheduled every 6 months during the first and second year of treatment and every 2 years thereafter. Recurrence and incontinence were evaluated during each visit. Continence was assessed according to the Wexner continence grading scale. Anal manometry was performed 3 and 12 months after treatment and every 2 years thereafter. Anal endosonography was conducted 6 months after treatment. RESULTS: Fistulas were classified as medium-high trans-sphincteric in 64 patients (91.42%) and were recurrent in 22 patients (32%). Before surgery, 22 patients (32%) reported fecal incontinence, which improved after surgery in 15 cases (70%), from 6.75 to 1.88 (P < 0.005) on the Wexner Scale. Eight preoperative continent patients (16.6%) reported postoperative incontinence (Wexner Score < 3), and 6 patients (8.5%) had recurrent incontinence. Among these patients, 2 developed recurrent incontinence 6 months after treatment, 2 developed recurrent incontinence 1 year after treatment, 1 developed recurrent incontinence 2 years after treatment, and 1 developed incontinence 5 years after treatment. CONCLUSIONS: Fistulotomy with sphincter reconstruction is an effective technique for the treatment of complex fistula-in-ano. Continence and anal manometry results were improved in incontinent patients and were not jeopardized in continent ones. Fistulotomy with sphincter reconstruction is an especially suitable technique for incontinent patients with recurrent fistulas.

TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.

In colorectal cancer (CRC), an inherited susceptibility risk affects about 35% of patients, whereas high-penetrance germline mutations account for <6% of cases. A considerable proportion of sporadic tumors could be explained by the coinheritance of multiple low-penetrance variants, some of which are common. We assessed the susceptibility to CRC conferred by genetic variants at the TGFBR1 locus. We analyzed 14 polymorphisms and the allele-specific expression (ASE) of TGFBR1 in 1025 individuals from the Spanish population. A case-control study was undertaken with 504 controls and 521 patients with sporadic CRC. Fourteen polymorphisms located at the TGFBR1 locus were genotyped with the iPLEX Gold (MassARRAY-Sequenom) technology. Descriptive analyses of the polymorphisms and haplotypes and association studies were performed with the SNPator workpackage. No relevant associations were detected between individual polymorphisms or haplotypes and the risk of CRC. The TGFBR1*9A/6A polymorphism was used for the ASE analysis. Heterozygous individuals were analyzed for ASE by fragment analysis using cDNA from normal tissue. The relative level of allelic expression was extrapolated from a standard curve. The cutoff value was calculated with Youden's index. ASE was found in 25.4% of patients and 16.4% of controls. Considering both bimodal and continuous types of distribution, no significant differences between the ASE values of patients and controls were identified. Interestingly, a combined analysis of the polymorphisms and ASE for the association with CRC occurrence revealed that ASE-positive individuals carrying one of the most common haplotypes (H2: 20.7%) showed remarkable susceptibility to CRC (RR: 5.25; 95% CI: 2.547-5.250; p<0.001) with a synergy factor of 3.7. In our study, 54.1% of sporadic CRC cases were attributable to the coinheritance of the H2 haplotype and TGFBR1 ASE. These results support the hypothesis that the allelic architecture of cancer genes, rather than individual polymorphisms, more accurately defines the CRC risk.

Updating controversies on the multidisciplinary management of gastric cancer.

The rates of relapse and death remain high in gastric cancer patients, especially in advanced stages. Local relapses in the tumour bed and regional lymph nodes, peritoneal spread as abdominal carcinomatosis, and distant metastasis are common mechanisms of failure after a R0 resection. To overcome this, a multidisciplinary approach has been prompted. In recent years, multidisciplinary treatment has been strengthened by some randomised controlled trials and it is now considered the standard by most groups, although the improvement in long-term survival rates achieved is still limited. This new therapeutic approach in gastric cancer is rapidly evolving and has led to a series of controversies on the best strategy to follow. Some of these controversies are discussed in this paper.

p53 genetic abnormalities and P-glycoprotein expression in stump and primary gastric carcinomas.

BACKGROUND/AIMS: Genetic abnormalities of the p53 gene may play a major role in the carcinogenesis of gastric stump carcinomas (GSC) and intestinal-type primary gastric carcinomas (IPGC). Also, they may modulate P-gp expression producing chemoresistance. The aim of this article is to analyze p53 genetic abnormalities and the influence of p53 gene status on P-gp expression in both types of carcinomas. METHODOLOGY: Forty-two paraffin-embedded samples of gastric carcinomas corresponding to 17 GSC and 25 IPGC were studied. P53 genetic abnormalities in exon 5-9 were screened by direct sequencing of PCR products. P53 and P-glycoprotein (P-gp) were assessed by a standard streptavidin-biotin immunoperoxidase method. Anti-p53 DO7 and anti-P-gp C494 were used as primary antibodies. RESULTS: Fourteen p53 mutations were found, 5 in GSC (29%) and 9 in IPGC (36%). Thirteen mutations were base-pair substitutions that produced a change in the amino acid sequence. Eight mutations were located at exon 7 (57%). P53 nuclear immunopositivity was observed in 12 GSC (71%) and 15 IPGC (60%). Only two carcinomas (1 IPGC and 1 GSC) harboring a p53 mutation did not show any p53 expression. All except one of the gastric carcinomas having a p53 mutation showed medium or high P-gp expression. However, there was no difference in P-gp expression between tumors with and without p53 mutation. CONCLUSIONS: The p53 genetic alterations found in GSC and IPGC could originate from a similar pathogenetic pathway. No association was demonstrated between p53 gene status and P-gp expression, although most of the carcinomas harboring a p53 mutation showed medium or high P-gp expression.

Giant splenic metastasis due to lung adenocarcinoma.

Lung cancer is the most prevalent malignancy in western countries and most of the patients present at advanced stages, but single splenic metastasis is exceptional instead. We report on a case of a seventy- three-year old male presenting with non-hemoptoic productive cough, constitutional syndrome and pain in the left lower quadrant. Physical examination and complementary radiological and histological procedures revealed the presence of an adenocarcinoma of the left lung with probable splenic metastasis. The patient underwent splenectomy, which confirmed the diagnose of splenic metastasis of lung adenocarcinoma and, secondly, lung resection was performed. Topics about lung cancer metastasis are discussed.

Giant splenic metastasis due to lung adenocarcinoma

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Lung cancer is the most prevalent malignancy inwestern countries and most of the patients presentat advanced stages, but single splenic metastasis isexceptional instead. We report on a case of a seventy-three-year old male presenting with non-hemoptoicproductive cough, constitutional syndrome andpain in the left lower quadrant. Physical examinationand complementary radiological and hystologycalprocedures revealed the presence of an adenocarcinomaof the left lung with probable splenicmetastasis. The patient underwent splenectomy,which confirmed the diagnose of splenic metastasisof lung adenocarcinoma and, secondly, lung resectionwas performed. Topics about lung cancermetastasis are discussed

Valoración de la 5ª edición de la clasificación TNM para el cáncer gástrico en nuestro medio / Appraisal of the fifth edition of the tumor-node-metastasis (TNM) classification for gastric cancer in our environment

Objetivo. Evaluar el número de casos de carcinoma gástrico que pueden ser estadificados con los criterios de la 5.a edición del sistema TNM y analizar qué factores pueden estar relacionados con la obtención de un número suficiente de ganglios. Pacientes y método. En 164 pacientes a los que se resecó un carcinoma gástrico, se estudiaron distintos factores que podían influir en el número de ganglios aislados, como el tamaño tumoral, el tipo de resección gástrica, el grado de diferenciación tumoral, el tipo histológico, la variabilidad entre patólogos que analizaron las piezas y la experiencia del cirujano. Resultados. La media de ganglios linfáticos analizados por los patólogos fue de 11,4 (intervalo de confianza del 95%, 10,12-12,66). Atendiendo a los criterios de la 5.a edición de la clasificación TNM, sólo se pudo clasificar correctamente al 31% de los pacientes. Encontramos una correlación positiva entre el tamaño tumoral y el número de ganglios aislados (p = 0,0018), así como un mayor número de ganglios analizados en las gastrectomías totales respecto de las subtotales (p = 0,034). No se observó una variación significativa en los ganglios analizados en relación con el patólogo que analizó la pieza ni con la experiencia del cirujano que efectuó la resección. Conclusiones. La 5.a edición del sistema TNM es fácilmente reproducible, aunque el número de ganglios necesarios para corroborar la afección ganglionar metastásica es difícil de conseguir en nuestro medio. Nuestros resultados sugieren que es necesario un esfuerzo conjunto por parte de cirujanos y patólogos para aumentar el número de pacientes estadificables con esta edición (AU)

Aim. To estimate the proportion of patients with gastric carcinoma that can be classified using the criteria of the fifth edition of the TNM system and to analyze which factors could be related to the finding of an adequate number of nodes. Patients and method. The influence of distinct factors that could influence the number of lymph nodes isolated was evaluated in 164 patients who underwent resection of gastric carcinoma. These factors included tumor size, surgical resection, grade, histological type, variability among the pathologists who analyzed the surgical specimens, and the surgeon's experience. Results. The mean number of lymph nodes examined by the pathologists was 11.4 (10.12-12.66). Applying the criteria of the fifth edition of the TNM classification, only 31% of the patients could be correctly classified. A positive correlation was found between tumor size and the number of resected nodes (p = 0.0018). In addition, a greater number of lymph nodes were found in total gastrectomies than in subtotal gastrectomies (p = 0.034). No significant association was found with the pathologist who analyzed the surgical specimen or with the experience of the surgeon who performed the resection. Conclusions. The fifth edition of the TNM system is easily reproducible, although the number of lymph nodes required to evaluate metastatic node involvement is difficult to obtain in our environment. Our results suggest that a combined effort between surgeons and pathologists is needed to increase the number of patients that can be reliably staged with this TNM edition (AU)

Surgical versus chemical (botulinum toxin) sphincterotomy for chronic anal fissure: long-term results of a prospective randomized clinical and manometric study.

BACKGROUND: The aim of this prospective randomized trial was to compare the effectiveness and morbidity of surgical versus chemical sphincterotomy in the treatment of chronic anal fissure after a 3-year follow-up. METHODS: Eighty patients with chronic anal fissure were treated by whether open lateral internal sphincterotomy (group 1) or chemical sphincterotomy with 25 U botulinum toxin injected into the internal sphincter (group 2). Clinical and manometric results were analyzed. RESULTS: Overall healing was 92.5% in the open sphincterotomy group and 45% in the toxin botulinum group (P<.001). There is a group of patients with clinical (duration of disease >12 months and presence of a sentinel pile before treatment) and manometric factors (persistently elevated mean resting pressure, % of time presence of slow waves, and number of patients or the time presence ultra slow waves after treatment) associated with a higher recurrence of anal fissure. The final percentage of incontinence was 5% in the open sphincterotomy group and 0% in the botulinum toxin group (P>.05). CONCLUSION: We recommend surgical sphincterotomy as the first therapeutic approach in patients with clinical and manometric factors of recurrence. We prefer the use of botulinum toxin in patients older than 50 years or with risk factors for incontinence, despite the higher rate of recurrence, since it avoids the greater risk of incontinence in the surgical group.

[Assessment of the fifth edition of the tumor-node-metastasis (TNM) classification for gastric cancer in our setting]. / Valoración de la 5.a edición de la clasificación TNM para el cáncer gástrico en nuestro medio.

AIM: To estimate the proportion of patients with gastric carcinoma that can be classified using the criteria of the fifth edition of the TNM system and to analyze which factors could be related to the finding of an adequate number of nodes. PATIENTS AND METHOD: The influence of distinct factors that could influence the number of lymph nodes isolated was evaluated in 164 patients who underwent resection of gastric carcinoma. These factors included tumor size, surgical resection, grade, histological type, variability among the pathologists who analyzed the surgical specimens, and the surgeon's experience. RESULTS: The mean number of lymph nodes examined by the pathologists was 11.4 (10.12-12.66). Applying the criteria of the fifth edition of the TNM classification, only 31% of the patients could be correctly classified. A positive correlation was found between tumor size and the number of resected nodes (p = 0.0018). In addition, a greater number of lymph nodes were found in total gastrectomies than in subtotal gastrectomies (p = 0.034). No significant association was found with the pathologist who analyzed the surgical specimen or with the experience of the surgeon who performed the resection. CONCLUSIONS: The fifth edition of the TNM system is easily reproducible, although the number of lymph nodes required to evaluate metastatic node involvement is difficult to obtain in our environment. Our results suggest that a combined effort between surgeons and pathologists is needed to increase the number of patients that can be reliably staged with this TNM edition.