mTOR regulates several processes that control tumor development, including cancer cell growth, angiogenesis and the immune response to tumor. Accordingly, mTOR inhibitors have been thoroughly explored in cancer therapy but have failed to provide long-lasting anticancer benefits. Several resistance mechanisms that counteract the antitumor effect of mTOR inhibitors have been identified and have highlighted the need to use mTOR inhibitors in combination therapies. In this context, emerging evidence has demonstrated that mTOR inhibitors, despite their immunosuppressive properties, provide anticancer benefits to immunotherapies. In fact, mTOR inhibitors also display immunostimulatory effects, in particular by promoting memory CD8+ T cell generation. Hence, mTOR inhibitors represent a therapeutic opportunity to promote antitumor CD8 responses and to boost the efficacy of different modalities of cancer immunotherapy. In this context, strategies to reduce the immunosuppressive activity of mTOR inhibitors and therefore to shift the immune response toward antitumor immunity will be useful. In this review, we present the different classes of mTOR inhibitors and discuss their effect on immune cells by focusing mainly on CD8+ T cells. We further provide an overview of the different preclinical studies that investigated the anticancer effects of mTOR inhibitors combined to immunotherapies.

Purpose: To evaluate the safety and efficacy of Preserflo® microshunt implantation in eyes with refractory glaucoma. Methods: In this retrospective study, a cohort of patients who underwent Preserflo® microshunt implantation between April 2019 and August 2020 for refractory glaucoma were evaluated. At the time of surgery, all eyes had uncontrolled intraocular pressure (IOP) despite maximally tolerated medical therapy and at least one previous failed glaucoma filtering surgery. The primary outcome was a complete success, defined as postoperative IOP ≤ 21 mm Hg with an IOP reduction ≥ 20% and no repeat filtering surgery. The secondary outcome was qualified success, defined as a complete success with the use of antiglaucoma medications. The rates of needling, bleb repair, and postoperative complications were also recorded. Results: Forty-seven eyes with a mean preoperative IOP of 30.1 ± 7.1 mm Hg and a mean of 3.4 ± 1 glaucoma medications were included. The mean number of previous surgeries prior to microshunt implantation was 2.3 ± 1.3. After 1 year, the mean IOP was significantly reduced to 18.8 ± 4.6 mm Hg, with the mean number of medications significantly reduced to 1.4 ± 1.2. Complete success was achieved in 35% of eyes, and a qualified success in 60% of eyes. A decrease in IOP of at least 30% was found in 55% of eyes. Needling or bleb repair was performed in 49% of eyes. Complications were minimal and transient, except for one eye which presented with tube extrusion, and another eye with a transected tube. A repeat glaucoma surgery had to be performed in 17% of eyes. Conclusions: The Preserflo® Microshunt provided moderate success but a significant reduction in IOP, with a good safety profile after one year of follow-up in eyes at high risk for failure of filtering surgery.

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Rationale:The association between intracranial hypertension (ICH) and ulcerative colitis (UC) is rare. We report the unusual case of a male patient with UC and ICH in whom both conditions resolved with mesalazine therapy.Patient concerns:A 48-year-old Caucasian man presented to our department in June 2016 for decreased vision, transient visual obscuration, pulsatile tinnitus and headaches of 7 months duration. Bilateral optic disc swelling was found at fundus examination. Brain MRI excluded any brain tumor and lumbar puncture showed cerebrospinal fluid (CSF) opening pressure of 26 cm of water with normal CSF contents.Diagnoses:Idiopathic ICH was suspected.Interventions:The patient was managed with oral acetazolamide. Headaches initially improved but the dosage could not be decreased under 750 mg a day without recurrence of the symptoms. Extensive review of systems showed that the patient had active UC. He was given oral mesalazine, 2000 mg a day.Outcomes:The symptoms of UC and ICH quickly resolved. Acetazolamide was progressively tapered over the course of the 9 subsequent months and the patient did not show any worsening of his symptoms or papilledema.Lessons:UC should be added to the list of disorders associated with ICH. In case of atypical ICH with drug dependency, investigations should seek for UC. Treating efficiently UC with mesalazine may improve ICH, suggesting an underlying inflammatory process.

Purpose: Cytomegalovirus (CMV) infection has been implicated in a number of complications after heart transplant. Our study aim was to determine the effects of CMV donor-recipient status in a large cohort of patients undergoing heart transplant. Methods: All adult heart transplants from 2000 to 2012 were identified using the United Network for Organ Sharing (UNOS) database. Patients were grouped accordingly to donor and recipient CMV status: Donor+/Recipient+ (D+/R+), Donor+/Recipient-(D+/R-), Donor-/Recipient-(D-/R-) and Donor-/Recipient+ (D-/R+). We further analyzed HLA mismatch and outcomes in these four groups. Kaplan-Meir survival curves were analyzed for 10-year survival. Cox proportional hazard models were performed to determine predictors of mortality. P-values< 0.05 were considered significant. Results: A total of 20,783 patients receiving a heart transplant were analyzed, 75% were male, 72% Caucasian and 42% had ischemic cardiomyopathy. Of the total cohort, 7,963 (38%) were D+/R+, 4,839 (24%) D+/R-, 4,847 (23%) D-/R+ and 3,134 (15%) D-/R-. Ten year censored survival estimates differed significantly (p< 0.05) between all donor/recipient CMV status groups with the exception of D+/R+ vs. D+/R-(p= 0.372) and D-/ R+ vs. D-/R-(p= 0.062; figure A). When compared to D-/R-patients, the group with the greatest hazard for mortality was the D+/R+ (HR= 1.24 95%CI:1.1-1.3; p-value< 0.01) followed by the D+/R-(HR= 1.20 95%CI: 1.1-1.3; p-value< 0.01). In the D+/R+ group the presence of ≥ 5 HLA mismatches further increased mortality while it had no effect on the other groups (p-value< 0.01, figure B). Conclusion: Our analysis has demonstrated that in a large cohort of patients, CMV positive donor status is associated with worse outcomes, independent of CMV status of the recipient. In those with CMV D+/R+ status having a ≥ 5 HLA mismatches significantly increases mortality.

Methods: We evaluated the UNOS registry for all adult heart transplant recipients from 1990 to 2014. Recipients with RVAD or BiVAD or TAH were excluded. Use of three different IM combinations at discharge or followup were assessed over time (1990s, 2000s, & 2010 to June 2014). These included steroid (S) with azathioprine (A) and cyclosporine (C), steroid with mycophenolate mofetil (M) and CSA, and steroid with M and tacrolimus (T). Chi-square analyses were employed to compare IM regimen with 1-year graft failure and 1-year rejection. Kaplan-Meier estimates were used to assess survival by IM regimen. Results: IM protocols utilizing SAC decreased over time from the 1990s n= 18,498 to n= 16,314 in the 2000s, to n= 8,691 in 2014.(Table) A similar decrease was observed in the use of SMC regimen while SMT usage has gained traction.(Table) Patients on SAC had statistically significant higher rejection episodes at 1 year and graft failures. In the SMT group, lower rates of both 1-year rejection (31.0% vs. 40.4%, p< 0.01) and graft failure (6.3% vs. 19.7%, p< 0.01) were observed. 10 year mortality rates in were statistically significantly lower in the SMT group when compared to SAC and SMC groups combined (37.2% vs 51%, p< .01). Conclusion: Increasing use of SMT IM has contributed to increasing 10 year survival in the heart transplant recipients. Careful follow up of this group is warranted to evaluate if the adverse effects of chronic IM are accelerated.

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