GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis.

Gasdermins are a family of structurally related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic mucosal inflammatory disorders is well established, little is known about its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids but instead point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based focal adhesions dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects, disrupting epithelial restitution/repair, which, altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.

Drug-Related Pneumonitis in Patients Receiving Vedolizumab Therapy for Inflammatory Bowel Disease.

Noninfective drug-related pneumonitis (DRP) is a well-known adverse effect of several drugs: clinical manifestations have mostly an acute/subacute onset and vary from mild to life-threatening. Several DRP cases have been described in patients receiving anti-tumor necrosis factor α, rituximab, and tocilizumab.1,2 To date, only 4 reports of vedolizumab-related pneumonitis have been presented.3-5.

Effects of infections on the pathogenesis of cancer.

Several studies have shown an inverse relationship between acute infections and cancer development. On the other hand, there is a growing evidence that chronic infections may contribute significantly to the carcinogenesis. Factors responsible for increased susceptibility to infections may include modifications of normal defence mechanisms or impairment of host immunity due to altered immune function, genetic polymorphisms, ageing and malnourishment. Studies have demonstrated that children exposed to febrile infectious diseases show a subsequent reduced risk for ovarian cancer, melanoma and many other cancers, while common acute infections in adults are associated with reduced risks for melanoma, glioma, meningioma and multiple cancers. Chronic inflammation associated with certain infectious diseases has been suggested as a cause for the development of tumours. Mechanisms of carcinogenesis due to infections include cell proliferation and DNA replication by mitogen-activated protein kinase pathway, production of toxins that affect the cell cycle and lead to abnormal cell growth and inhibition of apoptosis. This review was aimed to summarize the available evidence on acute infections as a means of cancer prevention and on the role of chronic infections in the development and progression of cancer.

Adenoid cystic carcinoma of trachea: long-term disease control after endoscopic surgery and radiotherapy.

Aim: Adenoid cystic carcinoma is a rare tumor of head and neck region and its development in the thoracic region is even less frequent. This implies the absence of guidelines for therapeutic management and a consequent case-by-case approach. The role of radiotherapy is not yet clearly defined, but intensity-modulated radiotherapy allows for improved organ-at-risk sparing. Materials & methods: We have collected the cases of four patients treated at our institutions by the means of intensity-modulated radiotherapy, after endoscopic resection. Results & conclusion: Patients treated achieved long-term disease control of about 5 years, with a minimal acute toxicity. Longer follow-up is needed to drain conclusion on the impact of this treatment on overall survival.

Trends in combined radio-chemotherapy for locally advanced rectal cancer: a survey among radiation oncology centers of Sicily region on behalf of AIRO.

AIM: To conduct a survey among Sicilian centers of radiation oncology belonging to Associazione Italiana di Radioterapia ed Oncologia Clinica (AIRO), to record the different methods of integration of radio-chemotherapy both in neoadjuvant and adjuvant settings, to evaluate surgical procedures in relation to the sphincter preservation and to report the different toxicity profiles of the treatment strategies. METHODS: A questionnaire was sent at the end of 2017 to all the radiation oncology centers of Sicily region in order to collect the data from individual centers and the treatment characteristics retrospectively over the previous 5 years, from 2012 to 2016. The required data were collected from 13 centers out of 17 which, in relation to the single catchment areas, correspond to approximately 85% of the Sicilian population. The requested data concerned the type of integrated treatment (neoadjuvant vs adjuvant vs radical), combination with chemotherapy (induction, concomitant, adjuvant), type of surgical intervention (sphincter-saving vs abdomino-perineal resection), disease stage, schedule and radiotherapy technique adopted, as well as toxicity detected over the treatment period. RESULTS: A total of 784 pts (M/F: 509/275) were treated between 2012 and 2016, with a median age of 67 years (range 25-92). The majority of patients was treated in the neoadjuvant phase (62% of the total) compared to the adjuvant phase (31%) and to those treated radically (7%). Twenty-five percent of patients did not receive combination chemotherapy mainly for cardiovascular problems. Chemotherapy used concomitantly to radiotherapy was single-agent capecitabine (73% of patients) or 5-fluorouracil (27%). The use of chemotherapy alone before concomitant treatment is more common for patients treated in the adjuvant phase (64% of this subgroup), while 14% of patients treated in the neoadjuvant phase received induction chemotherapy before the concomitant phase; in both cases of chemotherapy alone, the majority of patients (91%) received oxaliplatin-based protocols (FOLFOX/XELOX/CAPOX). Few patients (3%) received chemotherapy alone after the concomitant phase. Information on the surgical treatment received is available for 88% of the sample. Of these, 93% received a surgical treatment. The overall rate of sphincter-saving surgery (anterior resection) was 72%, but the contribution of neoadjuvant treatment allowed to reach a rate of 83% in this subgroup (against 65% found in the subgroup of patients treated in adjuvant phase). Traditional radiotherapy schedule (45-50 Gy in 25-28 fractions) was used in 90% of patients, of which an intensified treatment in neoadjuvant phase (45 Gy + boost of 9-10 Gy) was used in 11% of patients. A short-course regimen (25 Gy in 5 fraction) in neoadjuvant setting was opted rarely (7%). Three-dimensional conformal technique was preferred over intensity-modulated ones (73% vs 27%). Toxicity was mainly of grade I-II CTCAE (skin 23%, gastrointestinal 39%, genitourinary 14%) compared to grade III (gastrointestinal 4%, genitourinary and hematological < 1%). Interestingly, the toxicity rates were significantly higher in the adjuvant group compared to the neoadjuvant (GI: 58% vs 31%, GU: 21% vs 10%). CONCLUSION: The present survey shows that in the Sicily region integrated therapies for rectal cancer have allowed a neoadjuvant approach in the majority of patients, thus resulting in a greater use of sphincter conservative surgery. The toxicity has also been reported to be significantly less in this treatment setting.

Single-institution experience of intensity-modulated radiotherapy for malignant pleural mesothelioma at University of Catania.

AIM: The multimodal approach to malignant pleural mesothelioma is gradually becoming the standard of care for this disease in patients with good performance status. Materials & methods: We report our experience concerning eight cases treated with the use of static step-and-shoot intensity-modulated radiotherapy to the whole pleural cavity, in patients already undergoing surgical and/or antiblastic therapy. Results & conclusion: Results at a median follow-up of 16 months showed a median survival from the initial treatment of 29 months, with lung toxicity of grade II reported only in two patients.

Combined taxane-based chemotherapy and intensity-modulated radiotherapy with simultaneous integrated boost for gastroesophageal junction adenocarcinoma.

We describe our experience, gained over the past 3 years, in the treatment of gastroesophageal junction adenocarcinoma, whose incidence has been increasing in recent years. In our series, we present the results to a follow-up of about 2 years for a total of 18 patients, treated with a particularly intensive combination treatment. It consists of neoadjuvant induction chemotherapy with the protocol docetaxel-cisplatin-5-fluorouracil for four cycles, before a concomitant chemoradiotherapy treatment. During combined phase, patients received an intensity-modulated radiotherapy and a weekly cisplatin. We will present the data to a long follow-up time and we will discuss the literature, the integration with thoracoabdominal surgery and other specific issues of this pathology.

DEXAMETHASONE INTRAVITREAL IMPLANT VS RANIBIZUMAB IN THE TREATMENT OF MACULAR EDEMA SECONDARY TO BRACHYTHERAPY FOR CHOROIDAL MELANOMA.

PURPOSE: To evaluate the efficacy of an intravitreal dexamethasone (Dex) implant 0.7 mg compared with intravitreal ranibizumab (Ra) for the treatment of radiation maculopathy with macular edema secondary to plaque brachytherapy in choroidal melanoma. METHODS: Eight patients were treated with intravitreal Ra, and eight patients received the Dex intravitreal implant. Visual acuity and foveal thickness were evaluated using spectral domain optical coherence tomography. RESULTS: The mean calculated irradiation to the fovea and mean times from brachytherapy to maculopathy development did not differ significantly between groups. In the Ra group, a mean 7.8 ± 3.9 injections were given and the mean follow-up was 33 ± 15 months (range, 7-52 months). In the Dex group, a mean 2.1 ± 0.8 injections were given and the mean follow-up was 22 ± 7 months (range, 11-31 months). The mean visual acuity improved significantly from the baseline to the last follow-up visit in both groups. Foveal thickness decreased significantly in both groups from 459 ± 81 µm to 243 ± 58 µm and from 437 ± 71 µm to 254 ± 44 µm from the baseline to the last follow-up visit in the Ra and Dex groups, respectively. No patients developed significant cataract or ocular hypertension in both groups. CONCLUSION: Both Ra and Dex are effective treatments for macular edema secondary to plaque brachytherapy for uveal melanoma. Dex-treated patients required fewer injections to achieve anatomical and functional improvement.

Uveal melanoma: quantitative evaluation of diffusion-weighted MR imaging in the response assessment after proton-beam therapy, long-term follow-up.

PURPOSE: The purpose of this prospective study was to investigate the proton-beam-induced changes in apparent diffusion coefficient (ADC) values of ocular melanoma treated with proton-beam therapy (PBT) in patients undergoing long-term magnetic resonance imaging (MRI) follow-up and to assess whether variations in ADC constitute a reliable biomarker for predicting and detecting the response of ocular melanoma to PBT. METHODS: Seventeen patients with ocular melanoma treated with PBT were enrolled. All patients underwent conventional MRI and diffusion-weighted imaging (DWI) at baseline and 1, 3, 6, and 18 months after the beginning of therapy. Tumor volumes and ADC values of ocular lesions were measured at each examination. Tumor volumes and mean ADC measurements of the five examination series were compared; correlation of ADC values and tumor regression was estimated. RESULTS: Mean ADC values of ocular melanomas significantly increased already 1 month after therapy whereas tumor volume significantly decreased only 6 months after therapy. Pretreatment ADC value of ocular melanomas and early change in ADC value 1 month after therapy significantly correlated with tumor regression. CONCLUSIONS: In ocular melanoma treated with PBT, ADC variations precede volume changes. Both pretreatment ADC and early change in ADC value may predict treatment response, thus expanding the role of DWI from diagnostic to prognostic.

Intensity-modulated radiotherapy for relapsed malignant pleural mesothelioma.

The use of novel radiotherapy techniques is widely increasing, allowing clinicians to treat diseases that were previously difficult to treat with radiation therapy. Malignant pleural mesothelioma is a clear example of this clinical challenge. We describe our first experience with intensity-modulated radiotherapy technique which was used to treat a 73-year-old patient with multiple relapsing malignant pleural mesothelioma. Intensity-modulated radiation therapy has allowed to respect the QUANTEC (quantitative analyses of normal tissue effects in the clinic) dose constraints, patient has experienced a 14 months progression-free time, without relevant subacute or late lung toxicity.

Role, timing and technique of radiotherapy in pediatric pleuropulmonary synovial sarcoma.

The management of pediatric thoracic synovial sarcoma remains a matter of debate in clinical oncology, especially as regard to the local control of the disease. Surgery remains the gold standard, while the role and timing of radiotherapy is still controversial. We report a 14-year-old male, who has not received proper treatment at the time of diagnosis and initial management. Intensity-modulated irradiation was performed only at relapse, as a salvage treatment and, at 10-month follow-up, the young patient was free from relapse, without significant acute and subacute toxicity. We discuss the role and timing of radiotherapy in thoracic synovial sarcoma, a disease in which the need to increase local control should be placed in the foreground.

Follicular dendritic cell sarcoma of mediastinum: a key role of radiotherapy in a multidisciplinary approach.

Follicular dendritic cell sarcoma is a rare and aggressive tumor and its management is a major clinical challenge. Surgery is considered the mainstay of treatment and no adjuvant approach has demonstrated the ability to reduce the rate of relapses. We report on a case of a man with a 26-year clinical history of mediastinal follicular dendritic cell sarcoma, with several relapses after multiple surgical interventions. The impact of chemotherapy was very small, unlike the radiation therapy that was performed twice, with an interval time of 8 years, through an intensity-modulated technique and an altered fractionation schedule.

Wider implications of video-assisted thoracic surgery versus open approach for lung metastasectomy.

Lung metastasectomy is considered a safe and potentially curative procedure despite there is not a strong evidence that metastasectomy prolongs long-term survival in patients with lung metastases. Moreover, the debate is open regarding the best approach for lung metastasectomy, video-assisted thoracic surgery versus open approach. A systematic review of literature to clarify what is the best approach to prolong survival in patients with lung metastases was performed. Our study confirms that overall survival is equivalent for video-assisted thoracic surgery and thoracotomy, therefore the 'gold standard' surgical treatment for lung metastases remains a point of debate. The choice of the surgical approach still depends more on the single center or surgeon practice than on strong scientific evidence. A prospective randomized trial could clarify the question.

Cytoreductive surgery and hyperthermic intrapleural chemotherapy for malignant pleural diseases: preliminary experience.

Cytoreductive surgery and hyperthermic-intraoperative-intrapleural-chemotherapy (HITHOC) is a known approach for malignant pleural diseases (MPD). This study was started to clarify the role of cytoreductive surgery and HITHOC in MPD. Criteria of inclusion were early-stage disease in malignant pleural mesothelioma (MPM), young age, good condition and selected stage-M1a lung cancer. Six patients with MPM and two patients with lung cancer were enrolled. After surgical debulking, intrapleural cisplatin was administered for 60 min at 42.5°C. Wedge, rib resection and repaired diaphragm were added in three, one and one patient, respectively. Morbidity, toxicity and mortality was nil. Hospital stay was 8 days. Mean survival is 13.6 months. This experience confirms that cytoreductive surgery and HITHOC is a good option in the treatment of MPD. A randomized controlled trial is necessary.

Pleurectomy/decortication and hyperthermic intrapleural chemotherapy for malignant pleural mesothelioma: initial experience.

Cytoreductive surgery and hyperthermic intraoperative intrapleural chemotherapy (HITHOC) are a known option for malignant pleural mesothelioma (MPM). This prospective study was started to prove that pleurectomy/decortication and HITHOC could be successfully performed in a low volume center. Criteria of inclusion were a proven diagnosis of MPM, early-stage disease and good performance status. Six consecutive patients were enrolled. After pleurectomy/decortication, intrapleural cisplatin was administered for 60 min at 42.5 °C. Wedge resections and diaphragmatic reconstruction were added in two and one patient, respectively. Morbidity was 16.6%. Mortality was nil. Hospital stay was 7.8 days. Mean survival was 21.5 months (range: 6-30). This small experience confirms that pleurectomy/decortication and HITHOC are a good therapeutic option in the multimodality treatment of MPM. A randomized controlled trial is necessary.

Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles.

OBJECT: The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol. METHODS: A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m(2) starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30-72 years (mean 56.1 years), received 150 mg/m(2) for 5 days every 28 days for more than 6 cycles (range 7-101 cycles). The 18 patients in Group B, aged 46-82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered. RESULTS: All patients but 1 in Group A survived at least 18 months (range 18-101 months), and patients in Group B survived no more than 17 months (range 2-17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group. CONCLUSIONS: This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.

New drugs for the treatment of IBD during conception, pregnancy, and lactation.

The management of inflammatory bowel disease requires continuous medical therapy to achieve and maintain disease control. Thus, women can be exposed to different drugs during conception, pregnancy, and lactation with potentially harmful effects on the mother, foetus, or nursing infant. Conventional drugs and anti-tumour necrosis factor (TNF)-α are considered safe and can be maintained throughout all these phases. Emergent, although limited, data support safety of vedolizumab and ustekinumab, with pregnancy, as well as maternal and neonatal outcomes comparable to women unexposed or treated with anti TNF-α drugs. Placental pharmacokinetics differ between these two biologics, with an inverse infant-to-maternal ratio for vedolizumab, whereas ustekinumab shows a similar profile to anti TNF-α drugs. The clearance of vedolizumab in exposed offspring seems to be faster than anti TNF-α, estimated around 15 and 19 weeks of age, respectively. Currently, the decision to interrupt or maintain these treatments is up to physicians' judgement on a case-by-case basis. In animal studies, Janus kinase (JAK) inhibitors and ozanimod have shown embryotoxicity and teratogenicity. Moreover, tofacitinib and filgotinib seemingly affect female fertility. This review summarizes all existing data on the effects of administration of non-anti-TNF-α biologic agents and small molecules, during conception, pregnancy, and lactation.

The Importance of Th2 Immune Responses in Mediating the Progression of Gastritis-Associated Metaplasia to Gastric Cancer.

Gastric cancer is one of the leading causes of cancer deaths worldwide, with chronic gastritis representing the main predisposing factor initiating the cascade of events leading to metaplasia and eventually progressing to cancer. A widely accepted classification distinguishes between autoimmune and environmental atrophic gastritis, mediated, respectively, by T cells promoting the destruction of the oxyntic mucosa, and chronic H. pylori infection, which has also been identified as the major risk factor for gastric cancer. The original dogma posits Th1 immunity as a main causal factor for developing gastritis and metaplasia. Recently, however, it has become evident that Th2 immune responses play a major role in the events causing chronic inflammation leading to tumorigenesis, and in this context, many different cell types and cytokines are involved. In particular, the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages and eosinophils, are intertwined in the process, promoting chronic gastritis-dependent and more diffuse metaplasia. Herein, we provide an overview of the critical events driving the pathology of this disease, focusing on the most recent findings regarding the importance of Th2 immunity in gastritis and gastric metaplasia.

Predictors of Efficacy of Janus Kinase Inhibitors in Patients Affected by Ulcerative Colitis.

Personalised medicine and the identification of predictors of the efficacy of specific drugs represent the ultimate goal for the treatment of ulcerative colitis (UC) in order to break the current therapeutic ceiling. JAK inhibitors are a new class of advanced therapies, orally administered, showing a good profile of efficacy and safety in both randomised controlled trials (RCTs) and real-world studies. Unfortunately, to date, it is not possible to draw the ideal profile of a patient maximally benefiting from this class of drugs to guide clinicians' therapeutic choices. Baseline clinical activities and inflammatory biomarkers, as well as their early variation after treatment initiation, emerged as the main predictors of efficacy from post hoc analyses of RCTs with tofacitinib. Similar findings were also observed in the real-life studies including mainly patients with a history of pluri-refractoriness to biological therapies. At last, a few new biomarkers have been explored, even though they have not been validated in large cohorts. This paper provides a review of the current knowledge on clinical variables and biomarkers predicting response to JAK inhibitors in UC.