Endometrial adenocarcinoma recurring in the lung: impact of molecular profile and role of local therapies on prognosis.

OBJECTIVES: The objective of our study was to describe the characteristics of patients with endometrial cancer diagnosed with a first recurrence involving the lung, and to describe the prognostic role of the molecular profile. We also aimed to describe the prognostic outcomes after local treatment of recurrence (resection of lung metastases or stereotactic body radiation therapy) in a group of patients with isolated lung recurrence. METHODS: This was a retrospective, single-center study between June 1995 and July 2021. The study included patients diagnosed with a first recurrence of endometrial cancer involving the lung. We defined two groups of patients: patients with isolated lung recurrence (confined to the lung) and patients with multisystemic recurrence (in the lung and other locations). RESULTS: Among 1413 patients diagnosed with endometrial cancer in stage IA to IVA of the International Federation of Gynecology and Obstetrics (FIGO) 2009, 64 (4.5%) patients had a first recurrence involving the lung. Of these, 15 (39.1%) were of a non-specific molecular profile, 16 (25%) were p53-abnormal, 15 (23.4%) were mismatch-repair deficient, and 0% POLE-mutated. P53-abnormal patients had the shortest 3 year progression-free survival after recurrence and those with mismatch-repair deficient had the longest 3 year progression-free survival (14.3% (range; 1.6-40.3) and 47.6% (range; 9.1-79.5) respectively, p=0.001). We found no differences on overall survival after recurrence by molecular profile. Thirty-one of 64 (48.4%) patients had an isolated recurrence in the lung, and 16 (25%) patients received local treatment. When comparing patients with isolated lung recurrence, locally treated patients had a longer median progression-free survival than patients treated systemically (41.9 (range, 15.4-NA) vs 7.8 (range, 7.2-10.6) months respectively, p=0.029), a complete response rate of 80% for stereotactic body radiation therapy and a complete resection of 90.9% for surgery. CONCLUSION: Although few patients will benefit from local treatment (stereotactic body radiation therapy or resection) after a recurrence involving the lung, local therapies might be considered as an option in oligometastatic lung recurrences as they achieve high local control rates and better oncological outcomes than systemic treatment alone.

Postreatment squamous cell carcinoma antigen as a survival prognostic factor in patients with locally advanced cervical cancer. A Spanish multicenter study. The SEGO Spain-GOG group.

OBJECTIVE: To evaluate the clinical value of postreatment plasmatic levels of the squamous cell carcinoma antigen (SCC-Ag) as a survival independent prognostic factor in patients with LACC. METHODS: Retrospective, multicenter study including LACC patients (FIGO 2009 stages IB2, IIA2-IVA) managed at the Gynecology Oncological Units corresponding to eight reference hospitals in Spain between 2000 and 2016. Receiver operating characteristic (ROC) curve analysis was used to determine the cut-off values of postreatment SCC-Ag levels in prediction of survival. Survival curves were calculated by using the Kaplan-Meier method and were compared with the log-rank test. Cox models were used to analyze different factors in terms of their prognosis predictive value. RESULTS: The study included 447 patients with a median follow-up time of 53 months (IQR 26-101) and median pre- and postreatment SCC-Ag levels of 3.4 ng/ml (IQR 1.2-11) and 0.8 ng/ml (IQR 0.5-1.2), respectively. The cut-off level of pretreatment SCC-Ag was 11.75 ng/ml (sensibility 37.5%; specificity 80.5%) and that of postreatment SCC-Ag was 1.24 ng/ml (sensibility 34.6%; specificity 83.1%). In a multivariate Cox regression analysis, factors that were independent predictors of OS were: FIGO stage (HR 2.12; 95%CI 1.18-3.8; p = 0.011), paraaortic lymph node involvement (HR 3.56; 95%CI 2.04-6.2; p < 0.0001), postreatment SCC-Ag level ≥ 1.2 ng/ml (HR 1.95; 95%CI 1.11-3.44; p = 0.02) and incomplete response to treatment (HR 4.5; 95%CI 2.5-8.11; p < 0.0001). CONCLUSION: Postreatment plasmatic SCC-Ag level ≥ 1.2 ng/ml was an independent risk factor for the survival of patients with LACC. Further factors influencing survival included: paraaortic lymph node involvement, advanced disease and poor response to concomitant chemoradiotherapy.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

Does ITV vaginal procedure ensure dosimetric coverage during IMRT of post-operative gynaecological tumours without instructions concerning rectal filling?

AIM: To find out whether the internal target volume (ITV) vaginal procedure ensures dosimetric coverage during intensity-modulated radiation therapy (IMRT) of post-operative gynaecological tumours without instructions on rectal filling. BACKGROUND: The ITV vaginal procedure does not necessarily include all movements of the bladder, and does not include changes in the rectal volume. We should know if the vaginal ITV is a useful tool in maintaining CTV coverage during treatment. MATERIALS AND METHODS: A retrospective analysis of 24 patients treated between July 2012 and July 2014 with adjuvant IMRT for gynaecological cancer. All patients underwent empty and full bladder CT on simulation (CT-planning) and three weeks later (CT-control). ITV displacement was measured and the 3D vector was calculated. ITV coverage was then evaluated by comparing the volume covered by the prescription isodose on both CT's. Patients were asked to have full bladder but they did not follow recommendations for the rectum. RESULTS: The mean 3D vector was 0.64 ± 0.32 cm (0.09-1.30). The mean ITV coverage loss was 5.8 ± 5.7% (0-20.2). We found a significant positive correlation between the 3D vector and the loss of coverage (Pearson correlation, r = 0.493, 95% CI: 0.111-0.748, p = 0.0144). We did not find any significant correlation between the bladder and rectal parameters with the 3D vector and loss of dosimetric coverage. We found a trend between the maximum rectal diameter in CT-planning and 3D vector (r = 0.400, 95% CI: -0.004 to 0.692, p = 0.0529). CONCLUSION: ITV vaginal procedure contributed to ensuring a good dose coverage without instructions on rectal filling.

Effectiveness of radiotherapy for metastatic spinal cord compression in patients with short life expectancy.

AIM: To analyze the effect of radiotherapy (RT) in patients with metastatic spinal cord compression (MSCC) and poor prognosis in our center. BACKGROUND: RT is an effective treatment for MSCC. MATERIALS AND METHODS: Prospective evaluation on patients with MSCC and limited survival (according to Rades' scale), and treated with single-dose 8 Gy RT (February 2013-August 2014). Pain, ambulatory status and sphincter control were recorded. Pain relief was evaluated following the International Bone Metastases Consensus Working Party Guidelines. Ambulatory status was evaluated with Frankel's scale. Spinal fracture and instability were recorded. Health aspects were evaluated via a short survey and measuring the time spent on RT. RESULTS: 35 patients were included. 51% had unfavorable histologies; 60% bone fracture and 17% spinal instability. Median Karnofsky score was 60; 100% were on high doses of opioids. Median survival was 1.5 months. 49% had a partial pain response at 2 weeks post-radiation, and 47% at one month. Significant reductions in pain intensity were present at 2 weeks (Visual analog scale, VAS score, from 8 ± 1.5 to 5 ± 1.9). Negligible effects were observed on motor and bladder function, along with side effects. KPS score was maintained during follow-up. 80% of patients spent ≤5% of their remaining lifetime on RT. A survey comparison between clinical judgment and the results according to treatment decision consider that these patients merit treatment evaluation. CONCLUSIONS: A moderate pain response tailored to life expectancy can be obtained in patients treated with radiation. 8-Gy single-dose is an option for patients with limited survival.

RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) constitutes the most common subtype of soft tissue sarcoma. However, UPS is clinically and molecularly poorly understood, in great extent due to its intrinsic phenotypic and cytogenetic complexity, which in turn results in the absence of specific prognostic or predictive biomarkers. The RAS/mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathways are considered to be 2 major mechanisms for sarcoma proliferation and survival and to the authors' knowledge their role in UPS remains unclear. The objective of the current study was to investigate whether the RAS/MAPK and PI3K/mTOR pathways are activated in UPS, and whether pathway activation is associated with outcome. METHODS: Records for patients diagnosed and treated for UPS in the study institution between 2000 and 2009 were reviewed. Phosphorylation status of 4E-binding protein (4E-BP1), eukaryotic translation initiation factor 4E (eIF-4E), S6-RP, and ERK 1/2, together with total forms of 4E-BP1 and eIF-4E, were assessed using immunohistochemistry in paraffin-embedded tumor tissue. Mutational analysis for KRAS; NRAS; BRAF; and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) oncogenic mutations was performed as well. RESULTS: Critical lymph nodes within the RAS/MAPK and PI3K/mTOR pathways were found to be activated in >80% of UPS cases. Hyperactivation of the RAS/MAPK pathway, as assessed by expression of phosphorylated ERK 1/2, was found to independently predict a higher risk of disease recurrence and impaired overall survival. Only a KRAS A146V mutation was detected in 1 tumor. CONCLUSIONS: The RAS/MAPK and PI3K/mTOR pathways are activated in the majority of cases of UPS. The RAS/MAPK pathway distinguishes a subgroup of patients with localized UPS with a worse outcome.

Clinical effects of re-evaluating a lung SBRT failure mode and effects analysis in a radiotherapy department.

PURPOSE: The increasing complexity of radiation treatments can hinder its clinical success. This study aimed to better understand evolving risks by re-evaluating a Failure Mode and Effects Analysis (FMEA) in lung SBRT. METHODS: An experienced multidisciplinary team conducted an FMEA and made a reassessment 3 years later. A process map was developed with potential failure modes (FMs) identified. High-risk FMs and their possible causes and corrective actions were determined. The initial FMEA analysis was compared to gain a deeper perspective. RESULTS: We identified 232 FMs. The high-risk processes were plan approval, target contouring, and patient evaluation. The corrective measures were based on stricter standardization of plan approval, pre-planning peer review, and a supporting pretreatment checklist, which substantially reduced the risk priority number in the revised FMEA. In the FMEA reassessment, we observed that the increased complexity and number of patients receiving lung SBRT conditioned a more substantial presence of human factors and communication errors as causal conditions and a potential wrong dose as a final effect. CONCLUSIONS: Conducting a lung SBRT FMEA analysis has identified high-risk conditions that have been effectively mitigated in an FMEA reanalysis. Plan approval has shown to be a weak link in the process. The increasing complexity of treatments and patient numbers have shifted causal factors toward human failure and communication errors. The potential of a wrong dose as a final effect augments in this scenario. We propose that digital and artificial intelligence options are needed to mitigate potential errors in high-complexity and high-risk RT scenarios.

Adjuvant therapy in early-stage cervical cancer after radical hysterectomy: are we overtreating our patients? A meta-analysis.

OBJECTIVE: There is a gap in knowledge regarding the ideal management of patients with early-stage cervical cancer and intermediate-risk features. Here, we present a meta-analysis of the published literature on oncological outcomes in these patients and determine trends in postoperative management. METHODS: MEDLINE and PubMed were used for literature searches. The inclusion criteria were: English language articles including ≥ 10 patients, patients who underwent radical hysterectomy, nodes negative, studies reporting oncological outcomes and complications treatment-related and compare a surgery-only cohort with a radiotherapy cohort. The PRISMA guidelines were followed. Combined relative risk was calculated using DerSimonian-Laird random-effects model and a forest plot was drawn. RESULTS: We collected 183 manuscripts on early-stage cervical cancer treated with radical hysterectomy alone or with adjuvant radiotherapy after surgery. A total of eight studies met the inclusion criteria. Regarding oncological outcomes, survival was reported in five studies. The relative risk of recurrence and the relative risk of mortality was similar in both groups independently whether receive or not adjuvant therapy. Most of the studies did not report significant differences regarding morbidity treatment related between the groups, except for a higher rate of lymphedema after radiotherapy. CONCLUSION: We found that the relative risk of recurrence and mortality was similar in both groups not depending on adjuvant therapy. Therefore, whether radiotherapy adjuvant treatment is indicated remains a topic of debate.

Final Safety and Health-Related Quality of LIfe Results of the Phase 2/3 Act.In.Sarc Study With Preoperative NBTXR3 Plus Radiation Therapy Versus Radiation Therapy in Locally Advanced Soft-Tissue Sarcoma.

PURPOSE: Act.In.Sarc (NCT02379845) demonstrated that the first-in-class radioenhancer NBTXR3, activated by preoperative radiation therapy (RT), doubled the rate of pathologic complete response after resection compared with preoperative RT alone in adult patients with locally advanced soft tissue sarcoma of the extremity or trunk wall (16.1% vs 7.9%, P = .045), and more patients achieved R0 resections (77.0% vs 64.0%, P = .042). These are the toxicity and health-related quality of life (HRQoL) results. METHODS AND MATERIALS: Act.In.Sarc randomized eligible patients 1:1 to either NBTXR3 (single intratumoral injection, volume equivalent to 10% of baseline tumor volume, at 53.3 g/L) activated by external-beam RT (arm A) or external-beam RT alone (arm B) (50 Gy in 25 fractions), followed by surgery in both arms. Here, we report the safety analyses in the all-treated population with a long-term follow-up of at least 2 years, and HRQoL in the intention-to-treat full analysis set. RESULTS: During the on-treatment period, serious adverse events (SAEs) of all grades related to NBTXR3 occurred in 10.1% (9/89) of patients (arm A), and SAEs related to RT occurred in 5.6% (5/89) (arm A) versus 5.6% (5/90) (arm B); postsurgery hospitalization owing to SAEs occurred in 15.7% (14/89) (arm A) versus 24.4% (22/90) (arm B). During the follow-up period, posttreatment SAEs (regardless of relationship) occurred in 13.5% (12/89) (arm A) versus 24.4% (22/90) (arm B). NBTXR3 did not negatively affect HRQoL; during the follow-up period, there was an improvement in most mean Toronto extremity salvage, EuroQoL 5-dimension (EQ-5D), EQ5D02-EQ visual analog scale, reintegration to normal living index, and musculoskeletal tumor rating scale scores. CONCLUSIONS: NBTXR3 did not negatively affect safety or HRQoL. Long-term safety results reinforce the favorable benefit-risk ratio of NBTXR3 plus RT.

Total laparoscopic radical hysterectomy for cervical cancer in prolapsed uterus.

PURPOSE: The association between cervical cancer and uterine prolapse is rare and sparsely represented in literature, despite the high incidence of the latter. The suitable treatment in this clinical situation is not defined. The objective of this article is to review published cases about this clinical condition. METHODS: We report a case of cervical cancer in prolapsed uterus treated with radical hysterectomy performed totally by laparoscopic approach, and review other case reports published about this clinical condition. RESULTS: We present the first case reported in literature in our knowledge of cervical cancer in prolapsed uterus treated with radical hysterectomy performed totally by laparoscopic approach. Treatments previously reported are vaginal hysterectomies with adjuvant radiotherapy or concomitant chemo-radiotherapy. CONCLUSIONS: Radical hysterectomy can be correctly performed totally by laparoscopic approach even when cervical cancer is associated with severe uterine prolapse.

Impact of non-adherence to radiotherapy on 1-year survival in cancer patients in Catalonia, Spain.

BACKGROUND: This study aims to assess the effects of non-adherence to external beam radiation therapy in cancer patients receiving treatment with a curative. METHODS: This retrospective cohort study collected health records data for all cancer patients treated with external beam radiotherapy with curative intent in 2016 in Catalonia, Spain. Adherence was defined as having received at least 90% of the total dose prescribed. A logistic regression model was used to assess factors related to non-adherence, and its association with one-year survival was evaluated using Cox regression. RESULTS: The final sample included 8721 patients (mean age 63.6 years): breast cancer was the most common tumour site (38.1%), followed by prostate and colon/rectum. Treatment interruptions prolonged the total duration of therapy in 70.7% of the patients, and 1.0% were non-adherent. Non-adherence was associated with advanced age, female gender, and some localization of primary tumour (head and neck, urinary bladder, and haematological cancers). The risk of death in non-adherent patients was higher than in adherent patients (hazard ratio [HR] 1.63, 95% confidence interval 0.97-2.74), after adjusting for the potential confounding effect of age, gender, tumour site and comorbidity. CONCLUSION: Non-adherence to radiotherapy, as measured by the received dose, is very low in our setting, and it may have an impact on one-year survival.

Nerve-sparing versus non-nerve-sparing radical hysterectomy: surgical and long-term oncological outcomes.

OBJECTIVES: There are controversies regarding the long-term oncological safety of preservation of pelvic innervation during radical hysterectomy (RH). This study aimed to analyze the feasibility and safety of nerve-sparing radical hysterectomy (NSRH) for cervical cancer compared with non-NSRH following 17 years of experience in a tertiary cancer referral center. MATERIALS AND METHODS: Between May 1999 and June 2016, all patients who underwent RH for cervical cancer were followed-up prospectively. Comparison analyses regarding surgical outcomes, complications, overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were performed between patients treated with NSRH and non-NSRH. RESULTS: A total of 188 patients were included (113 non-NSRH and 75 NSRH). The median follow-up was 112 months. Estimated blood loss and hospital stay were all significantly lower in the NSRH group. Overall intraoperative complication rate (p = 0.02) and need for transfusion (p = 0.016) were lower in the NSRH group. There were no differences in the median operation time, OS, DFS, CSS, or recurrence rates between the NSRH and non-NSRH group. CONCLUSIONS: Our study provides a wide perspective on the developments of nerve-sparing procedures for the management of women with early-stage cervical cancer. Our results suggest that NSRH is a feasible and safe procedure, with reduced morbidity outcomes.

Effects of probiotic Lactobacillus casei DN-114 001 in prevention of radiation-induced diarrhea: results from multicenter, randomized, placebo-controlled nutritional trial.

PURPOSE: To determine whether a probiotic drink containing Lactobacillus casei DN-114 001 reduces the incidence of radiation-induced diarrhea in patients with gynecologic cancer. METHODS AND MATERIALS: Patients who were undergoing pelvic radiotherapy (45-50 Gy, conventional fractionation) for either cervical carcinoma (radiotherapy and weekly cisplatin) or endometrial adenocarcinoma (postoperative radiotherapy) were randomly assigned to a probiotic drink or placebo, in a double-blind fashion. The probiotic drink consisted of liquid yogurt containing L. casei DN-114 001 at 10(8) CFU/g. The patients recorded the daily the number of bowel movements and scored the stool consistency using the Bristol scale. Diarrhea was graded weekly according the Common Toxicity Criteria system. The primary endpoint was to reduce the incidence of diarrhea, defined by a Common Toxicity Criteria Grade of 2 or greater or the need for loperamide. RESULTS: A total of 85 patients were enrolled. Grade 2 or greater diarrhea and/or the use of loperamide was observed in 24 of 41 patients in the placebo group and 30 of 44 in the probiotic group (p = 0.568). No differences were found in the median time to the presentation of the primary endpoint. Probiotic intervention had a significant effect on stool consistency (p = 0.04). The median time for patients to present with Bristol scale stools of Type 6 or greater was 14 days for patients receiving the probiotic drink vs. 10 days for those receiving placebo. CONCLUSION: Nutritional intervention with the probiotic drink containing L. casei DN-114 001 does not reduce the incidence of radiation-induced diarrhea as defined by a Common Toxicity Criteria Grade 2 or greater. However, it had a significant effect on stool consistency as measured by the Bristol scale.

Usefulness of extraperitoneal laparoscopic paraaortic lymphadenectomy for lymph node recurrence in gynecologic malignancy.

OBJECTIVE: The aim of this study was to evaluate the safety and feasibility of extraperitoneal laparoscopic paraaortic lymphadenectomy for suspected lymph node recurrence of gynecological cancers. DESIGN: Descriptive study. SETTING: Unit of Gynecologic Oncology of an acute-care teaching hospital in Barcelona, Spain. POPULATION: Between December 2002 and October 2007, eight women underwent extraperitoneal laparoscopic paraaortic lymphadenectomy for suspected lymph node recurrence, detected by magnetic resonance image (MRI), computed tomography (CT) scan or 18F-fluorodeoxyglucose positron emission tomography (PET) scanning. The suspicious nodes were removed through an extraperitoneal laparoscopic approach. RESULTS: The median age of patients was 66.5 years (range: 54-74). The median operating time was 157.5 minutes (range: 120-240). The median blood loss was 112.5 mL (range: 50-150). The mean nodal yield was 9.4+/-4.72 (range: 1-16). There were no intraoperative or postoperative complications. The median hospital stay was two days. Histological examination revealed metastasis in seven of eight patients. CONCLUSIONS: The extraperitoneal laparoscopic paraaortic lymphadenectomy for lymph node recurrence of gynecological cancers is a safe and feasible procedure which should be considered where there is isolated involvement of retroperitoneal lymph nodes. This procedure is a minimally invasive technique that allows an excellent approach to the paraaortic lymph nodes.

New and safe experimental model of radiation-induced neurovascular histological changes for microsurgical research.

The aim is to create a new and safe experimental model of radiation-induced neurovascular histological changes with reduced morbidity and mortality for use with experimental microsurgical techniques. Seventy-two Sprague-Dawley rats (250-300 g) were divided as follows: Group I: control group, 24 rats clinically evaluated during six weeks; Group II: evaluation of acute side-effects (two-week follow-up period), 24 irradiated (20 Gy) rats; and Group III: evaluation of subacute side-effects (six-week follow-up period), 24 irradiated (20 Gy) rats. Variables included clinical assessments, weight, vascular permeability (arterial and venous), mortality and histological studies. No significant differences were observed between groups with respect to the variables studied. Significant differences were observed between groups I vs II-III regarding survival rates and histological changes to arteries, veins and nerves. Rat body weights showed progressive increases in all groups, and the mortality rate of the present model is 10.4% compared with 30-40% in the previous models. In conclusion, the designed model induces selective changes by radiotherapy in the neurovascular bundle without histological changes affecting the surrounding tissues. This model allows therapeutic experimental studies to be conducted, including the viability of microvascular and microneural sutures post radiotherapy in the cervical neurovascular bundle.

Effect of Previous Irradiation on Vascular Thrombosis of Microsurgical Anastomosis: A Preclinical Study in Rats.

BACKGROUND: The objective of the present investigation was to compare the effect of neoadjuvant irradiation on the microvascular anastomosis in cervical bundle using an experimental model in rats. METHODS: One hundred forty male Sprague-Dawley rats were allocated into 4 groups: group I, control, arterial microanastomosis; group II, control, venous microanastomosis; group III, arterial microanastomosis with previous irradiation (20 Gy); and group IV, venous microanastomosis with previous irradiation (20 Gy). Clinical parameters, technical values of anastomosis, patency, and histopathological parameters were evaluated. RESULTS: Irradiated groups (III and IV) and vein anastomosis groups (II and IV) showed significantly increased technical difficulties. Group IV showed significantly reduced patency rates (7/35) when compared with the control group (0/35). Radiotherapy significantly decreased the patency rates of the vein (7/35) when compared with the artery (1/35). Groups III and IV showed significantly reduced number of endothelial cells and also showed the presence of intimal thickening and adventitial fibrosis as compared with the control group. CONCLUSION: Neoadjuvant radiotherapy reduces the viability of the venous anastomosis in a preclinical rat model with a significant increase in the incidence of vein thrombosis.

Clinical practice guidelines for the diagnosis and treatment of patients with soft tissue sarcoma by the Spanish group for research in sarcomas (GEIS).

Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumours, which require a complex and specialized multidisciplinary management. The diagnostic approach should include imaging studies and core needle biopsy performed prior to undertaking surgery. Wide excision is the mainstay of treatment for localized sarcoma, and associated preoperative or postoperative radiotherapy should be administered in high-risk patients. Adjuvant chemotherapy was associated with a modest improvement in survival in a meta-analysis and constitutes a standard option in selected patients with high-risk STS. In metastatic patients, surgery must be evaluated in selected cases. In the rest of patients, chemotherapy and, in some subtypes, targeted therapy often used in a sequential strategy constitutes the treatment of election. Despite important advances in the understanding of the pathophysiology of the disease, the advances achieved in therapeutic results may be deemed still insufficient. Moreover, due to the rarity and complexity of the disease, the results in clinical practice are not always optimal. For this reason, the Spanish Group for Research on Sarcoma (GEIS) has developed a multidisciplinary clinical practice guidelines document, with the aim of facilitating the diagnosis and treatment of these patients in Spain. In the document, each practical recommendation is accompanied by level of evidence and grade of recommendation on the basis of the available data.

Overexpression of phosphorylated 4E-BP1 predicts for tumor recurrence and reduced survival in cervical carcinoma treated with postoperative radiotherapy.

PURPOSE: To examine the prognostic value of the 4E-BP1 activation state and related upstream/downstream signaling proteins on the clinical outcome of patients with intermediate- or high-risk early-stage cervical carcinoma treated with postoperative radiotherapy and to determine the optimal treatment of early-stage cervical carcinoma. METHODS AND MATERIALS: Immunohistochemical staining was performed on 64 formalin-fixed, paraffin-embedded cervical carcinoma surgical specimens for each protein of the panel (p4E-BP1, phosphorylated mitogen-activated protein kinase, pAkt, vascular endothelial growth factor, KDR, Bcl-2, TP53, receptor for activated C-kinase 1). The expression patterns were related to the clinical data. All patients received postoperative radiotherapy. Concurrent chemotherapy was added if high-risk features were present. The median follow-up was 40 months. RESULTS: Of the 64 patients, 13 received concomitant chemotherapy. p4E-BP1 overexpression in moderate/high-risk early-stage cervical carcinoma correlated significantly with disease-free survival (hazard ratio, 4.39; p = .009) and overall survival (hazard ratio, 4.88; p = .005). Vascular endothelial growth factor, and its receptor KDR, had positive immunoreactivity in all tumor samples. No correlation with clinical outcome was found for the remaining proteins evaluated. CONCLUSION: In this study, moderate/high-risk early-stage cervical carcinoma with low p4E-BP1 expression was highly curable with the current postoperative treatments. For tumors with p4E-BP1 overexpression, new investigational strategies are needed.

Total laparoscopic radical hysterectomy (type II-III) with pelvic lymphadenectomy in early invasive cervical cancer.

STUDY OBJECTIVE: To describe the feasibility and outcome of total laparoscopic radical hysterectomy with pelvic lymphadenectomy in early cervical cancer. DESIGN: Retrospective, nonrandomized study (Canadian Task Force classification II-2). SETTING: Acute-care, teaching hospital. PATIENTS: Twenty-seven nonconsecutive patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA2 (n = 4) or IB1 (n = 23) cancer of the cervix. INTERVENTION: Laparoscopic type II (n = 9) or type III (n = 18) hysterectomy with systematic bilateral pelvic lymphadenectomy. Monopolar coagulation, vascular clips, and harmonic scalpel were used. Resection of the cardinal and uterosacral ligaments was performed with Endo GIA stapling and the harmonic scalpel. MEASUREMENTS AND MAIN RESULTS: Histopathologically, there were 20 cases of squamous carcinoma, 6 adenocarcinomas, and 1 adenosquamous carcinoma. The operation was performed entirely by laparoscopy in 26 patients. One patient underwent laparotomy because of equipment failure. The patients' mean age was 45.1 years (95% CI 41.7-48.4), with a median body mass index of 26.0 kg/m2. The mean number of resected pelvic nodes was 19.1 (95% CI 17.02-21.2). Three patients had microscopic metastatic nodal disease. The surgical margins were free of disease in all cases. The median blood loss was 400 mL (range 250-700 mL). The median length of stay was 5 days. Major intraoperative complications did not occur. All patients are free of disease after a median follow-up of 32 months (range 4-52 months). CONCLUSION: Radical hysterectomy can be successfully completed by laparoscopy in patients with early cervical cancer. This procedure may reduce the morbidity associated with abdominal or transvaginal radical hysterectomy.