Abstract
Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated ...HER2-positive tumors. A recent study demonstrated that T-DXd not only suppressed tumor growth but also enhanced anti-tumor immunity through increasing the number of tumor-infiltrating CD8
+
T cells and enhancement of major-histocompatibility-complex class I expression on tumor cells in a mouse model. However, the effect of T-DXd on anti-tumor immune responses in human cancers is largely unknown. We investigated the effect of T-DXd on the expression of HLA class I and CXCL9/10/11, T-cell chemoattractants, in HER2-positive human gastric cancer (GC) cells. We found that T-DXd significantly inhibited GC cell proliferation in a HER2-dependent manner, while it slightly increased the expression of HLA class I in HER2-positive GC cells. Moreover, we revealed that T-DXd significantly induced mRNA expression of
CXCL9/10/11
in HER2-positive GC cells. T-DXd-triggered up-regulation of these chemokines was mediated through the activation of DNA damage signaling pathways. These results suggest that T-DXd triggers anti-tumor immune responses at least in part through induction of the expression of HLA class I and
CXCL9/10/11
on HER2-positive GC cells, resulting in the enhancement of anti-tumor immunity in human GC.
The tumor microenvironment (TME) plays a key role in the efficacy of neoadjuvant chemotherapy (NAC) in solid tumors including esophageal squamous cell carcinoma (ESCC). However, the TME profile of ...ESCC treated with NAC is not fully understood. In this study, we investigated the effect of NAC on the TME especially tumor-associated macrophages (TAM), the important immunosuppressive components of the TME, in ESCC. We quantified the expression of CD163, a crucial marker of TAM, in pretherapeutic biopsy and surgically resected ESCC specimens from patients who received NAC (
= 33) or did not receive NAC (
= 12). We found that NAC dramatically increased the expression of CD163 on TAMs in ESCC. Colony-stimulating factor 1 (CSF-1) and IL34 are crucial cytokines that recruit monocytes into tumor sites and differentiate them into TAMs. Interestingly, NAC significantly upregulated the expression of IL34 but not CSF-1 on tumor cells, and the frequencies of CD163
TAMs were significantly correlated with IL34 expression in ESCC after NAC. The expression of IL34 in NAC-nonresponsive patients was significantly higher than that in NAC-responsive patients, and patients with IL34-high ESCC exhibited worse prognosis as compared with patients with IL34-low ESCC. We also demonstrated that 5-fluorouracil (5-FU)/cisplatin preferentially increased mRNA expression of IL34 on human ESCC cell lines. Human peripheral blood monocytes co-cultured with ESCC cells treated with 5-FU/cisplatin increased the expression of CD163, which was attenuated by the treatment with CSF-1R inhibitors. These data suggest that IL34 expression by NAC shifts the TME toward CD163
TAM-rich immunosuppressive and chemo-insensitive microenvironment in ESCC. IMPLICATIONS: The blockade of IL34 signaling may offer a novel therapeutic strategy against chemoresistance in ESCC by inhibiting M2-TAM polarization.
Display omitted
•Surface rupture along the HFT in Nepal occurred after about 1050–1200 CE.•The size of the paleoearthquake approached or surpassed Mw 9.•Sufficient strain is now accumulated to ...produce similarly great earthquake.•Surface rupture during 1934 Mw 8.4 Bihar-Nepal earthquake did not occur at Khayarmara.
An exposure created by excavation of a trench across the Himalayan Frontal Thrust provides the basis to interpret that a single earthquake produced vertical separation of ∼7 m at Khayarmara, a small community ∼80 km southwest of Kathmandu. The fault trace at Khayarmara is expresssed by a topographic ridge resulting from folding up-dip and toward the surface at the expense of greater fault slip taking place at depth. Structure, stratigraphy, and radiocarbon data are interpreted to indicate displacement occurred after about 1050 CE to 1200 CE. The timing and displacement at Khayarmara are compared to that reported previously at six contiguous sites that extend from 200 km to the west and 250 km to the east of Khayarmara, respectively. The comparison leads us to conclude that the surface rupture at Khayarmara was part of a ≥250 km long synchronous surface rupture earthquake of magnitude approaching if not surpassing Mw 9. We observe in the exposure no record of surface rupture associated with the great 1934 Bihar-Nepal earthquake.
Synovial sarcoma is a mesenchymal tumour with partial epithelial differentiation. About 85-90% of SS occur in the extremities. We present a case of a 44-year-old woman diagnosed with recurrent ...synovial sarcoma with breast and pulmonary nodules. The primary treatment for synovial sarcoma is wide surgical excision, while chemotherapy is reserved for metastatic cases. In the first-line metastatic setting, combination treatment with adriamycin and ifosfamide is administered. Despite the unfavourable prognosis, the patient's extended survival is fortunately not the typical outcome.
case reports; chemotherapy; immunohistochemistry; synovial sarcoma.
Introduction: Microalbuminuria is an abnormal increase in albumin excretion rate with a specific range of 30-299 mg of albumin/g of creatinine or excretion of 20-200 mg/l of albumin in spot urine ...samples. Diabetic patients with microalbuminuria are at increased risk for cardiovascular death as compared with normoalbuminuria. The aim of this study was to find out the prevalence of microalbuminuria among patients visiting the Department of Nephrology in a tertiary care centre.
Methods: This is a descriptive cross-sectional study conducted among diabetic patients visiting the Department of Nephrology in a tertiary care centre after obtaining ethical approval from the Institutional Review Committee (Reference number: 04072022/04). The study was conducted between 1 October 2022 to 30 November 2022 where patients providing written consent and had documented diabetes were included in the study whereas patients without documented diabetes, having comorbidities such as congestive heart failure, nephritic/nephrotic syndrome and those who refused to give consent were excluded from the study. Convenience sampling was done. Point estimate and 95% Confidence Interval were calculated.
Results: Among 103 patients, microalbuminuria was found to be in 19 (18.45%) (10.96-25.94, 95% Confidence Interval). Out of 19 patients, 8 (42.11%) were male and 11 (57.89%) were female. The mean HbA1c among participants with microalbuminuria was 7.67±0.67%.
Conclusions: The prevalence of microalbuminuria among diabetic patients was similar to other studies done in similar settings.
With advances in therapeutics and longer survival across different cancer spectrums, the incidence of therapy-related acute myeloid leukemia (tAML) has continued to rise. This study aims to evaluate ...the trend of survival outcomes and their association with sociodemographic factors in tAML over the last 20 years.
We identified tAML patients between 2000 and 2020 from the Surveillance, Epidemiology, and End Results database. Patients were divided into 4 age groups: 18-39, 40-59, 60-69, and >= 70 years, and 4 diagnostic periods: 2000-2005, 2006-2010, 2011-2015, and 2016-2020. Overall survival (OS) was compared using Kaplan Meier and log-rank methods.
The 1-year (and 5-year) OS in patients with tAML was 59.3% (33.7%), 48.2% (24.8%), 37.2% (11.1%), and 32.9% (5.5%) in age groups 18-39, 40-59, 60-69, and >=70 years, respectively. The 1-year (and 5-year) OS based on the year of diagnosis was 20.9% (13.2%), 36.8% (15.2%), 41.9% (13.88%), and 40.4% (not reached) for 2000-2005, 2006-2010, 2011-2015, and 2016-2020 respectively. Among the youngest cohort aged 18-39 years, 1-year OS was 35.7%, 57.7%, 66.7%, and 59.6%, respectively, in 4 diagnostic periods, whereas 1-year OS was 10.5%, 23.9%, 32.2%, and 36.9%, respectively, in the oldest cohort aged >=70 years. Age, year of diagnosis, and geographic location were independent prognostic markers of OS.
Our study demonstrates a significant improvement in the 1-year OS of tAML patients over the last decade, but the long-term prognosis remains dismal. Older patients continue to show improved survival in recent years with the addition of newer intensive and nonintensive options.
We utilized the SEER database to evaluate the trend of survival outcomes and association with sociodemographic factors in therapy-related AML (tAML) over the last 20 years. The incidence of tAML has continued to rise between 2000-2020, directly related to newer advancements in cancer therapeutics. Despite a significant improvement in 1-year survival over the last decade, long-term prognosis remains dismal.
PDF
