Cannabidiol oil or placebo in advanced cancer-disease progression and survival: a secondary analysis.

OBJECTIVES: Medical cannabinoids have become increasingly popular over the last decade. Preclinical trials suggest cannabinoids, for example, cannabidiol (CBD), may provide an anticancer effect; however, good-quality clinical information supporting this is lacking. We assessed the effect of CBD treatment on disease progression and survival in patients enrolled in a study of CBD versus placebo for symptom management in patients with advanced cancer (MEDCAN-1). METHODS: We reviewed the clinical records of all patients enrolled in the MEDCAN-1 Study (CBD vs placebo) at days 14, 28 and 56 of study follow-up, for evidence of disease progression. The proportion of participants with disease progression by treatment arm at each time point was compared, as was survival between both groups from study entry to the censor date (end of study period) and the effect of treatment arm and disease progression status on survival. RESULTS: Of the 135 patient records assessed, 128 were included in the final analysis. 36% (n=46) had progressive disease documented at day 28, rising to 49.2% (n=63) by day 56. No significant difference in disease progression was noted between the two groups at days 14 (p=0.33), 28 (p=0.67) or 56 (p=0.50). There was no difference in survival between both groups from study entry to censor date (p=0.38). Disease progression at day 14 was highly predictive of mortality (p<0.001). CONCLUSIONS: In this substudy analysis, treatment with CBD oil did not affect disease progression or survival over the course of 56 days in patients with advanced cancer.

Palliative radiotherapy and the introduction of a Rapid Access Palliative Clinic in a national radiation oncology network.

BACKGROUND: Palliative radiotherapy (PRT) is commonly used to treat symptoms of advanced cancer. PRT has been associated with elevated 30-day mortality (30DM). A Rapid Access Palliative Clinic (RAPC) can streamline the treatment process for patients receiving treatment. AIMS: We reviewed the PRT practices in a radiation oncology network in Ireland, and the implementation of a RAPC. Patient outcomes were assessed to inform future treatment decisions. METHODS: A retrospective review of all patients who received PRT over 6 months in 2018 in St. Luke's Radiation Oncology Network (SLRON) was undertaken. We assessed 30DM rates, demographics and referral to specialist palliative care (SPC) services. Subsequently, a retrospective analysis was conducted of a RAPC which ran for 6 months from 2019 to 2020. We assessed treatment data and mortality. RESULTS: Over 6 months, 645 patients commenced PRT in the SLRON. The 30DM for this cohort was 15.8% (n = 102), with most patients having lung primaries. Of the 30DM cohort, only 55% (n = 56) were referred to SPC services and only 26.4% (n = 27) had performance status recorded. Over 6 months, 40 patients attended 28 RAPCs. Of these, 88% (n = 35) received PRT. Single fraction therapy was utilised in 60% and 48% of patients underwent CT simulation and treatment on the same day. Ultimately, 75% of patients received SPC referral. CONCLUSIONS: Referral rates to SPC services and documentation of performance status were low in our 30DM retrospective review cohort. The RAPC facilitated quick treatment turnaround, fewer hospital visits and referral to SPC services.

Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers.

Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and adagrasib) have now overcome this therapeutic hurdle. We discuss the evidence for these medications, their pitfalls and adverse effects, as well as future directions in this space. Though these medications demonstrate substantial response rates in a heavily pre-treated advanced NSCLC cohort, as phase-3 evidence does not yet demonstrate an overall survival benefit versus standard-of-care chemotherapy, docetaxel. Additionally, these medications appear to have a negative interaction in combination with immunotherapies, with substantially greater hepatotoxicity rates observed. Despite this, it is undeniable that these medications represent an important advancement in targeted and personalised oncological treatment. Current and future trials assessing these medications in combination and through sequencing strategies will likely yield further clinically meaningful outcomes to guide treatment in this patient cohort.

Vedolizumab-induced acute interstitial nephritis with failure of steroid prophylaxis on vedolizumab rechallenge.

Acute interstitial nephritis (AIN) is a common cause of acute kidney injury and renal failure. It is typically drug induced but can also be idiopathic or secondary to chronic infective or inflammatory conditions. Recent case reports suggest vedolizumab can be a causative agent for AIN. We report the case of a young man who presented with renal failure, fevers and constitutional symptoms. He had a complex history of refractory ulcerative colitis, prior colectomy and ileo-pouch-anal anastomosis with recurrent pouchitis. He had been receiving regular vedolizumab infusions for 6 months by the time of his presentation. A renal biopsy 4 months into his follow-up demonstrated AIN. Steroid prophylaxis with vedolizumab was trialled but ultimately failed, with worsening AIN and incomplete renal function recovery. To our knowledge, this is the first case of vedolizumab-induced AIN demonstrating a failure of steroid prophylaxis to prevent recurrence of AIN following vedolizumab rechallenge.

Development and clinical translation of tubular constructs for tracheal tissue engineering: a review.

Effective restoration of extensive tracheal damage arising from cancer, stenosis, infection or congenital abnormalities remains an unmet clinical need in respiratory medicine. The trachea is a 10-11 cm long fibrocartilaginous tube of the lower respiratory tract, with 16-20 tracheal cartilages anterolaterally and a dynamic trachealis muscle posteriorly. Tracheal resection is commonly offered to patients suffering from short-length tracheal defects, but replacement is required when the trauma exceeds 50% of total length of the trachea in adults and 30% in children. Recently, tissue engineering (TE) has shown promise to fabricate biocompatible tissue-engineered tracheal implants for tracheal replacement and regeneration. However, its widespread use is hampered by inadequate re-epithelialisation, poor mechanical properties, insufficient revascularisation and unsatisfactory durability, leading to little success in the clinical use of tissue-engineered tracheal implants to date. Here, we describe in detail the historical attempts and the lessons learned for tracheal TE approaches by contextualising the clinical needs and essential requirements for a functional tracheal graft. TE manufacturing approaches explored to date and the clinical translation of both TE and non-TE strategies for tracheal regeneration are summarised to fully understand the big picture of tracheal TE and its impact on clinical treatment of extensive tracheal defects.

The development of a tissue-engineered tracheobronchial epithelial model using a bilayered collagen-hyaluronate scaffold.

Today, chronic respiratory disease is one of the leading causes of mortality globally. Epithelial dysfunction can play a central role in its pathophysiology. The development of physiologically-representative in vitro model systems using tissue-engineered constructs might improve our understanding of epithelial tissue and disease. This study sought to engineer a bilayered collagen-hyaluronate (CHyA-B) scaffold for the development of a physiologically-representative 3D in vitro tracheobronchial epithelial co-culture model. CHyA-B scaffolds were fabricated by integrating a thin film top-layer into a porous sub-layer with lyophilisation. The film layer firmly connected to the sub-layer with delamination occurring at stresses of 12-15 kPa. Crosslinked scaffolds had a compressive modulus of 1.9 kPa and mean pore diameters of 70 µm and 80 µm, depending on the freezing temperature. Histological analysis showed that the Calu-3 bronchial epithelial cell line attached and grew on CHyA-B with adoption of an epithelial monolayer on the film layer. Immunofluorescence and qRT-PCR studies demonstrated that the CHyA-B scaffolds facilitated Calu-3 cell differentiation, with enhanced mucin expression, increased ciliation and the formation of intercellular tight junctions. Co-culture of Calu-3 cells with Wi38 lung fibroblasts was achieved on the scaffold to create a submucosal tissue analogue of the upper respiratory tract, validating CHyA-B as a platform to support co-culture and cellular organisation reminiscent of in vivo tissue architecture. In summary, this study has demonstrated that CHyA-B is a promising tool for the development of novel 3D tracheobronchial co-culture in vitro models with the potential to unravel new pathways in drug discovery and drug delivery.

Respiratory Tissue Engineering: Current Status and Opportunities for the Future.

Currently, lung disease and major airway trauma constitute a major global healthcare burden with limited treatment options. Airway diseases such as chronic obstructive pulmonary disease and cystic fibrosis have been identified as the fifth highest cause of mortality worldwide and are estimated to rise to fourth place by 2030. Alternate approaches and therapeutic modalities are urgently needed to improve clinical outcomes for chronic lung disease. This can be achieved through tissue engineering of the respiratory tract. Interest is growing in the use of airway tissue-engineered constructs as both a research tool, to further our understanding of airway pathology, validate new drugs, and pave the way for novel drug therapies, and also as regenerative medical devices or as an alternative to transplant tissue. This review provides a concise summary of the field of respiratory tissue engineering to date. An initial overview of airway anatomy and physiology is given, followed by a description of the stem cell populations and signaling processes involved in parenchymal healing and tissue repair. We then focus on the different biomaterials and tissue-engineered systems employed in upper and lower respiratory tract engineering and give a final perspective of the opportunities and challenges facing the field of respiratory tissue engineering.