Immunohistochemical biomarkers are prognostic relevant in addition to the ESMO-ESGO-ESTRO risk classification in endometrial cancer.

OBJECTIVE: Pre-operative immunohistochemical (IHC) biomarkers are not incorporated in endometrial cancer (EC) risk classification. We aim to investigate the added prognostic relevance of IHC biomarkers to the ESMO-ESGO-ESTRO risk classification and lymph node (LN) status in EC. METHODS: Retrospective multicenter study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), analyzing pre-operative IHC expression of p53, L1 cell-adhesion molecule (L1CAM), estrogen receptor (ER) and progesterone receptor (PR), and relate to ESMO-ESGO-ESTRO risk groups, LN status and outcome. RESULTS: A total of 763 EC patients were included with a median follow-up of 5.5-years. Abnormal IHC expression was present for p53 in 112 (14.7%), L1CAM in 79 (10.4%), ER- in 76 (10.0%), and PR- in 138 (18.1%) patients. Abnormal expression of p53/L1CAM/ER/PR was significantly related with higher risk classification groups, and combined associated with the worst outcome within the 'high and advanced/metastatic' risk group. In multivariate analysis p53-abn, ER/PR- and ESMO-ESGO-ESTRO 'high and advanced/metastatic' were independently associated with reduced disease-specific survival (DSS). Patients with abnormal IHC expression and lymph node metastasis (LNM) had the worst outcome. Patients with LNM and normal IHC expression had comparable outcome with patients without LNM and abnormal IHC expression. CONCLUSION: The use of pre-operative IHC biomarkers has important prognostic relevance in addition to the ESMO-ESGO-ESTRO risk classification and in addition to LN status. For daily clinical practice, p53/L1CAM/ER/PR expression could serve as indicator for surgical staging and refine selective adjuvant treatment by incorporation into the ESMO-ESGO-ESTRO risk classification.

Transferrin-functionalized lipid nanoparticles for curcumin brain delivery.

Curcumin is an anti-inflammatory and antioxidant compound with potent neuroprotective activity. Due to its poor water solubility, low bioavailability, rapid elimination and the challenges for crossing and transposing the blood-brain barrier (BBB), solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) loaded with curcumin were successfully produced and functionalized with transferrin, in order to mediate the transport of these particles through the BBB endothelium to the brain. The nanosystems revealed Z-averages under 200 nm, polydispersity index below 0.2 and zeta potential around -30 mV. Curcumin encapsulation around 65 % for SLNs and 80 % for NLCs was accomplished, while the functionalized nanoparticles presented a value around 70-75 %. A stability study revealed these characteristics remained unchanged for at least 3 months. hCMEC/D3 cells viability was firstly analysed by MTT and LDH assays, respectively, and a concentration of 10 µM of curcumin-loaded nanoparticles were then selected for the subsequent permeability assay. The permeability study was conducted using transwell devices with hCMEC/D3 cells monolayers and a 1.5-fold higher permeation of curcumin through the BBB was verified. Both SLNs and NLCs are promising for curcumin brain delivery, protecting the incorporated curcumin and targeting to the brain by the addition of transferrin to the nanoparticles surface.

Neoadjuvant chemotherapy followed by surgery for advanced-stage endometrial cancer.

Background: Data showing the value of neoadjuvant chemotherapy (nact) followed by interval debulking surgery (ids) in the management of advanced-stage serous endometrial carcinoma (eca) are limited; the aim of the present study was to expand the knowledge about that treatment strategy in patients with advanced eca, including endometrioid eca. Methods: Data were collected retrospectively from all patients with advanced-stage eca treated with nact between 2005 and 2014 at 3 oncology referral centres. Primary outcomes were the radiologic response to nact and achievement of optimal or complete ids. Secondary outcomes were recurrence rate and progression-free and overall survival. Results: Of 102 eca cases included, a complete radiologic response was achieved in only 4 cases, with a partial response being achieved in 72% (64% of endometrioid cases, 80% of serous cases). Complete ids was achieved in 62% of the endometrioid cases and in 56% of the serous eca cases, with optimal ids achieved in 31% and 28% of those cases respectively. Survival rates were calculated for all patients with complete and optimal ids; recurrence was observed in 56% and 67% of the cases respectively, and progression-free survival was 18 months and 13 months respectively. Median survival duration was 24 months for endometrioid eca and 28 months for serous eca. Conclusions: For patients with advanced eca who are not suitable for primary debulking, nact followed by ids can be considered regardless of histologic subtype. The treatment options for this group of patients are limited and have to be explored.

The opinion of gynecologists on the management of early-stage, high-grade endometrioid endometrial cancer.

PURPOSE OF INVESTIGATION: There is no consensus on the management of Stage I endometrioid endometrial cancer (EEC) with grade 3 histology. This study evaluates the opinion of gynecologists in The Netherlands on the management of Stage I, grade 3 EEC. MATERIALS AND METHODS: Members of the Dutch Gynecologic Oncology Working Group were requested to complete a digital questionnaire on the management of Stage I, grade 3 EEC. Actual treatment of patients with Stage I, grade 3 EEC was assessed by analysis of PALGA, the Dutch Pathology Registry. RESULTS: Most gynecologists prefer routine lymphadenectomy or complete staging (62.3%), while these were actually performed in 27.3% of the cases. Gynecologic oncologists are more likely to perform a lymphadenectomy than general gynecologists. There was a wide variation of clinical practice. CONCLUSION: The results of this study underline the need for additional research into management of Stage I, grade 3 EEC as well as the need for conclusive guidelines.

Diffusion-weighted MR imaging in head and neck cancer: comparison between half-fourier acquired single-shot turbo spin-echo and EPI techniques.

BACKGROUND AND PURPOSE: Several studies have reported on the clinical utility of DWI in head and neck cancer, but none of these studies compared HASTE with EPI-DWI in patients with head and neck cancer. The aim of our study was to compare detection and delineation of primary tumors and lymph nodes by using HASTE and EPI-DWI techniques in patients with HNSCC. MATERIALS AND METHODS: Twelve patients with HNSCC and a total of 12 primary tumors and 77 visualized lymph nodes on MR imaging underwent DWI by using both EPI-based and HASTE techniques. Interobserver agreement for detection, delineation, and ADC values of primary tumors and lymph nodes was assessed by 2 radiologists, and artifacts for both DWI techniques were described. RESULTS: The number of lesions (primary tumors and lymph nodes) identified on pretreatment EPI-DWI was higher compared with pretreatment HASTE-DWI, with means of total lesions of 88.5 and 69.0, respectively. Delineation of lesions was also better on pretreatment EPI-DWI compared with pretreatment HASTE-DWI, with means of well-delineated lesions of 80.5 and 27.5, respectively. Both EPI- and HASTE-DWI showed good interobserver agreement between radiologists of ADC values in lesions with ICC values of 0.79 and 0.92, respectively. Intraobserver agreement for ADC values in lesions assessed with EPI- versus HASTE-DWI techniques was low, with ICC values of 0.31 and 0.42, respectively. Significant interobserver disagreement concerning detection was only seen with HASTE-DWI, and none of the DWI techniques showed significant interobserver disagreements regarding delineation. EPI-DWI was more prone to susceptibility artifacts than HASTE-DWI: Ninety-one percent of primary tumors and 16% of lymph nodes were affected by susceptibility artifacts on pretreatment EPI-DWI, whereas these artifacts were not seen on HASTE-DWI. CONCLUSIONS: Primary tumors and lymph nodes are more easily visualized on EPI-DWI compared with HASTE-DWI. EPI-DWI has geometric distortion, however, which has a negative effect on interobserver agreement of ADC values.

Flap reconstruction of the hypopharynx: a defect orientated approach.

The present retrospective analysis evaluated the outcomes of different flap reconstructions for several hypopharyngeal defects in 136 patients who underwent hypopharyngeal reconstruction with a free or pedicled flap after excision of pharyngeal or laryngeal carcinoma.Functional and oncological outcome were the main measures. Nine patients had a type I-a hypopharyngeal defect (partial with larynx preserved), 33 type I-b (partial without larynx preserved), 85 type II (circumferential), 5 type III (extensive superior) and 4 vertical hemipharyngolaryngectomy. The flaps used to reconstruct these defects were pectoralis major (n = 34), free radial forearm (n = 25), jejunum (n = 72), pedicled latissimus dorsi (n = 2), sternocleidomastoid (n = 1), lateral thigh (n = 1) and deltopectoral (n = 1). Twelve defects (9%) needed a secondary flap reconstruction. Surgical and medical complications were seen in 29% and 8% of patients, respectively; 18% of patients developed a fistula. No difference in complication rate or admission days was found for pre-operative versus no previous radiotherapy, type of defect or free versus pedicled flap. After 12 months follow-up, 38% of patients had a tracheo-oesophageal voice prosthesis, in 82% a fully oral diet was obtained and the average body weight gain was 0.9 kg. Five-year overall and disease-specific survival rates were 35% and 49%, respectively, while local and regional control rates were 65% and 91%, respectively. Considering these results, a defect orientated approach may be helpful for deciding which flap should be used for reconstruction of the hypopharynx. An algorithm is proposed with similar functional and oncological outcomes for the different groups. The choice of flap should be based on expected morbidity and functional outcome.

Paratracheal lymph node dissection during laryngectomy after previous (chemo)radiotherapy: a retrospective analysis of complications and histopathological results.

OBJECTIVES: To evaluate complications and histopathological results of paratracheal lymph node dissection (PTLND) at laryngectomy after (chemo)radiotherapy. DESIGN, SETTING AND PARTICIPANTS: In a retrospective analysis, complications and histopathological results of paratracheal lymph node dissections were analysed in 191 patients with a recurrent or second primary laryngeal or hypopharyngeal carcinoma following radiotherapy with or without chemotherapy. MAIN OUTCOME MEASURES: The percentage of complications in patients with bilateral, unilateral or without PTLND. RESULTS: Forty-seven patients underwent laryngectomy with bilateral paratracheal lymph node dissection, 52 with unilateral and 92 without paratracheal lymph node dissection. Although the difference in total complications was not significant, significantly more fistulae developed in patients with bilateral paratracheal lymph node dissection (40%versus 22%; P =0.016). In multivariate analysis, this difference maintained significant (P = 0.038). Pathological examination of the lymph node dissection specimen showed tumour in 3 of the 96 ipsilateral dissections (3%) and in 1 of the 50 contralateral dissections (2%). This suggests that if unilateral instead of a bilateral paratracheal lymph node dissection had been performed, 17% less fistulae would have occurred in this group of patients, while paratracheal lymph node (PTLN) metastases would have been missed in one patient. Three of four patients with paratracheal lymph nodeparatracheal lymph node metastases had glottic carcinoma, all with subglottic extension. CONCLUSION: Because of the low incidence of lymph node metastases and the increased risk of fistulae, there is a need for a strict selection of patients who need a bilateral paratracheal lymph node dissection at laryngectomy after previous (chemo)radiotherapy.

Salvage laryngectomy: oncological and functional outcome.

The purpose of the research was to evaluate postoperative complications, functional outcome and survival after salvage laryngectomy. Second, to evaluate the management of the neck in combination with a laryngectomy in this group of patients. A retrospective analysis of all patients who underwent total laryngectomy for residual or recurrent squamous cell laryngeal carcinoma after (chemo)radiotherapy between November 1990 and June 2007 was performed. Of the 120 patients that were included, the complication rate was 56% (33% major and 23% minor). In univariate analyses, T-stage (p=0.05), bilateral neck dissection (p=0.09) and ASA score (p=0.08) showed a trend for postoperative major complications. Lymph node metastases were found in 26% of the neck dissection specimens, with a trend towards more regional disease at higher initial N-stage (p=0.06) and T-stage (p=0.08). Five-year disease specific survival was 58%. In univariate analyses pre-operative chemoradiation (vs. radiation) (p=0.0001), N3 neck (p=0.001) and positive surgical margins (p=0.02) were significant predictors for a worse disease specific survival, but only positive surgical margins (p<0.001) maintained significance in multivariate analysis. Eighty-seven percent of the patients were able to produce speech using a voice prosthesis, and 84% of the patients were able to have a 'normal' or 'soft' diet. There was an almost significant increase in mean body mass index (BMI) 6-12 months postoperative (p=0.057). Laryngectomy after radiotherapy offers good survival, with a substantial risk of complications and good functional outcome.

2-Deoxy-2[F-18]FDG-PET for detection of recurrent laryngeal carcinoma after radiotherapy: interobserver variability in reporting.

PURPOSE: To evaluate accuracy and interobserver variability in the assessment of 2-deoxy-2[F-18]fluoro-D-glucose-positron emission tomography (FDG-PET) for detection of recurrent laryngeal carcinoma after radiotherapy. PROCEDURES: Eleven experienced nuclear physicians from eight centres assessed 30 FDG-PET scans on the appearance of local recurrence (negative/equivocal/positive). Conservative (equivocal analysed as negative) and sensitive (equivocal analysed as positive) assessment strategies were compared to the reference standard (recurrence within 6months after PET). RESULTS: Seven patients had proven recurrences. For the conservative and sensitive strategy, the mean sensitivity was 87% and 97%, specificity 81% and 63%, positive predictive values 61% and 46% and negative predictive values 96% and 99%, respectively. Interobserver variability showed a reasonable relation in comparison to the reference standard (kappa = 0.55). CONCLUSIONS: FDG-PET has acceptable interobserver agreement and yields good negative predictive value for detection of recurrent laryngeal carcinoma. It could therefore be used as first diagnostic step and may reduce futile invasive diagnostics.