Cystine-glutamate transporter (xCT) is a plasma membrane transporter that imports cystine and indirectly contributes to the oxidative stress resistance associated with increased intracellular ...glutathione levels. Canine adipose-derived stem cells (CADSCs) include an xCT-positive subpopulation and show relatively low expression of osteogenic markers during in vitro osteogenic differentiation. Sulfasalazine (SSZ), a drug used to treat rheumatoid arthritis, suppresses xCT expression in cancer cells. In this study, we found that the SSZ treatment at 100 µM significantly suppressed xCT mRNA expression in CADSCs but did not significantly affect cell proliferation under the same conditions. Additionally, this treatment decreased the intracellular glutathione concentration. During in vitro osteogenic differentiation, the SSZ treatment at 50 µM and 100 µM significantly increased alizarin red staining and its quantification, as well as the concentration-dependent osteogenic differentiation markers (BMP1 and SPP) mRNA expression. Our results suggested that SSZ enhances the osteogenic differentiation potential of CADSCs and can potentially exhibit a superior therapeutic profile in canine bone regenerative medicine.
The pedigrees of 3 Dalmatian dogs afflicted with copper-associated hepatitis were investigated to discover the mode of inheritance. A composite family pedigree showed that the 3 affected Dalmatians ...were related. None of the parents of the affected dogs showed clinical symptoms of liver disease, and the disease had no sex predisposition. The estimated segregation ratio was approximately 3:1 based on surviving littermates. These findings suggested that the copper-associated hepatitis in these Dalmatians was an autosomal recessive mode of inheritance. In addition, some male Dalmatians imported from abroad might have been involved in the occurrence of this disease in Japan.
•The prognostic impact of irAEs remains unclear in mRCC patients treated with nivolumab plus ipilimumab.•Overall, 72% of patients experienced irAEs.•Patients who experienced irAEs, especially severe ...irAEs, exhibited a longer PFS.•A landmark analysis for initial four cycles of treatment demonstrated a longer PFS in patients with irAEs.•A subset of patients had durable responses after treatment discontinuation due to irAEs.
Evidence regarding the prognostic impact of immune-related adverse events (irAEs) remains limited in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab as a first-line systemic therapy. Thus, we investigated the association between irAE development and oncological outcomes during nivolumab plus ipilimumab therapy.
We retrospectively evaluated 46 patients with mRCC who were treated with nivolumab plus ipilimumab at our hospital and its affiliated institutions. The associations between irAE development and progression-free survival (PFS), overall survival (OS), and objective response rates (ORRs) were assessed after treatment initiation.
A total of 60 irAEs occurred in 33 patients (72%), with 24 grade ≥ 3 irAEs developed in 20 patients (43%). PFS was significantly longer in patients with irAEs than that in patients without irAEs (P < 0.0001); however, OS was not different (P = 0.571). Multivariable analysis further revealed that the development of irAEs was an independent predictor of a longer PFS (hazard ratio: 0.18, P = 0.0005). A landmark analysis for the initial four cycles of nivolumab plus ipilimumab administration also showed that PFS was significantly longer in patients with irAEs than that in patients without irAEs (P = 0.0386). The ORRs were also higher in patients with irAEs (P = 0.0064). Furthermore, in 22 patients (48%) who discontinued nivolumab plus ipilimumab treatment, the 6-month PFS rate was 87%.
This multi-institutional study showed that irAE development was significantly associated with PFS but not with OS in patients treated with nivolumab plus ipilimumab as a first-line therapy. The development of irAEs may be used as a surrogate prognostic marker for PFS in this treatment regimen.
The impact of the controlling nutritional status (CONUT) score on oncological outcomes after radical cystectomy (RC) for advanced bladder cancer (BC) is unknown.
We retrospectively evaluated 115 ...patients who underwent RC for advanced BC at our department between November 2003 and February 2019. The CONUT score was calculated from serum albumin levels, total lymphocyte counts, and total cholesterol levels. Relapse-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) after RC were analyzed.
For the CONUT score, the area under curve was 0.651 and the optimal cut-off value determined using the Youden index was 3. The high CONUT group had significantly shorter RFS, CSS, and OS than the low CONUT group. Multivariate analyses showed that the CONUT score was an independent prognostic factor of RFS, CSS, and OS.
The CONUT score could be an effective predictor for survival and tolerability following RC for advanced BC.
Abstract
Background
Prognostic impact of sex in patients with malignancies treated with immune checkpoint inhibitors has been intensively discussed but remains unclear, especially in advanced renal ...cell carcinoma.
Methods
We retrospectively evaluated a total of 184 patients with advanced renal cell carcinoma treated with either nivolumab plus ipilimumab combined treatment as first-line therapy (n = 73) or nivolumab as later-line therapy (n = 111) at our affiliated institutions. Progression-free survival, overall survival and objective response rate as well as adverse event profile were compared between sexes.
Results
Of the total 184 patients, 48 (26%) were female. Female patients had a significantly shorter progression-free survival than male patients (median: 3.8 vs. 8.3 months, P = 0.0005), but overall survival (median: 39.2 vs. 45.1 months, P = 0.283) and objective response rate (29% vs. 42%, P = 0.119) were not different between them. Similar findings were observed when analyzing within each treatment; in both patient groups treated with nivolumab plus ipilimumab combined therapy and nivolumab monotherapy, progression-free survival was significantly shorter in female than in male patients (P = 0.007, P = 0.017), but overall survival (P = 0.914, P = 0.117) and objective response rate (P = 0.109, P = 0.465) were comparable between them. Moreover, in a more restricted cohort consisting of patients with clear-cell renal cell carcinoma, a shorter progression-free survival in female patients was also observed (3.8 vs. 11.0 months, P < 0.0001).
Conclusions
This retrospective study showed that immune checkpoint inhibitors-based treatment for renal cell carcinoma exhibited less marked effects in female than in male patients. Thus, sex may be an important factor for decision-making on systemic therapy as renal cell carcinoma treatment, although further studies are required to validate the present findings.
This multicenter retrospective study showed that immune checkpoint inhibitors-based treatment exhibited milder effects in female than in male patients with advanced renal cell carcinoma.
Intraoperative acridine orange-photodynamic therapy (AO-PDT) and cribriform plate irradiation are used to treat canine intranasal tumors. The purpose of this study was to evaluate the effects of ...AO-PDT on intranasal tumors and the recurrence rate of tumors after this treatment. Treatments with AO-PDT were performed on 38 dogs through a narrow window of the dorsal nasal cavity. The median progression-free interval was 12 mo and recurrence was detected in 21 dogs. Based on computed tomography, recurrence in 16 dogs was biased to the following areas: lateral (
= 10), medial (
= 2), ventral (
= 0), rostral (
= 0), and caudal (
= 8). Side effects were mild and included subcutaneous emphysema and rhinitis. The median survival time was 24 mo. Although AO-PDT with cribriform irradiation is an effective treatment for intranasal tumors, AO-PDT techniques should be improved to treat the nasal cavity more uniformly and thoroughly.
Background
There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) ...for advanced renal cell carcinoma (RCC), especially in real-world settings.
Methods
We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups.
Results
Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months;
p
= 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months;
p
= 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%;
p
= 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%;
p
< 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%;
p
= 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%;
p
= 0.001).
Conclusion
IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.
Fractures occurring in the distal radius and ulna of toy breed dogs pose distinctive challenges for veterinary practitioners, requiring specialized treatment approaches primarily based on anatomical ...features. Finite Element Analysis (FEA) was applied to conduct numerical experiments to determine stress distribution across the bone. This methodology offers an alternative substitute for directly investigating these phenomena in living dog experiments, which could present ethical obstacles. A three-dimensional bone model of the metacarpal, carpal, radius, ulna, and humerus was reconstructed from Computed Tomography (CT) images of the toy poodle and dachshund forelimb. The model was designed to simulate the jumping and landing conditions from a vertical distance of 40 cm to the ground within a limited timeframe. The investigation revealed considerable variations in stress distribution patterns between the radius and ulna of toy poodles and dachshunds, indicating notably elevated stress levels in toy poodles compared to dachshunds. In static and dynamic stress analysis, toy poodles exhibit peak stress levels at the distal radius and ulna. The Von Mises stresses for toy poodles reach 90.07 MPa (static) and 1,090.75 MPa (dynamic) at the radius and 1,677.97 MPa (static) and 1,047.98 MPa (dynamic) at the ulna. Conversely, dachshunds demonstrate lower stress levels for 5.39 MPa (static) and 231.79 MPa (dynamic) at the radius and 390.56 MPa (static) and 513.28 MPa (dynamic) at the ulna. The findings offer valuable insights for modified treatment approaches in managing fractures in toy breed dogs, optimizing care and outcomes.
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