Prognostic factors for and pattern of lymph-node involvement in patients with operable cervical cancer.

PURPOSE: Lymph node metastases significantly worsen the prognosis in cervical carcinoma. Risk factors-pathological and patient related-could select patients at high risk for lymph node involvement. METHODS: This retrospective analysis was performed by analyzing data from patients with cervical carcinoma treated between 2000 and 2017 at the Department of Obstetrics and Gynecology of the University Hospital Ulm. RESULTS: In total, 261 patients with cervical carcinoma (International Federation of Gynecology and Obstetrics (FIGO) stage IA-IIB) and lymphadenectomy with at least 10 removed lymph nodes were available for analysis. Overall, 86 (33.0%) patients had lymph node metastases; 73 patients had pelvic lymph node metastases only and 13 patients had both pelvic and paraaortic lymph node metastases. Lymph node metastases were found most often in the region of the external iliac artery and obturator fossa, with 57.0% and 54.7% of all 86 node-positive patients, respectively. Univariable analyses showed that presence of lymph node metastases was significantly associated with both preoperative FIGO stage (p = 0.001) and final pathological tumor stage (p < 0.001), status of resection margin (p = 0.002), lymphovascular space invasion (LVSI), (p < 0.001) and vascular space invasion, (p < 0.001). In a multivariable logistic regression model with presence of lymph node metastases (yes/no) as binary response variable, only LVSI (p < 0.001) and body mass index (BMI), (p = 0.035) remained as significant independent predictors of lymph node involvement. Subgroup analyses showed that LVSI was a significant predictive factor for lymph node involvement in patients with a preoperatively assessed FIGO stage < IIB (p < 0.001), but not for patients with a preoperatively assessed FIGO stage ≥ IIB (p = 0.122). CONCLUSIONS: The risk factor LVSI should play an important role in deciding whether an individualized therapy concept is based on escalating or deescalating treatment. In future, the sentinel concept could reduce morbidity and at the same time provide an important prognostic assessment for a subset of cervical cancer patients.

Pelvic exenteration as ultimate ratio for gynecologic cancers: single-center analyses of 37 cases.

BACKGROUND: Pelvic exenterations are a last resort procedure for advanced gynecologic malignancies with elevated risks in terms of patients' morbidity. METHODS: This single-center analysis reports surgical details, outcome and survival of all patients treated with exenteration for non-ovarian gynecologic malignancies at our university hospital during a 13-year time period. We collected data regarding patients and tumor characteristics, surgical procedures, peri- and postoperative management, transfusions, complications, and analyzed the impact on survival outcomes. RESULTS: We identified 37 patients between 2005 and 2013 with primary or relapsed cervical cancer (59.5%), vulvar cancer (24.3%) or endometrial cancer (16.2%). Median age was 60 years and most patients (73%) had squamous cell carcinomas. Median progression-free survival was 26.2 months and median overall survival was 49.9 months. The 5-year survival rates were 34.4% for progression-free survival and 46.4% for overall survival. There were no significant differences in progression-free survival and overall survival with regard to disease entity. Patients with tumor at the resection margins (R1) had a nearly significantly worse progression-free survival (median: 28.5 vs. 7.3 months, HR 2.59, 95% CI 0.98-6.88, p = 0.056) and a significantly worse overall survival (median: not reached vs. 10.9 months, HR 4.04, 95% CI 1.40-11.64, p = 0.010) compared to patients with complete tumor resection (R0). In addition, patients without lymphovascular space invasion had a significantly better progression-free survival (p = 0.017) and overall survival (p = 0.034) then patients with lymphovascular space invasion. We observed complications in 14 patients (37.8%), 10 of those were classified as Clavien-Dindo 3 or 4. There was a trend to worse progression-free survival in patients that suffered complications (p = 0.052). Median total amount of transfused blood products was 4 (range 0-20). CONCLUSION: Pelvic exenteration is a procedure that provides substantial progression-free survival and overall survival improvement and-in selected patients-can even achieve cure in otherwise hopeless clinical situations. Patients need to be offered earnest counseling for sufficient informed consent with realistic expectations what to expect.

Sex differences in food choices, adherence to dietary recommendations and plasma lipid profile in type 2 diabetes - The TOSCA.IT study.

BACKGROUND AND AIMS: Diabetic women have a more adverse plasma lipid profile than men. Sex differences in dietary habits may play a role, but are little investigated. The study evaluates the quality of diet, adherence to the nutritional recommendations of the Diabetes and Nutrition Study Group and their relation with plasma lipid in men and women with diabetes. METHODS AND RESULTS: We studied 2573 people, aged 50-75, enrolled in the TOSCA.IT study (clinicaltrials.gov; NCT00700856). Plasma lipids were measured centrally. Diet was assessed with a semi-quantitative food frequency questionnaire. Women had a more adverse plasma lipid profile than men. Women consumed significantly more legumes, vegetables, fruits, eggs, milk, vegetable oils, and added sugar, whereas men consumed more starchy foods, soft drinks and alcoholic beverages. This stands for a higher proportion (%) of energy intake from saturated fat and added sugar (12.0 ± 2.4 vs 11.5 ± 2.5 and 3.4 ± 3.2 vs 2.3 ± 3.2, P < 0.04), and a higher intake of fiber (11.2 ± 2.8 vs 10.4 ± 2.6 g/1000 Kcal/day) in women. Adherence to the recommendations for saturated fat and fiber consumption was associated with significantly lower LDL-cholesterol regardless of sex. Adherence to the recommendations for added sugars was associated with significantly lower triglycerides and higher HDL-cholesterol in men and women. CONCLUSIONS: Men and women with diabetes show significant differences in adherence to nutritional recommendations, but sex differences in plasma lipid profile are unlikely to be explained by nutritional factors. Adherence to the nutritional recommendations is associated with a better plasma lipid profile regardless of sex, thus reinforcing the importance of substituting saturated for unsaturated fat sources, increasing fiber and reducing added sugar intake.

Embolization of left spermatic vein in non-obstructive azoospermic men with varicocele: role of FSH to predict the appearance of ejaculated spermatozoa after treatment.

PURPOSE: Varicocele repair in non-obstructive azoospermia (NOA) was occasionally associated to ejaculated spermatozoa independently from clinical and laboratory measures. We performed a prospective study in infertile men affected by NOA and left side varicocele to find whether or not the appearance of ejaculated spermatozoa after varicocele repair is predicted by baseline measures. METHODS: Patients with NOA and grade II, or grade III left side varicocele were submitted to hormone analysis and to scrotal color Doppler ultrasound (CDU). Azoospermia was confirmed in 23 patients aged 25-47 years who were than submitted to varicocele repair through a retrograde internal spermatic vein embolization. Patients were re-evaluated after 6 months. RESULTS: Six months after varicocele repair 12 patients (52.2 %) were still azoospermic (Group 1) while 11 patients (47.8 %) reported ejaculated spermatozoa (Group 2) [sperm count: 1.3 × 10(6)/mL; 0.5 × 10(6)/mL-1.6 × 10(6)/mL (median 25th-75th centiles)]. Serum baseline FSH was lower in Group 2 compared to Group 1 (p = 0.012), while no differences between groups were revealed for all other clinical and laboratory parameters. ROC analysis indicated that baseline FSH level predicted the appearance of ejaculated spermatozoa after treatment [AUC = 0.811; 95 % Confidence Interval (CI) 0.6-0.9; p = 0.0029]. A cut-off level of FSH <10.06 mIU/mL identified 82.0 % of cases with ejaculated spermatozoa with a specificity of 81.8 % and a sensitivity of 83.3 %. CONCLUSION: Selected patients with NOA may show ejaculated spermatozoa after a non-invasive repair of a left side varicocele, therefore avoiding testicular sperm extraction. Baseline serum FSH was a valuable predictor for ejaculated spermatozoa after treatment.

IOeRT conventional and FLASH treatment planning system implementation exploiting fast GPU Monte Carlo: The case of breast cancer.

Partial breast irradiation for the treatment of early-stage breast cancer patients can be performed by means of Intra Operative electron Radiation Therapy (IOeRT). One of the main limitations of this technique is the absence of a treatment planning system (TPS) that could greatly help in ensuring a proper coverage of the target volume during irradiation. An IOeRT TPS has been developed using a fast Monte Carlo (MC) and an ultrasound imaging system to provide the best irradiation strategy (electron beam energy, applicator position and bevel angle) and to facilitate the optimisation of dose prescription and delivery to the target volume while maximising the organs at risk sparing. The study has been performed in silico, exploiting MC simulations of a breast cancer treatment. Ultrasound-based input has been used to compute the absorbed dose maps in different irradiation strategies and a quantitative comparison between the different options was carried out using Dose Volume Histograms. The system was capable of exploring different beam energies and applicator positions in few minutes, identifying the best strategy with an overall computation time that was found to be completely compatible with clinical implementation. The systematic uncertainty related to tissue deformation during treatment delivery with respect to imaging acquisition was taken into account. The potential and feasibility of a GPU based full MC TPS implementation of IOeRT breast cancer treatments has been demonstrated in-silico. This long awaited tool will greatly improve the treatment safety and efficacy, overcoming the limits identified within the clinical trials carried out so far.

GPU-accelerated Monte Carlo simulation of electron and photon interactions for radiotherapy applications.

Objective. The Monte Carlo simulation software is a valuable tool in radiation therapy, in particular to achieve the needed accuracy in the dose evaluation for the treatment plans optimisation. The current challenge in this field is the time reduction to open the way to many clinical applications for which the computational time is an issue. In this manuscript we present an innovative GPU-accelerated Monte Carlo software for dose valuation in electron and photon based radiotherapy, developed as an update of the FRED (Fast paRticle thErapy Dose evaluator) software.Approach. The code transports particles through a 3D voxel grid, while scoring their energy deposition along their trajectory. The models of electromagnetic interactions in the energy region between 1 MeV-1 GeV available in literature have been implemented to efficiently run on GPUs, allowing to combine a fast tracking while keeping high accuracy in dose assessment. The FRED software has been bench-marked against state-of-art full MC (FLUKA, GEANT4) in the realm of two different radiotherapy applications: Intra-Operative Radio Therapy and Very High Electron Energy radiotherapy applications.Results. The single pencil beam dose-depth profiles in water as well as the dose map computed on non-homogeneous phantom agree with full-MCs at 2% level, observing a gain in processing time from 200 to 5000.Significance. Such performance allows for computing a plan with electron beams in few minutes with an accuracy of ∼%, demonstrating the FRED potential to be adopted for fast plan re-calculation in photon or electron radiotherapy applications.

Low dose rate γ-irradiation protects fruit fly chromosomes from double strand breaks and telomere fusions by reducing the esi-RNA biogenesis factor Loquacious.

It is still continuously debated whether the low-dose/dose-rate (LDR) of ionizing radiation represents a hazard for humans. Model organisms, such as fruit flies, are considered valuable systems to reveal insights into this issue. We found that, in wild-type Drosophila melanogaster larval neuroblasts, the frequency of Chromosome Breaks (CBs), induced by acute γ-irradiation, is considerably reduced when flies are previously exposed to a protracted dose of 0.4 Gy delivered at a dose rate of 2.5 mGy/h. This indicates that this exposure, which is associated with an increased expression of DNA damage response proteins, induces a radioadaptive response (RAR) that protects Drosophila from extensive DNA damage. Interestingly, the same exposure reduces the frequency of telomere fusions (TFs) from Drosophila telomere capping mutants suggesting that the LDR can generally promote a protective response on chromatin sites that are recognized as DNA breaks. Deep RNA sequencing revealed that RAR is associated with a reduced expression of Loquacious D (Loqs-RD) gene that encodes a well-conserved dsRNA binding protein required for esiRNAs biogenesis. Remarkably, loss of Loqs mimics the LDR-mediated chromosome protection as it decreases the IR-induced CBs and TFs frequency. Thus, our molecular characterization of RAR identifies Loqs as a key factor in the cellular response to LDR and in the epigenetic routes involved in radioresistance.

Diagnosis of presence and extent of deep infiltrating endometriosis by preoperative MRI-improvement of staging accuracy by expert training.

INTRODUCTION: This study evaluates the clinical utility of magnetic resonance imaging (MRI) for the determination of presence and extent of DIE with special emphasis on effects of MRI reporting training MATERIAL AND METHODS: Data from 80 patients with clinically suspected DIE presented at our certified endometriosis center between 2015 and 2018 were analyzed. For all patients an ENZIAN score (describing DIE related to individual anatomical localizations) was obtained based on the preoperative MRI findings. The intraoperatively determined ENZIAN score served as the reference for assessment of diagnostic performance of the MRI. RESULTS: Overall, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of DIE by MRI were 76.9%, 53.3%, 87.7% and 34.8%, respectively. Analysis by compartment revealed a sensitivity, specificity, PPV and NPV of 59.5%, 88.2%, 86.2% and 63.9%, respectively, for compartment A, with similar values for compartment B, and 50.0%, 88.9%, 64.7% and 81.4%, respectively, for the less often affected compartment C. Expert training (n = 32 before, n = 48 after) led to a considerable increase in sensitivities for the overall detection of DIE (84.6% vs. 65.4%, p = 0.071) and for the detection of DIE in compartment A (71.4% vs. 35.7%, p = 0.026), compartment B (66.7% vs. 37.5%, p = 0.057) and compartment C (75.0% vs. 20.0%, p = 0.010), without significant loss in specificity (all p > 0.50). DISCUSSION: After expert training, MRI has a good sensitivity with fair specificity regarding preoperative assessment of presence, location and extent of DIE.

Perspectives in linear accelerator for FLASH VHEE: Study of a compact C-band system.

PURPOSE: In order to translate the FLASH effect in clinical use and to treat deep tumors, Very High Electron Energy irradiations could represent a valid technique. Here, we address the main issues in the design of a VHEE FLASH machine. We present preliminary results for a compact C-band system aiming to reach a high accelerating gradient and high current necessary to deliver a Ultra High Dose Rate with a beam pulse duration of 3µs. METHODS: The proposed system is composed by low energy high current injector linac followed by a high acceleration gradient structure able to reach 60-160 MeV energy range. To obtain the maximum energy, an energy pulse compressor options is considered. CST code was used to define the specifications RF parameters of the linac. To optimize the accelerated current and therefore the delivered dose, beam dynamics simulations was performed using TSTEP and ASTRA codes. RESULTS: The VHEE parameters Linac suitable to satisfy FLASH criteria were simulated. Preliminary results allow to obtain a maximum energy of 160 MeV, with a peak current of 200 mA, which corresponds to a charge of 600 nC. CONCLUSIONS: A promising preliminary design of VHEE linac for FLASH RT has been performed. Supplementary studies are on going to complete the characterization of the machine and to manufacture and test the RF prototypes.

Cardiovascular events in patients with antiphospholipid antibodies: strategies of prevention.

Antiphospholipid antibodies are a heterogeneous group of auto-antibodies against phospholipids-binding proteins. The antiphospholipid syndrome is an autoimmune disorder characterized by the clinical association of antiphospholipid antibodies with a condition of hypercoagulability that can affect any blood vessel. Involvement of larger vessels, such as arteries or veins, manifests in the form of thrombosis or thromboembolism, whereas involvement of small vessels manifests as thrombotic micro-angiopathy. The antiphospholipid syndrome is also characterized by the presence of recurrent fetal loss. Patients who are persistently positive for antiphospholipid tests, and who have an arterial thrombosis or venous thrombosis history, are at increased risk of recurrence. Oral anticoagulant therapy is the mainstay of treatment for the thrombotic manifestations of the syndrome. Therapy with anticoagulant drugs should be long-term. On the other hand, although the thromboembolic potential of antiphospholipid antibodies has been well documented, there is still no general consensus on the prophylactic treatment of antiphospholipid antibodies carriers who have never developed vascular/obstetric manifestations. The effect of primary prophylaxis in antiphospholipid antibodies positive individuals is not well known and no evidence-based recommendations exist for thrombosis prevention in these individuals. However, the presence of risk factors for thrombosis increases the risk of first event of antiphospholipid antibodies positive patients. In conclusion, there is still much to learn on primary prophylaxis of asymptomatic antiphospholipid antibodies carriers. Hopefully, evidence-based guidelines will be available in the future.

Endocytoscopy can identify dysplasia in aberrant crypt foci of the colorectum: a prospective in vivo study.

BACKGROUND AND STUDY AIM: A catheter-type endocytoscope has recently been developed that is able to provide in vivo cellular images of gastrointestinal mucosa. Aberrant crypt foci (ACF) represent the earliest precursor of colorectal cancer featuring the dysplasia-carcinoma sequence. The aim of the current study was to assess the potential of the endocytoscopy system (ECS) in the "in vivo" detection of dysplasia in colorectal ACF. PATIENTS AND METHODS: Consecutive patients with colorectal ACF were studied with endocytoscopy. Blinded endoscopic and histological assessments were obtained. Lesions were excised en bloc for histology. RESULTS: A total of 48 colorectal lesions were examined in 41 patients. The mean duration of the ECS procedure was 44 +/- 12 minutes (range 31 - 62 minutes). The quality of ECS images was rated as good in 39/48, medium in six, and poor in three (6.2 %). It was possible to observe lesions at the cellular level and evaluate both cellular and structural atypia in vivo. In normal mucosa, crypts had preserved individuality and round-shaped contours. Nuclei were located at the basal third of the crypt in a single line, and the lumen was circular. In dysplastic ACF, crypt contours were polygonal, cell nuclei were elongated with pseudostratification toward the luminal half of the crypt and irregularly arranged, and the lumen was linear. In all, 23 endocytoscopic images were labeled as dysplastic and 25 as nondysplastic. Histology confirmed low-grade dysplasia in 21/23 cases (91.4 % sensitivity). Absence of dysplasia was confirmed in the remaining 25 cases (100 % specificity). Interobserver agreement between trained endoscopist and pathologist was good (wK 0.68; 95 % CI 0.59 - 0.78). CONCLUSIONS: Endocytoscopy provides real-time histological images in vivo, with clear visualization of cellular details and features of dysplasia in colorectal ACF.

XEN glaucoma treatment system in the management of refractory glaucomas: a short review on trial data and potential role in clinical practice.

The recent development of new devices that are significantly less invasive, collectively termed minimally invasive glaucoma surgery, offers new perspective of intraocular pressure reduction with less risk, short operating times, and rapid recovery. The aim of this work is to provide a panoramic review of the currently published clinical data to assess the potential role of XEN gel stent (Allergan PLC, Irvine, CA, USA) in the management of glaucoma, which is the only filtering minimally invasive glaucoma surgery device that allows the subconjunctival filtration. The ab interno placement of the XEN gel stent offers an alternative for lowering intraocular pressure in refractory glaucoma as a final step, and in patients intolerant to medical therapy as an early surgical approach with minimum conjunctival tissue disruption, restricted flow to avoid hypotony, and long-term safety.

Anti-Müllerian hormone (AMH) levels in premenopausal breast cancer patients treated with taxane-based adjuvant chemotherapy - A translational research project of the SUCCESS A study.

BACKGROUND: Premenopausal women undergoing chemotherapy are at high risk for premature ovarian failure and its long-term consequences. Data on potential markers to evaluate ovarian reserve pre- and posttreatment are limited. Anti-Müllerian hormone (AMH) known for ovarian reserve in reproductive medicine could be a surrogate marker and was assessed in premenopausal breast cancer patients of the SUCCESS A study (EUDRA-CT no. 2005-000490-21). METHODS: We identified 170 premenopausal patients, age ≤ 40 years at trial entry, who received FEC-Doc as taxane-anthracylince based chemotherapy. Blood samples were taken at three time points: Before, four weeks after and two years after adjuvant chemotherapy. Serum AMH-levels were evaluated in a central laboratory by a quantitative immunoassay AMH Gen II ELISA (Beckman Coulter, Brea, USA). RESULTS: Median age was 36 years (21-40 years). Median serum AMH-level before chemotherapy was 1.37 ng/ml (range < 0.1-11.3 ng/ml). Four weeks after chemotherapy AMH-levels dropped in 98.6% of the patients to <0.1 ng/ml (range < 0.1-0.21 ng/ml). After two years, 73.3% (n = 101) showed no evidence of ovarian function recovery (AMH <0.1 ng/ml, range < 0.1-3.9 ng/ml). Permanent chemotherapy induced amenorrhea occurred only in 50.6% of the patients. CONCLUSIONS: In this analysis, premenopausal patients showed a high rate of ovarian impairment reflected by low AMH-levels after chemotherapy.

Extradural low cervical chordoma. Case report.

Chordoma of the mobile segments of the spine are infrequent lesions and especially rare are those located in the lower part of the cervical spine. We present the case of a cervical chordoma located in the C6 vertebral body diagnosed by means of magnetic resonance imaging and operated on by an anterior approach. The authors discuss the clinical and neuroradiological features of this disease also analysing some controversial therapeutic aspects.

Effect of some vasodilators on cat femoral arteries.

Adenosine, cyclic-AMP (cAMP), papaverine and 1-methyl-3-isobutylxanthine (MIX) evoked dose-dependent vasodilatation in cat femoral arteries precontracted with 75 mM K+. The vasodilator response induced at maximal concentration used was: papaverine greater than MIX greater than adenosine = cAMP. With regard to the potency of relaxant effects (IC10) the order was MIX = cAMP = papaverine greater than adenosine. The dilatation elicited by papaverine, adenosine and cAMP was increased by MIX. Preincubation with adenosine enhanced the relaxation induced by MIX and reduced that produced by cAMP. These results indicate that the effects of adenosine and cAMP seem not to be mediated by specific surface receptors but by a cAMP-dependent mechanism. The interference between adenosine and cAMP could be due to competition for a similar site and/or mechanism.

SCP and crude pectinase production by slurry-state fermentation of lemon pulps.

Single cell protein (SCP) and crude pectinolytic enzymes production from citrus pulps is reported. SCP and enzymes were produced by slurry-state flask cultivation of Aspergillus niger and Trichoderma viride on pulps from lemon juice clarification. Production as well as crude pectinase activity was not affected by the high dry matter content of the pulps. Both the protein content in the residue and the enzyme activity in the supernatant were higher in T. viride than in A. niger culture. The crude pectinase of T. viride, whose specific activity was similar to that found for a commercial concentrated preparation, could be utilized in the same citrus processing factory as well as in other factories which use large amounts of pectinolytic crude preparations, for example to enhance depuration plant performance.

Malignant lymphoma, Burkitt's type: histologic report of two cases in Italy.

Two cases of undifferentiated Burkitt's type malignant lymphoma with prevalent ovarian localization and observed in Italy are described histologically. Some brief considerations about the extra African diffusion of this lymphoma are pointed out.

[Leiomyosarcoma of the small intestine and the colorectum. A case contribution]. / Il leiomiosarcoma del tenue e del colon-retto. Contributo casistico.

Smooth muscle tumors of the alimentary tract are uncommon. A retrospective study was made of 7 patients treated for leiomyosarcoma of the small and large bowel to identify prognostic factors that influence results. The symptoms associated with these tumors varied according to the anatomic sites of the lesions and the position of the growth in relation to the intestinal lumen but the most common presenting clinical signs are bleeding or obstruction. The differential diagnosis between benign and malignant smooth muscle tumors is sometimes quite difficult. Clinical behavior of the myosarcomas of the gastrointestinal tract can be predicted to a large extent by the site of the tumor, the presence or absence of invasion of adjacent vital organs, and the histopathologic grade of malignancy. Although the mitotic activity of a gastrointestinal stromal tumor remains the most critical prognostic factor, tumors have been seen to recur locally and to metastasize even with rare or absent mitotic figures. Further studies are needed to pinpoint the factors that may be correlated to the prognosis.