The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population

ImportanceImmunotherapy has emerged as an effective treatment option for the management of advanced cancers. The effects of these immune checkpoint inhibitors in the older patient population has not been adequately assessed.ObjectiveTo understand the impact of aging on CTLA-4 and PDL-1 inhibitors efficacy and immune-related adverse events (irAE) in the context of real-world management of advanced solid cancers.Design, Setting, and ParticipantsThis retrospective study involved all non-study patients with histologically-confirmed metastatic or inoperable solid cancers receiving immunotherapy at Kingston Health Sciences Centre. We defined ‘older patient’ as age ≥ 75. All statistical analyses were conducted under SPSS IBM for Windows version 24.0.Main Outcomes and MeasuresStudy outcomes included immunotherapy treatment response, survival, as well as number, type, and severity of irAEs.ResultsOur study (N = 78) had 29 (37%) patients age <65, 26 (33%) patients age 65–74, and 23 (30%) patients age ≥75. Melanoma, non-small cell lung cancer, and renal cell carcinoma accounted for 70%, 22%, and 8% of the study population, respectively. Distributions of ipilimumab (32%), nivolumab (33%), and pembrolizumab (35%) were similar in the study. The response rates were 28%, 27%, and 39% in the age <65, age 64–74, age ≥75 groups, respectively (P = 0.585). Kaplan-Meier curve showed a median survival of 28 months (12.28–43.9, 95% CI) and 17 months (0–36.9, 95% CI) in the age <65 and age 64–74 groups, respectively; the estimated survival probability did not reach 50% in the age ≥75 group (P = 0.319). There were no statistically significant differences found in terms of irAEs, multiple irAEs, severity of grade 3 or higher, types of irAEs, and irAEs resolution status when comparing between different age groups.Conclusion and RelevanceOur results suggest that patients age ≥75 are able to gain as much benefit from immunotherapy as younger patients, without excess toxicity. Our findings suggest that single agent immunotherapy is generally well-tolerated across different age groups with no significant difference in the type, frequency or severity of irAEs. Future studies evaluating aging and combination immunotherapy are warranted.     

Conventional Ultrafiltration During Elective Cardiac Surgery and Postoperative Acute Kidney Injury

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Role of Natural Killer Cell Subsets in Cardiac Allograft Rejection

To achieve donor-specific immune tolerance to allogeneic organ transplants, it is imperative to understand the cell types involved in acute allograft rejection. In wild-type mice, CD4(+) T cells are necessary and sufficient for acute rejection of cardiac allografts. However, when T-cell responses are suboptimal, such as in mice treated with costimulation-targeting agents or in CD28-deficient mice, and perhaps in transplanted patients taking immunosuppressive drugs, the participation of other lymphocytes such as CD8(+) T cells and NK1.1(+) cells becomes apparent. We found that host NK but not NKT cells were required for cardiac rejection. Ly49G2(+) NK cells suppressed rejection, whereas a subset of NK cells lacking inhibitory Ly49 receptors for donor MHC class I molecules was sufficient to promote rejection. Notably, rejection was independent of the activating receptors Ly49D and NKG2D. Finally, our experiments supported a mechanism by which NK cells promote expansion and effector function of alloreactive T cells. Thus, therapies aimed at specific subsets of NK cells may facilitate transplantation tolerance in settings of impaired T-cell function.     

Survival of hepatitis A virus on human hands and its transfer on contact with animate and inanimate surfaces.

The survival of hepatitis A virus (HAV; strain HM175) on the hands of five volunteers was determined by depositing 10 microliters of fecally suspended virus on each fingerpad and eluting the inoculum after 0, 20, 60, 120, 180, and 240 min. The amount of virus recovered from each fingerpad at 0 min was approximately 6.0 x 10(4) PFU. At the end of 4 h, 16 to 30% of the initially recoverable virus remained detectable on the fingerpads. HAV inocula (10 microliters; approximately 1.0 x 10(4) PFU) placed on fingerpads or 1-cm-diameter metal disks were used to determine virus transfer to clean surfaces upon a 10-s contact at a pressure of nearly 0.2 kg/cm2. When the inoculum was dried for 20 min, virus transfer from fingerpad to fingerpad, fingerpad to disk, and disk to fingerpad ranged from 2,667 to 3,484 PFU, while 0 to 50 PFU could be transferred after 4 h of drying. Elevation of the contact pressure alone from 0.2 to 1.0 kg/cm2 resulted in an approximately threefold increase in the amount of virus transferred. Incorporation of friction (10 half turns of the finger during 10 s of contact) with the low and high levels of pressure gave two- and threefold increases in the PFU of virus transferred, respectively. Pressure and friction were found to significantly affect HAV transfer (F = 33.98; P less than 0.05), irrespective of the mode of transfer used. No statistically significant interaction was observed between mode of transfer and pressure or friction. The findings of this quantitative study suggest that human hands may play an important role in the direct as well as the indirect spread of HAV.     

Characteristics of antibody responses induced in mice by protein allergens

Whereas many foreign proteins are immunogenic, only a proportion is also allergenic, having the capacity to induce the quality of immune response necessary to support the production of IgE antibody. We have demonstrated previously that intraperitoneal administration to mice of proteins such as ovalbumin (OVA) or the industrial enzyme A. oryzae lipase, which possess significant allergenic potential, stimulates the production of both IgG and IgE antibody. Identical exposure to bovine serum albumin (BSA), a protein with limited potential to cause immediate respiratory or gastrointestinal hypersensitivity reactions, induced IgG responses only. In the current investigations, the quality of immune responses induced following exposure to these proteins via mucosal tissue (intranasal) has been compared with those provoked following administration via a non-mucosal (intraperitoneal) route of exposure. Intranasal or intraperitoneal administration of BSA, OVA or A. oryzae lipase elicited in each case vigorous IgG and IgG1 antibody responses. For all three proteins, at every concentration tested, and via both routes of exposure, IgG1 antibody titres paralleled closely IgG titres. However, the three materials displayed a differential potential to provoke IgE responses and this correlated with their known allergenic potential in humans. Thus, OVA and A. oryzae lipase stimulated strong IgE antibody responses, whereas BSA provoked low titre IgE only at the highest concentration tested (5% administered intraperitoneally). The quality of induced responses was not affected by the route of exposure. It would appear, therefore, that the stimulation of IgG and IgG1 antibody responses is a reflection of protein immunogenicity whereas protein allergenicity is associated with the induction of strong IgE responses.     

Peritoneal protein loss in children with nephrotic syndrome during peritoneal dialysis

Background: The passage of proteins across the glomerular filtration barrier is mainly determined by the size of the protein. In nephrotic syndrome (NS) the glomerular permselectivity is affected, causing proteinuria. Some authors suggest the existence of a generalized basement membrane defect. The permeability characteristics of the peritoneal basement membrane in children with NS are not known. Methods: The transperitoneal transport of proteins with a different molecular weight ({beta}2-microglobulin MW 11 800 D, albumin MW 69 000 D, IgG MW 160 000 D, and &agr;2-macroglobulin MW 820 000 D) was studied in a study group (group A) consisting of six stable nephrotic children (three with glomerulosclerosis and three with congenital nephrotic syndrome, one of them with mesangial sclerosis) and compared to a control group (group B) consisting of eight stable children on peritoneal dialysis. After a dwell of 6 h with Dianeal 1.36% dialysate and serum samples were collected. For each patient the dialysate to plasma (D/P) ratio of the four proteins were calculated. The D/P ratios of the nephrotic patients in group A were compared to the D/P ratios of the patients in the control group B. Data were expressed as mean ±SD. Results: The values for the D/P ratios (in percentage) of {beta}2-microglobulin, albumin, IgG and &agr;2-macroglobulin in group A were 19.6±9.9, 2.7±1.7, 1.6±0.9, and 0.5±0.4, compared to 24.9±10.2, 4.0±2.3, 2.2±1.2, and 0.7±0.3 in the control group B. The ratios were plotted against MW on a double logarithmic scale. In all patients a linear relationship between molecular weight and D/P ratio of the proteins was obtained. The D/P ratios of the study group did no differ significantly from the control group. Conclusion: We conclude that the size selectivity of the capillary permeability is not affected in the peritoneal membrane in children with NS due to glomerulosclerosis and congenital nephrotic syndrome.     

Block copolymers of fluoral oligomer with urethanes: Preparation and thermal properties

Two series of block copolymers have been synthesized comprising of soft polytrifluoroacetaldehyde (polyacetal) segments and of hard 4,4′-methylenedi(phenyl isocyanate)/cis-cyclohexane-1,4-diol polyurethane segments. The series-A copolymers in which the soft segments were directly bound to the hard segments had significantly lower thermal stability than the series-B copolymers in which the soft segments were linked to the hard segments by sebacic ester units. In both series the thermal stability decreased with increasing soft segment content. The series-A copolymers exhibited two thermal transitions both characteristic of T_g's and separated by about 60 K. In contrast the series-B copolymers exhibited two characteristic T_g's separated by 200–250 K, depending on composition, together with an additional endothermic transition at about ambient temperature. All transitions for both series decreased with increasing soft segment content. The observations have been compared with those of other polyether and polyester based polyurethanes.