Sarcopenia, adiposity and large discordance between cystatin C and creatinine-based estimated glomerular filtration rate in patients with cancer.

BACKGROUND: Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with sarcopenia. While cystatin C-based eGFR (eGFRCYS) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition defined by computed tomography (CT) scans and discordance between creatinine, eGFRCRE and eGFRCYS in adult patients with cancer. METHODS: This study is a cross-sectional study of consecutive adults with cancer with an abdominal CT scan performed within 90 days of simultaneous eGFRCRE and eGFRCYS measurements between May 2010 and January 2022. Muscle and adipose tissue cross-sectional areas were measured at the level of the third lumbar vertebral body using a validated deep-learning pipeline. CT-defined sarcopenia was defined using independent sex-specific cut-offs for skeletal muscle index (<39 cm2/m2 for women and <55 cm2/m2 for men). High adiposity was defined as the highest sex-specific quartile of the total (visceral plus subcutaneous) adiposity index in the cohort. The primary outcome was eGFR discordance, defined by eGFRCYS > 30% lower than eGFRCRE; the secondary outcome was eGFRCYS > 50% lower than eGFRCRE. The odds of eGFR discordance were estimated using multivariable logistic regression modelling. Unadjusted spline regression was used to evaluate the relationship between skeletal muscle index and the difference between eGFRCYS and eGFRCRE. RESULTS: Of the 545 included patients (mean age 63 ± 14 years, 300 [55%] females, 440 [80.7%] non-Hispanic white), 320 (58.7%) met the criteria for CT-defined sarcopenia, and 136 (25%) had high adiposity. A total of 259 patients (48%) had >30% eGFR discordance, and 122 (22.4%) had >50% eGFR discordance. After adjustment for potential confounders, CT-defined sarcopenia and high adiposity were both associated with >30% eGFR discordance (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12-3.24; aOR 2.01, 95% CI 1.15-3.52, respectively) and >50% eGFR discordance (aOR 2.34, 95% CI 1.21-4.51; aOR 2.23, 95% CI 1.19-4.17, respectively). A spline model demonstrated that as skeletal muscle index decreases, the predicted difference between eGFRCRE and eGFRCYS widens considerably. CONCLUSIONS: CT-defined sarcopenia and high adiposity are both independently associated with large eGFR discordance. Incorporating valuable information from body composition analysis derived from CT scans performed as a part of routine cancer care can impact the interpretation of GFR estimates.

Adverse kidney outcomes of CDK 4/6 inhibitors for metastatic breast cancer.

Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved overall and progression free survival of patients with metastatic breast cancer, but their effect on short and long-term kidney function is unknown. We found that early, mild estimated glomerular filtration rate (eGFR) decline was common in patients treated with CDK 4/6 inhibitors; however, severe kidney injury is rare and long-term eGFR decline is uncommon.

Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer.

Importance: Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR (eGFRcys) is an alternative marker of GFR. Objective: To determine whether the therapeutic drug levels and adverse events (AEs) associated with renally cleared medications were higher in patients with cancer whose eGFRcys was more than 30% lower than their eGFRcr. Design, Setting, and Participants: This cohort study analyzed adult patients with cancer at 2 major academic cancer centers in Boston, Massachusetts. These patients had their creatinine and cystatin C measured on the same day between May 2010 and January 2022. The date of the first simultaneous eGFRcr and eGFRcys measurement was considered to be the baseline date. Exposure: The primary exposure was eGFR discordance, defined as an eGFRcys that was more than 30% lower than the eGFRcr. Main Outcomes and Measures: The primary outcome was risk of the following medication-related AEs within 90 days of the baseline date: (1) supratherapeutic vancomycin trough level greater than 30 µg/mL, (2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5 mEq/L), (3) baclofen toxic effect, and (4) supratherapeutic digoxin level (>2.0 ng/mL). For the secondary outcome, a multivariable Cox proportional hazards regression model was used to compare 30-day survival of those with vs without eGFR discordance. Results: A total of 1869 adult patients with cancer (mean [SD] age, 66 [14] years; 948 males [51%]) had simultaneous eGFRcys and eGFRcr measurement. There were 543 patients (29%) with an eGFRcys that was more than 30% lower than their eGFRcr. Patients with an eGFRcys that was more than 30% lower than their eGFRcr were more likely to experience medication-related AEs compared with patients with concordant eGFRs (defined as eGFRcys within 30% of eGFRcr), including vancomycin levels greater than 30 µg/mL (43 of 179 [24%] vs 7 of 77 [9%]; P = .01), trimethoprim-sulfamethoxazole-related hyperkalemia (29 of 129 [22%] vs 11 of 92 [12%]; P = .07), baclofen toxic effects (5 of 19 [26%] vs 0 of 11; P = .19), and supratherapeutic digoxin levels (7 of 24 [29%] vs 0 of 10; P = .08). The adjusted odds ratio for vancomycin levels more than 30 µg/mL was 2.59 (95% CI, 1.08-7.03; P = .04). Patients with an eGFRcys more than 30% lower than their eGFRcr had an increased 30-day mortality (adjusted hazard ratio, 1.98; 95% CI, 1.26-3.11; P = .003). Conclusions and relevance: Results of this study suggest that among patients with cancer with simultaneous assessment of eGFRcys and eGFRcr, supratherapeutic drug levels and medication-related AEs occurred more commonly in those with an eGFRcys more than 30% lower than their eGFRcr. Future prospective studies are needed to improve and personalize GFR estimation and medication dosing in patients with cancer.

Kidney function in patients with ovarian cancer treated with poly (ADP-ribose) polymerase (PARP) inhibitors.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of ovarian cancer; however, real-world data on kidney function among patients treated with PARPi are lacking. METHODS: We identified adults treated with olaparib or niraparib between 2015 and 2021 at a major cancer center in Boston, MA, USA. We determined the incidence of any acute kidney injury (AKI), defined as at least a 1.5-fold rise in serum creatinine from baseline in the first 12 months following PARPi initiation. We calculated the percentage of patients with any AKI and sustained AKI and adjudicated the etiologies by manual chart review. We compared trajectories in estimated glomerular filtration rate (eGFR) among PARPi-treated and carboplatin and paclitaxel-treated patients with ovarian cancer, matched by baseline eGFR. RESULTS: Of 269 patients, 60 (22.3%) developed AKI, including 43 of 194 (22.1%) olaparib-treated patients and 17 of 75 (22.7%) niraparib-treated patients. Only 9 of 269 (3.3%) had AKI attributable to the PARPi. Of the 60 patients with AKI, 21 (35%) had sustained AKI, of whom 6 had AKI attributable to the PARPi (2.2% of the whole cohort). eGFR declined within 30 days post-PARPi initiation by 9.61 (SD = 11.017) mL/min per 1.73 m2 but recovered by 8.39 (SD = 14.05) mL/min per 1.73 m2 within 90 days after therapy cessation. There was no difference in eGFR at 12 months post-therapy initiation in patients receiving PARPi or controls receiving carboplatin and paclitaxel (P = .29). CONCLUSIONS: AKI is common following PARPi initiation as is a transient decline in eGFR; however, sustained AKI directly attributable to the PARPi and long-term eGFR decline are uncommon.

Clinical Features of Acute Kidney Injury in the Early Post-Transplantation Period Following Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative therapy for patients with hematologic malignancies but is associated with acute kidney injury (AKI). To date, few studies have examined risk factors for AKI at engraftment, or the relationship between AKI and clinical outcomes. This study examined the incidence and risk factors for periengraftment AKI, as well as the association between AKI and overall survival (OS) and nonrelapse mortality (NRM). We conducted a retrospective analysis of adult patients undergoing reduced-intensity conditioning (RIC) allogeneic HCT at the Dana-Farber Cancer Institute between 2012 and 2019. Periengraftment (day 0 to day 30) AKI incidence and severity were defined using modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Factors associated with periengraftment AKI risk were examined using Cox regression analysis. The impact of periengraftment AKI on OS and NRM (defined as death without recurrent disease after HCT), was evaluated using Cox regression and the Fine and Gray competing risks model, respectively. Kidney recovery, defined as a return of serum creatinine (SCr) to within 25% of baseline or liberation from kidney replacement therapy (KRT), was examined at day 90 post-HCT. Periengraftment AKI occurred in 330 of 987 patients (33.4%) at a median of 13 days (interquartile range, 4 to 30 days) post-transplantation. Factors associated with a higher multivariable-adjusted risk of AKI were supratherapeutic rapamycin (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.20 to 2.03; P < .001), fludarabine/melphalan conditioning (HR, 1.35, 95% CI, 1.01 to 1.81; P = .05, compared to fludarabine/busulfan and fludarabine, cyclophosphamide, and total body irradiation), HCT Comorbidity Index ≥4 (HR, 1.43; 95% CI, 1.14 to 1.79; P = .002), albumin <3.4 g/dL (HR, 2.04; 95% CI, 1.33 to 3.12; P = .001), hemoglobin ≤12 (HR, 1.96; 95% CI, 1.38 to 2.78; P < .001), supratherapeutic tacrolimus (HR, 1.45; 95% CI, 1.07 to 1.95; P = .02), and baseline SCr >1.1 mg/dL (HR, 1.87; 95% CI, 1.48 to 2.35; P < .001). Periengraftment AKI was associated with worse OS (HR, 1.40; 95% CI, 1.16 to 1.71; P < .001) and NRM (subdistribution HR, 2.10; 95% CI, 1.52 to 2.89; P < .001). Kidney recovery occurred in 18%, 15%, and 30% of patients with stage 1, stage 2, and stage 3 AKI without KRT, respectively, and 4 of 16 patients (25%) were liberated from KRT. Periengraftment AKI is common among RIC allogeneic HCT recipients. We identified several important risk factors for periengraftment AKI. Its association with worse OS and NRM underscores the importance of timely recognition and management.

Safety of Immune Checkpoint Inhibitors in Patients With Advanced Chronic Kidney Disease: A Retrospective Cohort Study.

BACKGROUND: Clinical trials of immune checkpoint inhibitors (ICIs) often do not include patients with advanced chronic kidney disease (CKD). We aimed to determine the safety of ICIs in patients with cancer and advanced CKD (stages 4-5 CKD, estimated glomerular filtration rate [eGFR] <30 mL/minute/1.73 m2). PATIENTS AND METHODS: Patients with advanced CKD from the Mass General Brigham network who received ICIs (n = 91) were compared against those receiving nephrotoxic (n = 113) and non-nephrotoxic (n = 130) antineoplastic therapies, respectively. Rates of new-onset kidney failure (end-stage kidney disease or sustained eGFR ≤10 mL/minute/1.73 m2) and AKI were compared. Among ICI-treated patients, we modeled Fine-Gray subdistribution hazards to compare immune-related adverse event (irAE) risk and used Kaplan-Meier analysis to compare overall survival in patients with advanced CKD to those with eGFR ≥30 mL/minute/1.73 m2. RESULTS: Rates of new-onset kidney failure were similar at 1 year following initiation of ICIs (10.0%), nephrotoxic (6.2%), and non-nephrotoxic antineoplastic therapies (9.3%) (P = .28). AKI rates were also similar: 17.5%, 17.6%, and 20% of patients in each cohort, respectively (P = .87). Advanced CKD did not increase the risk of developing irAEs (adjusted hazard ratio [HR] 1.28, 95% CI, 0.91-1.81). However, patients with advanced CKD who received ICIs had a decreased overall survival compared with patients with eGFR ≥30 mL/minute/1.73 m2 (HR 1.30 for death, 95% CI, 1.02-1.66, P = .03). CONCLUSION: ICIs are not associated with increased risk of AKI or new-onset kidney failure compared with other antineoplastic therapies in patients with advanced CKD. Advanced CKD did not increase the risk of extra-renal irAEs, although these patients suffered from lower overall survival.

Medication-related adverse events in patients with cancer and discrepancies in cystatin C- versus creatinine-based eGFR.

Background: Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with cancer. Cystatin C-based eGFR (eGFRCYS) is an alternative marker of kidney function. We investigated whether patients with an eGFR discrepancy, defined as eGFRCYS >30% lower than the concurrent eGFRCRE, had an increased risk of adverse events resulting from renally-cleared medications. Patients and Methods: We conducted a cohort study of adult patients with cancer who had serum creatinine and cystatin C measured on the same day between May 2010 and January 2022 at two academic cancer centers in Boston, MA. The primary outcome was the incidence of each of the following medication-related adverse events: 1) supratherapeutic vancomycin levels (>30µg/mL); 2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5mEq/L); 3) baclofen-induced neurotoxicity; and 4) supratherapeutic digoxin levels (>2.0ng/mL). Results: 1988 patients with cancer had simultaneous eGFRCYS and eGFRCRE. The mean age was 66 years (SD±14), 965 (49%) were female, and 1555 (78%) were non-Hispanic white. eGFR discrepancy occurred in 579 patients (29%). Patients with eGFR discrepancy were more likely to experience medication-related adverse events compared to those without eGFR discrepancy: vancomycin levels >30µg/mL (24% vs. 10%, p=0.004), trimethoprim- sulfamethoxazole-related hyperkalemia (24% vs. 12%, p=0.013), baclofen-induced neurotoxicity (25% vs. 0%, p=0.13), and supratherapeutic digoxin levels (38% vs. 0%, p=0.03). The adjusted OR for vancomycin levels >30µg/mL was 2.30 (95% CI 1.05 - 5.51, p = 0.047). Conclusion: Among patients with cancer with simultaneous assessment of eGFRCYS and eGFRCRE, medication-related adverse events occur more commonly in those with eGFR discrepancy. These findings underscore the importance of accurate assessment of kidney function and appropriate dosing of renally-cleared medications in patients with cancer.

Decreasing the burden: An unusual GIST presentation, a case report.

INTRODUCTION: Gastrointestinal stromal tumours (GIST) are notoriously one of the most common mesenchymal tumours of the alimentary canal. Most commonly originating from the gastric stroma, they are recognized by their mass effects on the abdominal cavity. Recurrence frequently occurs with GIST and these tumours may become refractory to tyrosine kinase inhibitors (TKIs). Therefore, resection may be indicated for improved outcomes. PRESENTATION OF CASE: We present a 52-year-old African American male with a surgical history of GIST resection with recurrence that came to the emergency room with worsening diffuse abdominal pain. The tumour was refractory to two TKIs, Imatinib and Sunitinib. Computed tomography (CT) of the abdomen and pelvis was done which showed severe metastatic disease with carcinomatosis, multiple dilated loops of small bowel in the left hemiabdomen without discrete transition point. After seventeen days on nasogastric tube, antiemetics, the patient worsened, and it was decided to go to surgery. In this report, attention is focused on the surgical approach of tumour debulking with subsequent Regorafenib therapy for decreased obstructive symptoms and improved quality of life. CONCLUSION: This case serves as an example of the importance of surgical debulking in addition to molecular therapy for patients with severely extensive GISTs. Tumour debulking is important to decrease tumour burden, improve chemotherapeutic response and improve quality of life especially in persons refractory to pharmacological therapy.

A perineal cystic hamartoma causing constipation in an intact female Irish water spaniel.

A perineal fluid-filled structure was discovered in a 6-year-old intact female Irish water spaniel suffering from intermittent constipation. Diagnostic tests revealed the structure was immediately caudal to the vagina and compatible with a cyst. Surgical excision was required for resolution of clinical signs. Histology confirmed the structure was a cyst. The exact origin is unknown; however, the variety of lining epithelia, including sections with mucin production, and a well-differentiated smooth muscle layer, were most consistent with development from the lower hindgut or urogenital sinus during embryonic growth. The histologic and anatomical similarities with human retrorectal cystic hamartomas were key in establishing the diagnosis of a perineal cystic hamartoma. Following removal, constipation resolved, and the cyst did not recur.

Hamartome kystique périnéal causant de la constipation chez une femelle intacte de race épagneul d'eau irlandais. Une structure périnéale remplie de liquide fut découverte chez une chienne intacte de race épagneul d'eau irlandais âgée de 6 ans souffrant de constipation intermittente. Les tests diagnostiques ont révélé que la structure était immédiatement caudale au vagin et était compatible avec un kyste. L'excision chirurgicale était requise pour la résolution des signes cliniques. L'histologie confirma que la structure était un kyste. L'origine exacte est inconnue; toutefois, la diversité de l'épithélium de couverture, incluant des sections avec production de mucine, et une couche bien différenciée de muscle lisse, étaient plus cohérentes avec un développement à partir du tractus digestif postérieur ou du sinus urogénital lors de la croissance embryonnaire. Les similarités histologique et anatomique avec l'hamartome rétro-rectal humain étaient critiques pour établir le diagnostic d'hamartome kystique périnéal. À la suite du retrait, la constipation s'est résolue, et il n'y a pas eu de récurrence du kyste.(Traduit par Dr Serge Messier).

Gigantic GIST: A Case of the Largest Gastrointestinal Stromal Tumor Found to Date.

Gastrointestinal stromal tumors are uncommon when compared to all gastrointestinal neoplasms but are the most common mesenchymal tumors of the gastrointestinal tract. The largest gastrointestinal stromal tumor ever recorded in literature weighed approximately 6.1 kg and measured 39 cm × 27 cm × 14 cm. About two-thirds of GISTs are malignant. The tumor size, mitotic rate, cellularity, and nuclear pleomorphism are the most important parameters when considering prognosis and recurrence. The definitive treatment for these tumors is resection. In the year 2000, the first patient was treated with the tyrosine kinase inhibitor imatinib and since then, gastrointestinal stromal tumors with high-risk features have been treated successfully with tyrosine kinase inhibitors. We present the largest gastrointestinal stromal tumor recorded in medical literature measuring 42.0 cm × 31.0 cm × 23.0 cm in maximum dimensions and weighing in at approximately 18.5 kg in a 65-year-old African-American male who presented with increased abdominal distention. The mass was successfully excised, and the patient was treated with imatinib without local or distant recurrence 1.5 years postoperatively.

Predicting within-herd prevalence of infection with bovine leukemia virus using bulk-tank milk antibody levels.

Enzootic bovine leukosis (EBL) is an economically important infection of dairy cattle caused by bovine leukemia virus (BLV). Estimating the prevalence of BLV within dairy herds is a fundamental step towards pursuing efficient control programs. The objectives of this study were: (1) to determine the prevalence of BLV infection at the herd level using a bulk-tank milk (BTM) antibody ELISA in the Maritime region of Canada (3 provinces); and (2) to develop appropriate statistical models for predicting within-herd prevalence of BLV infection using BTM antibody ELISA titers. During 2013, three monthly BTM samples were collected from all dairy farms in the Maritime region of Canada (n=623) and tested for BLV milk antibodies using a commercial indirect ELISA. Based on the mean of the 3 BTM titers, 15 strata of herds (5 per province) were defined. From each stratum, 6 herds were randomly selected for a total of 90 farms. Within every selected herd, an additional BTM sample was taken (round 4), approximately 2 months after the third round. On the same day of BTM sampling, all cows that contributed milk to the fourth BTM sample were individually tested for BLV milk antibodies (n=6111) to estimate the true within-herd prevalence for the 90 herds. The association between true within-herd prevalence of BLV and means of various combinations of the BTM titers was assessed using linear regression models, adjusting for the stratified random sampling design. Herd level prevalence of BLV in the region was 90.8%. In the individual testing, 30.4% of cows were positive. True within-herd prevalences ranged from 0 to 94%. All linear regression models were able to predict the true within-herd prevalence of BLV reasonably well (R(2)>0.69). Predictions from the models were particularly accurate for low-to-medium spectrums of the BTM titers. In general, as a greater number of the four repeated BTM titers were incorporated in the models, narrower confidence intervals around the prediction lines were achieved. The model including all 4 BTM tests as the predictor had the best fit, although the models using 2 and 3 BTM tests provided similar results to 4 repeated tests. Therefore, testing two or three BTM samples with approximately two-month intervals would provide relatively precise estimates for the potential number of infected cows in a herd. The developed models in this study could be applied to control and eradication programs for BLV as cost-effective tools.