Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is often incomplete. METHODS: To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI's approval by the US FDA and/or EMA up to December 2019. We analysed real-world data from all lung cancer (LC) and melanoma (Mel) patients treated with approved ICIs at the University Hospital of Lausanne (CHUV) from 2011 to 2019. To account for the immortal time bias, we used a time-dependent analysis to assess the potential association between irAEs and overall survival (OS). RESULTS: Duration of irAEs and proportion of patients with ongoing toxicities at data cut-off were not specified in 56/62 (90%) publications of ICIs registration trials. In our real-world analysis, including 437 patients (217 LC, 220 Mel), 229 (52.4%) experienced at least one grade ≥2 toxicity, for a total of 318 reported irAEs, of which 112 (35.2%) were long-lasting (≥6 months) and about 40% were ongoing at a median follow-up of 369 days [194-695] or patient death. The cumulative probability of irAE onset from treatment initiation was 42.8%, 51.0% and 57.3% at 6, 12 and 24 months, respectively. The rate of ongoing toxicity from the time of first toxicity onset was 42.8%, 38.4% and 35.7% at 6, 12 and 24 months. Time-dependent analysis showed no significant association between the incidence of irAEs and OS in both cohorts (log Rank p = 0.67 and 0.19 for LC and Mel, respectively). CONCLUSIONS: Late-onset and long-lasting irAEs are underreported but common events during ICIs therapy. Time-dependent survival analysis is advocated to assess their impact on OS. Real-world evidence is warranted to fully capture and characterise late-onset and long-lasting irAEs in order to implement appropriate strategies for patient surveillance and follow-up.

Process mining to optimize palliative patient flow in a high-volume radiotherapy department.

INTRODUCTION: In radiotherapy, palliative patients are often suboptimal managed and patients experience long waiting times. Event-logs (recorded local files) of palliative patients, could provide a continuative decision-making system by means of shared guidelines to improve patient flow. Based on an event-log analysis, we aimed to accurately understand how to successively optimize patient flow in palliative care. METHODS: A process mining methodology was applied on palliative patient flow in a high-volume radiotherapy department. Five hundred palliative radiation treatment plans of patients with bone and brain metastases were included in the study, corresponding to 290 patients treated in our department in 2018. Event-logs and the relative attributes were extracted and organized. A process discovery algorithm was applied to describe the real process model, which produced the event-log. Finally, conformance checking was performed to analyze how the acquired event-log database works in a predefined theoretical process model. RESULTS: Based on the process discovery algorithm, 53 (10%) plans had a dose prescription of 8 Gy, 249 (49.8%) plans had a dose prescription of 20 Gy and 159 (31.8%) plans had a dose prescription of 30 Gy. The remaining 39 (7.8%) plans had different dose prescriptions. Considering a median value, conformance checking demonstrated that event-logs work in the theoretical model. CONCLUSIONS: The obtained results partially validate and support the palliative patient care guideline implemented in our department. Process mining can be used to provide new insights, which facilitate the improvement of existing palliative patient care flows.

(68Ga)-PSMA-PET/CT for the detection of postoperative prostate cancer recurrence: Possible implications on treatment volumes for radiation therapy.

PURPOSE: The aim of this study was to define the pattern of relapse of postoperative prostate cancer in patients by using 68Ga-labeled prostate-specific membrane antigen positron-emission tomography/computed tomography ([68Ga]-PSMA PET/CT). MATERIAL AND METHODS: Forty patients received a (68Ga)-PSMA PET/CT for biochemical failure. Following the Radiation Therapy Oncology Group (RTOG) guidelines, the pelvic clinical target volume has been contoured. Bone metastases were considered as outside the clinical target volume. Two subgroups of patients were defined, patients having relapse: (1) inside, or (2) outside the clinical target volume. RESULTS: Globally, eight patients out of 32 presented with a positive lymph node failure inside the clinical target volume according to RTOG guidelines (25%), 22 patients had nodal relapses outside this clinical target volume (68.75%) and in two patients nodal relapses occurred both inside and outside of the clinical target volume (6.25%). Overall, 36 positive lymph node lesions were identified: of these, 23 nodal relapses were identified within the clinical target volume contoured according to RTOG and/or at the lomboaortic level (63%). To cover 95% of these 23 relapses, a hypothetical clinical target volume should encompass the nodal regions of the RTOG-defined clinical target volume as well as the paraaortic lymph node level up to T12-L1. CONCLUSION: Most of the patients in the present study, presented with distant lymph node and/or bone metastases. Therefore, larger target volumes should be adopted to treat at least 95% of lymph node regions at risk for an occult relapse.

A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia.

This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes inferred for specific transcription factors, among which MAFB was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells. Using the Connectivity Map, similarity among transcriptional signatures elicited by treatment with different compounds was investigated, showing a high degree of similarity between transcriptional signatures of trabectedin and those of the topoisomerase I inhibitor, irinotecan, and an anti-dopaminergic antagonist, thioridazine. The study highlights the potential importance of systems biology approaches to generate new hypotheses that are experimentally testable to define the specificity of the mechanism of action of drugs.

PRODIGE: PRediction models in prOstate cancer for personalized meDIcine challenGE.

AIM: Identifying the best care for a patient can be extremely challenging. To support the creation of multifactorial Decision Support Systems (DSSs), we propose an Umbrella Protocol, focusing on prostate cancer. MATERIALS & METHODS: The PRODIGE project consisted of a workflow for standardizing data, and procedures, to create a consistent dataset useful to elaborate DSSs. Techniques from classical statistics and machine learning will be adopted. The general protocol accepted by our Ethical Committee can be downloaded from cancerdata.org . RESULTS: A standardized knowledge sharing process has been implemented by using a semi-formal ontology for the representation of relevant clinical variables. CONCLUSION: The development of DSSs, based on standardized knowledge, could be a tool to achieve a personalized decision-making.

Mechanism of action of trabectedin in desmoplastic small round cell tumor cells.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive disease, that can be described as a member of the family of small round blue cell tumors. The molecular diagnostic marker is the t(11;22)(p13;q12) translocation, which creates an aberrant transcription factor, EWS-WT1, that underlies the oncogenesis of DSRCT. Current treatments are not very effective so new active drugs are needed. Trabectedin, now used as a single agent for the treatment of soft tissue sarcoma, was reported to be active in some pre-treated DSRCT patients. Using JN-DSRCT-1, a cell line derived from DSRCT expressing the EWS-WT1 fusion protein, we investigated the ability of trabectedin to modify the function of the chimeric protein, as in other sarcomas expressing fusion proteins. After detailed characterization of the EWS-WT1 transcripts structure, we investigated the mode of action of trabectedin, looking at the expression and function of the oncogenic chimera. METHODS: We characterized JN-DSRCT-1 cells using cellular approaches (FISH, Clonogenicity assay) and molecular approaches (Sanger sequencing, ChIP, GEP). RESULTS: JN-DSRCT-1 cells were sensitive to trabectedin at nanomolar concentrations. The cell line expresses different variants of EWS-WT1, some already identified in patients. EWS-WT1 mRNA expression was affected by trabectedin and chimeric protein binding on its target gene promoters was reduced. Expression profiling indicated that trabectedin affects the expression of genes involved in cell proliferation and apoptosis. CONCLUSIONS: The JN-DSRCT-1 cell line, in vitro, is sensitive to trabectedin: after drug exposure, EWS-WT1 chimera expression decreases as well as binding on its target promoters. Probably the heterogeneity of chimera transcripts is an obstacle to precisely defining the molecular mode of action of drugs, calling for further cellular models of DSRCT, possibly growing in vivo too, to mimic the biological complexity of this disease.

Nasopharyngeal carcinoma in a low incidence European area : A prospective observational analysis from the Head and Neck Study Group of the Italian Society of Radiation Oncology (AIRO).

PURPOSE: To evaluate the outcomes with respect to long-term survival and toxicity in patients with nasopharyngeal carcinoma (NPC) treated in a European country with low incidence. MATERIALS AND METHODS: A prospective observational study carried out by the AIRO Head and Neck group in 12 Italian institutions included 136 consecutive patients treated with radiotherapy (RT) ± chemotherapy (CHT) for NPC (without distant metastasis) between January 1, 2008 and December 31, 2010. RESULTS: The disease-specific survival (DSS), overall survival (OS), and disease-free survival (DFS) at 5 years were 92 (±2), 91 (±3), and 69 % (±5 %), respectively. Distant failure was the most frequent modality of relapse. The local, regional, and locoregional control at 5 years were 89 (±3), 93 (±3), and 84 % (±4 %), respectively. The incidence of acute and late toxicity and the correlations with different clinical/technical variables were analyzed. Neoadjuvant CHT prolongs radiotherapy overall treatment time (OTT) and decreases treatment adherence during concomitant chemoradiotherapy. An adequate minimum dose coverage to PTV(T) is a predictive variable well related to outcome. CONCLUSION: Our data do not substantially differ in terms of survival and toxicity outcomes from those reported in larger series of patients treated in countries with higher incidences of NPC. The T stage (TNM 2002 UICC classification) is predictive of DSS and OS. The GTV volume (T ± N) and an adequate minimum PTV(T) coverage dose (D95 %) were also identified as potential predictive variables. Sophisticated technologies of dose delivery (IMRT) with image-guided radiotherapy could help to obtain better minimum PTV(T) coverage dose with increased DFS; distant metastasis after treatment still remains an unresolved issue.

Could machine learning improve the prediction of pelvic nodal status of prostate cancer patients? Preliminary results of a pilot study.

We tested and compared performances of Roach formula, Partin tables and of three Machine Learning (ML) based algorithms based on decision trees in identifying N+ prostate cancer (PC). 1,555 cN0 and 50 cN+ PC were analyzed. Results were also verified on an independent population of 204 operated cN0 patients, with a known pN status (187 pN0, 17 pN1 patients). ML performed better, also when tested on the surgical population, with accuracy, specificity, and sensitivity ranging between 48-86%, 35-91%, and 17-79%, respectively. ML potentially allows better prediction of the nodal status of PC, potentially allowing a better tailoring of pelvic irradiation.

Mode of action of trabectedin in myxoid liposarcomas.

To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes, we have developed and characterized three MRCL xenografts, namely ML017, ML015 and ML004 differing for the break point of the fusion gene FUS-CHOP, respectively of type I, II and III. FUS-CHOP binding to the promoters of some target genes such as Pentraxin 3 or Fibronectin 1, assessed by chromatin immunoprecipitation, was strongly reduced in the tumor 24 h after the first or the third weekly dose of trabectedin, indicating that the drug at therapeutic doses causes a detachment of the FUS-CHOP chimera from its target promoters as previously shown in vitro. Moreover, the higher sensitivity of MRCL types I and II appears to be related to a more prolonged block of the transactivating activity of the fusion protein. Doxorubicin did not affect the binding of FUS-CHOP to target promoters. Histologically, the response to trabectedin in ML017 and ML015 was associated with a marked depletion of non-lipogenic tumoral cells and vascular component, as well as lipidic maturation as confirmed by PPARγ2 expression in western Blot. By contrast, in ML004 no major changes either in the cellularity or in the amount of mature were found, and consistently PPARγ2 was null. In conclusion, the data support the view that the selective mechanism of action of trabectedin in MRCL is specific and related to its ability to cause a functional inactivation of the oncogenic chimera with consequent derepression of the adypocytic differentiation.

Clinical similarities: an innovative approach for supporting medical decisions.

Taking decisions in the medical domain is a very complex task. The context is strongly affected by uncertainty and the possible undesired side effects of the treatments have to be carefully considered. Currently, these decisions are based on the physician's own experience and the evidences of the published literature, according, when available, with the philosophy of Evidence Based Medicine. The main issues of this approach are that the own experience can be different, and the results in the literature are sometimes contrasting. For helping physicians while taking medical decisions, we are proposing an innovative approach based on the idea of the clinical similarity. Given a set of clinical variables, the proposed approach selects patients that are similar, presenting to the physician the respective decisions taken and the corresponding clinical effects.

Open-source, low-cost, high-reliability solutions for digital imaging systems: example of a "dicom router".

PURPOSE: The purpose of this article is to illustrate a case where acquisition of digital imaging know-how by a modern radiotherapy division has helped to solve a technical problem while allowing substantial savings through the use of free and open-source resources. The problem was related to the necessity to route, with complex policies, the images produced by different digital imaging and communications in medicine (DICOM) sources within the department or in other divisions and/or hospitals. MATERIALS AND METHODS: The problem was solved by using completely free, well-tested and stable technologies (PHP, Apache, MySQL, DCMTK OFFIS, Red Hat Linux 9A and Linux Fedora Core 4) and low-cost hardware to contain costs. In the development, we also considered integration of the routed images with the existing electronic clinical records. RESULTS: The system developed, called the dicom router, implemented two kinds of routing: manual and automatic, both oriented to link the images acquired with the existing electronic clinical records. System stability was enhanced in a second phase by using a low-cost hardware redundancy solution. The system has now been operating for 1 year and has proved the value of the technologies used. CONCLUSIONS: The need to operate with more than one provider creates a series of integration issues, so that it becomes economically appealing to acquire internally the knowledge needed to interact more precisely with providers of big information technology (IT) solutions. This need is well catered for by open-source technologies, which are well documented and available to everyone. By using them, in-house IT technicians are able to implement valuable technical solutions for small-to medium-sized informatization problems, which would otherwise remain unsolved except with great economic efforts.

Pneumatosis coli induced by acarbose administration for diabetes mellitus. Case report and literature review.

The authors report a case report of rare disease interesting the digestive tract and often associated to the other gastrointestinal pathologies and/or pulmonary diseases and can be also associated to not gastrointestinal conditions such as collagen-vascular disease, transplantation, AIDS, use of corticosteroid and chemotherapy; other causes can be iatrogenic such as traumatic gastrointestinal endoscopy (a mucoses biopsy, a polipectomy) or the assumption of lattulosio; in 15-20% of cases the pneumatosis cystoides intestinalis is considered primitive. In the our case the Pneumatosis coli was associated to administration of acarbose; in international literature only four papers in the English language were reported. Our patient showed a strongly aspecific symptomatology and easily attributable in first line or to the pathology of base (diabetic patient) or to the assumption of the acarbose; from about 7-8 months she showed unexplained episodes of crampy abdominal pain, diarrhea with 3-4 defecations/die with semiliquid and normochromic stools, tenesmus and a not better specified loss of weight. The diagnosis was been performed by colonoscopy and confirmed by abdominal CT scan with water enema and histologically; we have used the traditional radiology only to exclude the involvement of other gastroenteric districts. The patient was been treated with O2-therapy associated to antibiotics treatment; the suspension of the causal factor, the acarbose, has been of not secondary importance; the complete resolution of disease was obtained after 15 days of therapy.

Postoperative radiotherapy after radical prostatectomy for prostate carcinoma: the experience of the Brescia Radium Institute.

PURPOSE: The purpose of this study was to evaluate the efficacy of postoperative radiotherapy in reducing the incidence of prostate carcinoma (PCa) recurrences after radical prostatectomy (RP), define the importance of the time interval between surgery and radiotherapy for prognosis and the toxicity of the treatment in comparison with radiotherapy or surgery alone. MATERIALS AND METHODS: We examined 97 patients who consecutively underwent postoperative radiotherapy after RP between 1980 and 2003. The treatment was considered "adjuvant" if was conducted less than 6 months after RP, if there was no macroscopic residual disease and if there was no progressive increase in serum prostate-specific antigen (PSA) and "salvage" if performed more than 6 months after RP, for the presence of macroscopic recurrence or with rising PSA. Radiotherapy was salvage in 56 patients and adjuvant in 41. Age range was 60-70 years in 80% of patients, and the Karnofsky index was over 80 in 78% of cases. Histology revealed extracapsular spread in 60% of patients. Preradiotherapy PSA was higher than 1 ng/ml in 36%. Radiotherapy was performed on the surgical bed only in 80%, and the total dose was 70 Gy in 62% of cases. RESULTS: Recurrence-free survival (RFS) at 5 years and 10 years was 53+/-8% and 32+/-14.2%, respectively, for the whole sample; 76+/-9% and 38+/-2.7% for patients treated with adjuvant radiotherapy and 36+/-10% and 28+/-10% for those treated with salvage radiotherapy (p<0.01). Moreover, the 5-year RFS was better in the group treated with adjuvant radiotherapy and PSA less than or equal to 1 ng/ml (p<0.05). Treatment toxicity was acceptable. CONCLUSIONS: Postoperative radiotherapy improves RFS and reduces the risk of local recurrence. The best results are obtained with early postoperative treatment ("adjuvant"); adjuvant radiotherapy of high-risk forms yields better results if performed with PSA less than or equal to 1 ng/ml.

Twenty-four hours blood pressure and heart rate profiles in diabetics with and without autonomic neuropathy.

Previous studies have shown an increased incidence of sudden deaths and lower survival in diabetics with autonomic neuropathy. In hypertensive non diabetic patients a direct correlation has been found between nocturnal blood pressure levels and left ventricular hypertrophy. We have shown in diabetics with autonomic neuropathy a flattening in nocturnal blood pressure reduction and increased 24 hours blood pressure values compared to diabetics without autonomic neuropathy and controls. Our results suggest that abnormalities in 24 hours blood pressure profile might play a role in the increased incidence of cardiovascular morbidity and mortality in diabetics with autonomic neuropathy.

[Can the Body Mass Index and the waist:hips ratio (WHR) affect the correlation between impedance measurement and anthropometry in the evaluation of body composition?]. / Possono il Body Mass Index (BMI) ed il rapporto vita/fianchi (WHR) influenzare la correlazione tra impedenziometria ed antropometria nella valutazione della composizione corporea?

Among the numerous techniques used to measure body composition, this study utilised anthropometric methods (weight, height, circumference and skin folds) and impedance measurement (measurement of bioelectric impedance). Results from the two methods were compared in order to assess whether BMI parameters and the waist/hips ratio (WHR) influenced this correlation. One hundred and eighty patients (133 F, 47 M) were included in the study. Patients were divided into groups according to the degree of obesity expressed as BMI and WHR. Body composition was evaluated using anthropometric methods (according to Garrow Webster, Durnin-Womersley, modified Durnin-Womersley and Jackson-Pollock) and impedance measurement in which resistive bioelectric impedance is measured using a tetrapolar technique. A good correlation was generally observed in the female population between impedance assessment and anthropometric methods, and this correlation was not influenced by either BMI or WHR. In the male group, on the other hand, the correlation between the two methods was limited by BMI greater than 30 and WHR greater than 1. In conclusion, impedance measurement and plicometric methods are generally compatible, but areas of uncertainty arise in the male population with BMI greater than 30 and WHR greater than 1.