Minimally Invasive Approaches in Locally Advanced Cervical Cancer Patients Undergoing Radical Surgery After Chemoradiotherapy: A Propensity Score Analysis.

PURPOSE: Chemoradiation (CT/RT) followed by radical surgery (RS) may play a role in locally advanced cervical cancer (LACC) patients with suboptimal response to CT/RT or in low-income countries with limited access to radiotherapy. Our aim is to evaluate oncological and surgical outcomes of minimally invasive radical surgery (MI-RS) compared with open radical surgery (O-RS). PATIENTS AND METHODS: Data for stage IB2-IVA cervical cancer patients managed by CT/RT and RS were retrospectively analyzed. RESULTS: Beginning with 686 patients, propensity score matching resulted in 462 cases (231 per group), balanced for FIGO stage, lymph node status, histotype, tumor grade, and clinical response to CT/RT. The 5-year disease-free survival (DFS) was 73.7% in the O-RS patients and 73.0% in the MI-RS patients (HR 1.034, 95% CI 0.708-1.512, p = 0.861). The 5-year locoregional recurrence rate was 12.5% (O-RS) versus 15.2% (MI-RS) (HR 1.174, 95% CI 0.656-2.104, p = 0.588). The 5-year disease-specific survival (DSS) was 80.4% in O-RS patients and 85.3% in the MI-RS group (HR 0.731, 95% CI 0.438-1.220, p = 0.228). Estimated blood loss was lower in the MI-RS group (p < 0.001), as was length of hospital stay (p < 0.001). Early postoperative complications occurred in 77 patients (33.3%) in the O-RS group versus 88 patients (38.1%) in the MI-RS group (p = 0.331). Fifty-six (24.2%) patients experienced late postoperative complications in the O-RS group, versus 61 patients (26.4%) in the MI-RS group (p = 0.668). CONCLUSION: MI-RS and O-RS are associated with similar rates of recurrence and death in LACC patients managed by surgery after CT/RT. No difference in early or late complications was reported.

The Role of Radiotherapy in Extramammary Paget Disease: A Systematic Review.

OBJECTIVE/PURPOSE: Extramammary Paget disease (EMPD) is a rare neoplasm of the skin generally affecting the anogenital area. Because of the low-frequency of the disease, no specific guidelines about the treatment strategy are available. Surgery is the recommended therapy for resectable and localized disease, but several other local treatments have been reported such as radiotherapy (RT). Most articles report small retrospective studies, referring to patients treated decades ago with large heterogeneity in terms of RT dose and technique. The aim of this study was to systematically review the main experiences in RT for the treatment of EMPD in the past 30 years. MATERIALS AND METHODS: A systematic search of the bibliographic databases PubMed and Scopus from January 1986 to January 2017 was performed including studies published in English, Italian, Spanish, French, and German language. RESULTS: According to the search strategy, 19 full-text articles, published from 1991 to 2015, fulfilled inclusion criteria and were included in the final review. All articles were retrospective analyses with no randomized controlled trials. These studies evaluated 195 EMPD patients treated with RT, delivered in several settings. A large variability in terms of RT doses, fractionation, clinical setting, and techniques was found.Radiotherapy was administered as definitive treatment for primary or recurrent disease after surgery in 18 studies with doses ranging from 30 to 80.2 Gy delivered in 3 to 43 fractions. Radiotherapy was administered as postoperative adjuvant treatment in 9 articles with doses ranging between 32 and 64.8 Gy in 20 to 30 fractions. Two studies reported the RT use in preoperative neoadjuvant setting with doses ranging between 40 and 43.30 Gy, and 2 experiences reported the RT treatment for in situ EMPD, using 39.6 to 40 Gy. Adverse events were reported in almost all but 2 articles and were grade 2 or lower.The 18 studies evaluating RT as definitive treatment for primary or recurrent disease after surgery reported a complete response rate ranging from 50% to 100%, with a variable rate of local relapse or persistent disease ranging from 0% to 80% of cases. The 9 studies evaluating RT as postoperative adjuvant treatment reported a local relapse or persistent disease rate of 0% to 62.5%. A dose-response relationship was reported suggesting doses greater than or equal to 60 Gy for gross tumor volume treatment. Local control, disease-free survival, and overall survival at 12, 20, and 60 months have been retrieved for available data, respectively.In patients with EMPD and concurrent underlying internal malignancy, the prognosis was often worsened by the latter. In this setting, literature analysis showed a potential RT palliative role for symptoms control or local control maintenance.Derma tumor invasion greater than 1 mm and lymph node metastases were reported to be important prognostic factors for distant metastases or death. CONCLUSIONS: To date, literature highlights the role of RT in the management of EMPD, but with low level of evidences.

Clinical outcome of recurrent locally advanced cervical cancer (LACC) submitted to primary multimodality therapies.

OBJECTIVES: Recurrence of disease represents a clinical challenge in cervical cancer patients, especially when all available treatment modalities have been used in the primary setting. The aim of this study was to analyze the patterns of recurrence and their association with clinical outcome in locally advanced cervical cancer (LACC) patients submitted to primary chemoradiation (CTRT) followed by radical surgery (RS). METHODS: This study was conducted on 364 LACC patients treated with CTRT plus RS since January 1996 to July 2012. For each relapse, information on date of clinical/pathological recurrence, and pattern of disease presentation were retrieved. Post-relapse survival (PRS) was recorded from the date of recurrence to the date of death for disease or last seen. Survival probabilities were compared by the log rank test. Cox's regression model with stepwise variable selection was used for multivariate prognostic analysis for PRS. RESULTS: Within a median follow-up of 42months, 75 recurrences (20.6%) and 54 disease-associated deaths (14.8%) were recorded. By analysing the pattern of relapse, most of the recurrences were outside the irradiated field (n=43, 57.3%) and the most frequently observed site was visceral (n=16, 21.3%). Among the parameters of the recurrence associated with PRS including the pattern of recurrence, the size of recurrence, SCC-Ag serum levels at recurrence, and secondary radical surgery, only the last one retained an independent predictive role in reducing the risk of death (p=0.037). CONCLUSIONS: The feasibility of secondary radical resection positively impacts on PRS of LACC patients submitted to multimodality primary treatments.

Successful treatment of a young patient with locally advanced clear cell adenocarcinoma of the uterine cervix undergoing chemoradiation followed by radical surgery.

Clear cell adenocarcinoma (CCAC) of the uterine cervix is a rare variant of cervical adenocarcinoma accounting for approximately 4-9% of this disease. Given the rarity of this pathological entity, the optimal treatment management is far from being defined. Earlier evidence suggested that the prognosis of patients bearing cervical CCAC is worse than with other histotypes, thus making the investigation of multimodal treatment strategies clinically worthwhile. Herein, we report the first case of locally advanced, large size cervical CCAC in a young woman who was triaged to concomitant chemoradiotherapy followed by radical surgery and experienced a pathologically assessed optimal response to this multimodal approach.

Volumetric Intensity-Modulated Arc Stereotactic Radiosurgery Boost in Oligometastatic Patients with Spine Metastases: a Dose-escalation Study.

AIMS: To report the final results of a dose-escalation study of volumetric intensity-modulated arc stereotactic radiosurgery (VMAT-SRS) boost after three-dimensional conformal radiation therapy in patients with spine metastases. MATERIALS AND METHODS: Oligometastatic cancer patients bearing up to five synchronous metastases (visceral or bone, including vertebral ones) and candidates for surgery or radiosurgery were considered for inclusion. 25 Gy was delivered in 10 daily fractions (2 weeks) to the metastatic lesion, affected vertebrae and adjacent ones (one cranial and one caudal vertebra). Sequentially, the dose to spinal metastases was progressively increased (8 Gy, 10 Gy, 12 Gy) in the patient cohorts. Dose-limiting toxicities were defined as any treatment-related non-hematologic acute adverse effects rated as grade ≥3 or any acute haematological toxicity rated as ≥ 4 by the Radiation Therapy Oncology Group scale. RESULTS: Fifty-two lesions accounting for 40 consecutive patients (male/female: 29/11; median age: 71 years; range 40-85) were treated from April 2011 to September 2020. Most patients had a primary prostate (65.0%) or breast cancer (22.5%). Thirty-two patients received 8 Gy VMAT-SRS boost (total BED α/ß10: 45.6 Gy), 14 patients received 10 Gy (total BED α/ß10: 51.2 Gy) and six patients received 12 Gy (total BED α/ß10: 57.6 Gy). The median follow-up time was over 70 months (range 2-240 months). No acute toxicities > grade 2 and no late toxicities > grade 1 were recorded. The overall response rate based on computed tomography/positron emission tomography-computed tomography/magnetic resonance was 78.8%. The 24-month actuarial local control, distant metastases-free survival and overall survival rates were 88.5%, 27.1% and 90.3%, respectively. CONCLUSION: A 12 Gy spine metastasis SRS boost following 25 Gy to the affected and adjacent vertebrae was feasible with an excellent local control rate and toxicity profile.

Stereotactic Body Reirradiation in Gynaecological Cancer: Outcomes and Toxicities from a Single Institution Experience.

AIMS: To report toxicity profile, outcomes and quality of life (QoL) data in patients with recurrent gynaecological cancer who underwent stereotactic body radiotherapy (SBRT) retreatment. MATERIALS AND METHODS: Data from patients' folders were retrospectively extracted, focusing on the primary neoplasm, previous systemic therapies and previous radiotherapy. Concerning SBRT, the total dose (five daily fractions) was delivered with a linear accelerator using intensity-modulated radiotherapy techniques. Acute and late toxicities were assessed by the CTCAE 4.03 scale. QoL was evaluated according to the Cancer Linear Analogue Scale [CLAS1 (fatigue), CLAS2 (energy level), CLAS3 (daily activities)]. RESULTS: Between December 2005 and August 2021, 23 patients (median age 71 years, range 48-80) with 27 lesions were treated. Most patients had endometrial (34.8%), ovarian (26.1%) and cervical cancer (26.1%) as the primary tumour. The most common SBRT schedules in five fractions were 30 Gy (33.3%), 35 Gy (29.6%) and 40 Gy (29.6%). The median follow-up was 32 months (range 3-128). There were no patients reporting acute or late toxicities higher than grade 2, except for a bone fracture. One- and 2-year local control was 77.9% and 70.8%, respectively. One- and 2-year overall survival was 82.6% and 75.1%, respectively. The overall response rate was 96.0%. Regarding QoL, no statistically significant difference was identified between the baseline and follow-up values: the median CLAS1, CLAS2 and CLAS3 scores for each category were 6 (range 4-10) at baseline and 6 (range 3-10) 1 month after SBRT. CONCLUSIONS: This preliminary experience suggests that SBRT retreatment for recurrent gynaecological cancer is a highly feasible and safe treatment with limited side-effects and no short-term QoL impairment.

Contouring of emerging organs-at-risk (OARS) of the female pelvis and interobserver variability: A study by the Italian association of radiotherapy and clinical oncology (AIRO).

Purpose: To provide straightforward instructions for daily practice in delineating emerging organs-at-risk (OARs) of the female pelvis and to discuss the interobserver variability in a two-step multicenter study. Methods and materials: A contouring atlas with anatomical boundaries for each emerging OAR was realized by radiation oncologists and radiologists who are experts in pelvic imaging, as per their knowledge and clinical practice. These contours were identified as quality benchmarks for the analysis subsequently carried out. Radiation oncologists not involved in setting the custom-built contouring atlas and interested in the treatment of gynecological cancer were invited to participate in this 2-step trial. In the first step all participants were supplied with a selected clinical case of locally advanced cervical cancer and had to identify emerging OARs (Levator ani muscle; Puborectalis muscle; Internal anal sphincter; External anal sphincter; Bladder base and trigone; Bladder neck; Iliac Bone Marrow; Lower Pelvis Bone Marrow; Lumbosacral Bone Marrow) based on their own personal knowledge of pelvic anatomy and experience. The suggested OARs and the contouring process were then presented at a subsequent webinar meeting with a contouring laboratory. Finally, in the second step, after the webinar meeting, each participant who had joined the study but was not involved in setting the benchmark received the custom-built contouring atlas with anatomical boundaries and was requested to delineate again the OARs using the tool provided. The Dice Similarity Coefficient (DSC) and the Jaccard Similarity Coefficient (JSC) were used to evaluate the spatial overlap accuracy of the different volume delineations and compared with the benchmark; the Hausdorff distance (HD) and the mean distance to agreement (MDA) to explore the distance between contours. All the results were reported as sample mean and standard deviation (SD). Results: Fifteen radiation oncologists from different Institutions joined the study. The participants had a high agreement degree for pelvic bones sub-structures delineation according to DICE (IBM: 0.9 ± 0.02; LPBM: 0.91 ± 0.01). A moderate degree according to DICE was showed for ovaries (Right: 0.61 ± 0.16, Left: 0.72 ± 0.05), vagina (0.575 ± 0.13), bladder sub-structures (0.515 ± 0.08) and EAS (0.605 ± 0.05), whereas a low degree for the other sub-structures of the anal-rectal sphincter complex (LAM: 0.345 ± 0.07, PRM: 0.41 ± 0.10, and IAS: 0.4 ± 0.07). Conclusion: This study found a moderate to low level of agreement in the delineation of the female pelvis emerging OARs, with a high degree of variability among observers. The development of delineation tools should be encouraged to improve the routine contouring of these OARs and increase the quality and consistency of radiotherapy planning.

Stereotactic radiosurgery for bone metastases in oligometastatic prostate cancer patients: DESTROY-2 clinical trial subanalysis.

INTRODUCTION: Aim of this analysis was to report toxicity and clinical outcomes in oligorecurrent prostate cancer (PCa) patients treated with single fraction stereotactic radiosurgery (SRS) for bone metastases. METHODS: We separately analyzed clinical data of PCa patients with bone oligometastases enrolled in a prospective phase I trial (DESTROY-2). DESTROY-2 was based on SRS delivered using volumetric modulated arc therapy in patients with primary or metastatic tumors in several extra-cranial body sites. Acute and late toxicity, biochemical tumor response, local control (LC), distant metastases-free (DPFS), progression-free (PFS), time to next-line systemic treatment-free (NEST-FS), and overall survival (OS) were calculated. RESULTS: Data on 37 PCa patients, carrying out 50 bone metastases, candidates for curative-intent treatment and treated with SRS at our Institution were collected. SRS dose ranged between 12 and 24 Gy. One grade 1 acute skin toxicity in one patient treated on the hip (24 Gy) and one grade 1 late skin toxicity in a patient with a scapular lesion (24 Gy) were recorded. No cases of bone fracture were registered in the treated population. With a median follow-up of 25 months (range 3-72 months) 2-year actuarial LC, DPFS, PFS, and OS were 96.7%, 58.1%, 58.1%, and 95.8%, respectively. Median and 2-year NEST-FS were 30 months (range 1-69 months) and 51.2%, respectively. CONCLUSIONS: Data analysis showed few toxicity events, high local control rate and prolonged NEST-FS after linear accelerator-based radiosurgery of bone oligometastases from PCa. The possibility of postponing systemic treatments in patients with oligometastatic PCa by means of SRS should be taken into account. Further prospective studies on larger series are needed to confirm the reported results.

A complete pathological response to treatment in a young patient with locally advanced minimal deviation adenocarcinoma of the uterine cervix undergoing chemoradiation followed by radical surgery.

Minimal deviation adenocarcinoma (MDA) is a very rare variant of cervical adenocarcinoma, this pathological entity is composed of mucinous very-well-differentiated glands deeply invading cervical stroma, and often surrounded by a desmoplastic reaction. Despite its benign histological appearance, MDA is typically characterized by aggressive clinical behavior and by relevant difficulties in achieving a final diagnosis. Moreover, the intrinsic chemotherapy resistance, as well as the frequent failure of radiotherapy approaches has raised the need to investigate the efficacy of multimodal strategies for the treatment of MDA patients. Here, we report a case of locally advanced MDA of the uterine cervix in a very young woman, who was successfully treated with concomitant chemoradiation followed by radical surgery.

Stereotactic body radiotherapy to lymph nodes in oligoprogressive castration-resistant prostate cancer patients: a post hoc analysis from two phase I clinical trials.

The prognosis of prostate cancer (PC) is generally favorable but the incidence of metastases is relatively high after the treatment of the primary tumor, especially in high-risk patients. Fractionated stereotactic body radiotherapy (SBRT) or single fraction stereotactic body radiosurgery (SRS) are emerging treatment options in this setting. However, data on SBRT/SRS in patients with metastatic castration-resistant PC (mCRPC) are largely lacking, particularly in subjects with nodal lesions. Therefore, we evaluated outcomes and toxicity recorded in mCRPC patients with nodal oligoprogression. Patients included in this analysis had ≤ 5 metastatic sites without visceral lesions and underwent SBRT/SRS on nodal metastases. Thirty-eight patients carrying out 61 nodal metastases were analyzed. The median SRS dose was 20 Gy (range 12-24 Gy) and the most common schedule was 20 Gy (44.8%). The median SBRT dose was 45 Gy (range 20-50 Gy) and the most common regimen was 45 Gy in 5 fractions (37.9%). Thirty-seven patients (97.4%) showed only grade 0-1 acute toxicity while one patient reported grade 2 dysphagia. In terms of late toxicity, one grade 2 laryngeal, one grade 1 skin and one grade 1 gastrointestinal toxicities were recorded. Two-year actuarial local control (LC), distant progression-free survival, progression-free survival (PFS) and overall survival were 94.0, 47.2, 47.2, and 90.2%, respectively. Two-year next line systemic therapy-free survival (NEST-FS) was 67.7%. In conclusion, the efficacy in terms of LC of SBRT/SRS in patients with nodal metastases from PC was confirmed. Moreover, this analysis suggests the efficacy in terms of PFS and NEST-FS also in the setting of oligoprogressive PC. In fact, about one-third of patients were free from progressive disease and two-third of subjects did not require hormonal therapy switch or discontinuation three years after treatment.

The role of brachytherapy (interventional radiotherapy) for primary and/or recurrent vulvar cancer: a Gemelli Vul.Can multidisciplinary team systematic review.

OBJECTIVE: The aim of our systematic review was to assess the role of interventional radiotherapy (IRT, brachytherapy) in the management of primary and/or recurrent vulvar carcinoma. EVIDENCE ACQUISITION: A systematic research using PubMed, Scopus and Cochrane library was performed. ClinicalTrials.gov was searched for ongoing or recently completed trials, and PROSPERO was searched for ongoing or recently completed systematic reviews. Only full-text English-language articles related to IRT for treatment of primary or recurrent VC were identified and reviewed. Conference paper, survey, letter, editorial, book chapter and review were excluded. Time restriction (1990-2018) as concerns the years of the publication was considered. EVIDENCE SYNTHESIS: Primary disease: the median 5-year LC was 43.5% (range 19-68%); the median 5-year DFS was 44.5% (range 44-81%); the median 5-year OS was 50.5% (range 27-85%). Recurrent disease: the median 5-year DFS was 64% (range 56-72%) and the median 5-year OS was 45% (range 33%-57%). Acute ≥ grade 2 toxicity was reported in three patients (1.6%). The severe late toxicity rates (grade 3-4) ranged from 0% to 14.3% (median 7.7%). CONCLUSION: IRT as part of primary treatment for primary and/or recurrent vulvar cancer is associated with promising clinical outcomes.

Long-term analysis of clinical outcome and complications in locally advanced cervical cancer patients administered concomitant chemoradiation followed by radical surgery.

OBJECTIVE: Preoperative chemoradiation (CT/RT) has been shown to achieve encouraging results in terms of clinical outcome in locally advanced cervical cancer (LACC). The study aims at analyzing the long-term results of this multimodal approach in a single institution series of 184 cases. METHODS: Patients underwent whole pelvic irradiation combined with cisplatin and 5-fluorouracil. After evaluation of clinical response, patients were triaged to surgery. Surgical morbidity was classified according to Chassagne grading system. Univariate and multivariate analyses were used to assess the prognostic and predictive role of clinicopathological parameters. RESULTS: Clinical response was observed in 96.1% of cases. A total of 174 cases were submitted to radical surgery: 124 patients (71.3%) showed complete/microscopic pathological response. In multivariate analysis, clinical response, stage of disease, and histotype predicted response to CT/RT. With a median follow-up of 58 months, recurrence and death of disease were observed in 42 and 40 patients, respectively. The 5-year DFS was 75.5%, while the 5-year OS was 77.4%. Patients with no residual disease showed a significant longer DFS than patients with microscopic (p value = 0.0128), and macroscopic (p value = 0.0001) residual tumor after treatment. In multivariate analysis, residual tumor and stage of disease were the two most relevant prognostic factors for DFS and OS. As far as long-term toxicity is concerned, 8 out of 22 complications were grade 3/4. CONCLUSION: Preoperative CT/RT is worth further investigation in LACC patients, providing encouraging survival outcomes and a favourable long-term toxicity profile.

On the analysis of the Cr-Cr multiple bond in several classes of dichromium compounds.

Since the discovery of a formal quintuple bond in Ar'CrCrAr' (CrCr = 1.835 A) by Power and co-workers in 2005, many efforts have been dedicated to isolating dichromium species featuring quintuple-bond character. In the present study we investigate the electronic configuration of several, recently synthesized dichromium species with ligands using nitrogen to coordinate the metal centers. The bimetallic bond distances of Power's compound and Cr(2)-diazadiene (1) (CrCr = 1.803 A) are compared to those found for Cr(2)(mu-eta(2)-ArNC(R)NAr)(2) (2) (CrCr = 1.746 A; R = H, Ar = 2,6-Et(2)C(6)H(3)), Cr(2)(mu-eta(2)-Ar(Xyl)NC(H)NAr(Xyl))(3) (3) (CrCr = 1.740(reduced)/1.817(neutral) A; Ar(Xyl)= 2,6-C(6)H(3)-(CH(3))(2)), Cr(2)(mu-eta(2)-TippPyNMes)(2) (4) (CrCr = 1.749 A; TippPyNMes = 6-(2,4,6-triisopropylphenyl)pyridin-2-yl (2,4,6-trimethylphenyl)amide), and Cr(2)(mu-eta(2)-DippNC(NMe(2))N-Dipp)(2) (5) (CrCr = 1.729 A, Dipp = 2,6-i-Pr(2)C(6)H(3)). We show that the correlation between the CrCr bond length and the effective bond order (EBO) is strongly affected by the nature of the ligand, as well as by the steric hindrance due to the ligand structure (e.g., the nature of the coordinating nitrogen). A linear correlation between the EBO and CrCr bond distance is established within the same group of ligands. As a result, the CrCr species based on the amidinate, aminopyridinate, and guanidinate ligands have bond patterns similar to the Ar'CrCrAr' compound. Unlike these latter species, the dichromium diazadiene complex is characterized by a different bonding pattern involving Cr-Npi interactions, resulting in a lower bond order associated with the short metal-metal bond distance. In this case the short CrCr distance is most probably the result of the constraints imposed by the diazadiene ligand, implying a Cr(2)N(4) core with a closer CrCr interaction.

Proteomic analysis of plasma exosomes from Cystic Echinococcosis patients provides in vivo support for distinct immune response profiles in active vs inactive infection and suggests potential biomarkers.

The reference diagnostic method of human abdominal Cystic Echinococcosis (CE) is imaging, particularly ultrasound, supported by serology when imaging is inconclusive. However, current diagnostic tools are neither optimal nor widely available. The availability of a test detecting circulating biomarkers would considerably improve CE diagnosis and cyst staging (active vs inactive), as well as treatments and follow-up of patients. Exosomes are extracellular vesicles involved in intercellular communication, including immune system responses, and are a recognized source of biomarkers. With the aim of identifying potential biomarkers, plasma pools from patients infected by active or inactive CE, as well as from control subjects, were processed to isolate exosomes for proteomic label-free quantitative analysis. Results were statistically processed and subjected to bioinformatics analysis to define distinct features associated with parasite viability. First, a few parasite proteins were identified that were specifically associated with either active or inactive CE, which represent potential biomarkers to be validated in further studies. Second, numerous identified proteins of human origin were common to active and inactive CE, confirming an overlap of several immune response pathways. However, a subset of human proteins specific to either active or inactive CE, and central in the respective protein-protein interaction networks, were identified. These include the Src family kinases Src and Lyn, and the immune-suppressive cytokine TGF-ß in active CE, and Cdc42 in inactive CE. The Src and Lyn Kinases were confirmed as potential markers of active CE in totally independent plasma pools. In addition, insights were obtained on immune response profiles: largely consistent with previous evidence, our observations hint to a Th1/Th2/regulatory immune environment in patients with active CE and a Th1/inflammatory environment with a component of the wound healing response in the presence of inactive CE. Of note, our results were obtained for the first time from the analysis of samples obtained in vivo from a well-characterized, large cohort of human subjects.

Concurrent chromothripsis events in a case of TP53 depleted acute myeloid leukemia with myelodysplasia-related changes.

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous hematological disorder defined by morphological, genetic, and clinical features. Patients with AML-MRC often show cytogenetic changes, which are associated with poor prognosis. Straightforward criteria for AML-MRC diagnosis and a more rigorous characterization of the genetic abnormalities accompanying this disease are needed. Here we describe an informative AML-MRC case, showing two separate, but concurrent, chromothripsis events, occurred at the onset of the tumor, and originating an unbalanced t(5;7) translocation and a derivative chromosome 12 with a highly rearranged short arm. Conversely, despite chromothripsis has been often associated with genomic amplification in cancer, in this case a large marker chromosome harboring amplified sequences from chromosomes 19 and 22 arose from a stepwise mechanism. Notably, the patient also showed a TP53 mutated status, known to be associated with an increased susceptibility towards chromothripsis and a poor prognosis. Our results indicate that multiple chromothripsis events may occur early in neoplastic transformation and act in a synergistic way with progressive chromosomal alterations to determine a dramatic impact on disease outcome, as suggested by the gene expression profile analysis.

A role for protein kinase C activity in interleukin-1 (IL-1) induction of IL-2 gene expression but not in IL-1 signal transduction.

Interleukin-1 (IL-1) is known to synergize with phorbol esters in the induction of interleukin-2 (IL-2) expression in T-lymphoid leukemia cells and proliferation of mouse thymocytes. We used a plasmid construct containing the bacterial gene for chloramphenicol acetyltransferase under the control of the human IL-2 promoter to study the nature of this synergism in the murine thymoma cell line EL4. Although IL-1 induction of the IL-2 promoter in these cells required costimulus with phorbol myristate acetate, the signal induced by IL-1 was qualitatively different. We provide evidence to support the hypothesis that the phorbol ester signal is mediated by protein kinase C, and we show that the IL-1 signal is not. That IL-1 and phorbol myristate acetate represent different stimuli was shown by their response to protein kinase C inhibitors, capacity to synergize with increased intracellular free calcium, and requirement for protein synthesis. In addition we show that pretreatment with IL-1 can prime EL4 cells to subsequent activation by concentrations of phorbol esters not normally sufficient to induce IL-2 expression. Pretreated cells remained primed for at least 40 h after removal of the IL-1. Neither phorbol myristate acetate nor a calcium ionophore was capable of preactivating EL4 cells.

Portal dose measurements by a 2D array.

A 2D array (PTW, type 10024), equipped with 729 vented plane parallel ion-chambers, has been calibrated as a detector for the in vivo comparison between measured and predicted portal doses for head-neck tumors. The comparison of absolute portal doses measured to ones predicted by a commercial treatment planning system within the field of view of the CT scanner, can help the delivered dose verification during different treatment fractions, in particular when the patient's present weight loss. This paper reports the preliminary results of the comparison of the portal doses measured by a PTW 2D array during several radiotherapy fractions and the predicted portal doses for seven patients undergoing head-neck tumor radiotherapy. The gamma index analysis supplied an agreement of more than 95% of the dose-point P(gamma)>95% within acceptance criteria, in terms of dose difference, DeltaD(max), and distance-agreement, Deltad(max), equal to 5% and 4mm, respectively. After the third week, one patient showed a decrease of P(gamma) values due to the markedly reduced patient's thickness. Even if the spatial resolution of the 2D array was 1cm, there were two advantages in the use of this 2D array as a portal dose device for IMRT quality control. The first one was the use of a stable and efficient absolute dosimeter for in vivo verification, although its construction and behavior for other gantry angles need to be tested, and the second one was the time efficiency in verifying the correct dose delivery in several fractions of the therapy. This study presents acceptance criteria for the comparison of TPS-predicted portal dose images with in vivo 2D ion-chamber measurements for IMRT. In particular, portal dose measurements offer clues for additional studies as to which indicators can signal the need for replanning during treatment.

D-aspartate and reproductive activity in sheep.

D-aspartic acid (D-Asp) has been isolated from neuroendocrine tissues of many invertebrates and vertebrates. Recently, it has been demonstrated that this D-amino acid may be converted to N-methyl-D-aspartic acid (NMDA), a neuromodulator associated with sexual activity. In this study, we determined D-Asp and NMDA concentrations in endocrine glands and other tissues in ewes after D-Asp administration and in controls. We also evaluated the effects of d-Asp administration on the reproductive activity of ewes by determining either progesterone concentrations or LH pulses in the presence or absence of estradiol benzoate. The pineal gland showed the highest natural content of D-Asp (1.47+/-0.22 micromol/g tissue), whereas the pituitary gland had the highest capability to store d-Asp, with a peak value (9.7+/-0.81 micromol/g tissue) 6 h after its administration. NMDA increased sharply 12 h following D-Asp administration, reaching values three times higher than the baseline in both the pituitary and brain. D-Asp was quickly adsorbed after subcutaneous administration, with a peak in plasma levels 2 h after administration and a return to baseline values after 6 h. D-Asp administration achieved a significant (P < 0.001) increase in LH values with respect to estradiol or estradiol + D-Asp treatments. d-Asp treatment once or twice a week did not successfully drive acyclic ewes into reproductive activity. In conclusion, the results obtained in this study demonstrated that D-Asp is endogenously present in sheep tissues and electively stored in endocrine glands and brain after its administration. NMDA and LH increase following D-Asp administration suggesting a role of this D-amino acid in the reproductive activity of sheep.

Intraluminal brachytherapy without stenting in intrahepatic papillary cholangiocarcinoma: a case report.

A 46-year-old female patient, with mild cholestasis by a large papillary cholangiocarcinoma involving the left hepatic duct, received intraluminal brachytherapy (50 Gy at 1 cm from the source axis) with the aim to relieve biliary obstruction without stent positioning. The patient presented with haemobilia and vegetant lesions in the left main biliary duct, and thus she had a high risk of early stent obstruction. Eighteen months after the treatment the patient presented tumour progression in the controlateral hepatic lobe, but had a patent left hepatic duct, without signs of cholestasis and/or cholangitis. Based on this and other published reports, intraluminal brachytherapy may be tested in a setting different from standard setting with the aim to safely palliate jaundice in patients with intraductal tumour growth in the biliary tract.

p21ras contributes to HIV-1 activation in T-cells.

Activation of T-cells infected by HIV-1 results in activation of long terminal repeat (LTR)-dependent viral transcription and ultimately the production of infectious virus. Although full T-cell activation requires a complex series of intracellular signals, including protein kinase C activation, calcium mobilisation, and less-well defined lymphokine-induced signals, the HIV-1 LTR can be activated by subsets of these signals. We have studied the interaction of these signals in the human lymphoma line, Jurkat, in activation of the HIV-1 LTR. The HIV promoter was induced by IL-1 and phorbol ester activation of PKC but not by a calcium ionophore. The constitutively active form of Ha-ras could replace phorbol ester stimulation of the HIV promoter and of a synthetic promoter containing NF kappa B binding sites.