A type I interferon regulatory network for human plasmacytoid dendritic cells based on heparin, membrane-bound and soluble BDCA-2.

Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) after sensing viral/bacterial RNA or DNA by toll-like receptor (TLR) 7 or TLR9, respectively. However, aberrant pDCs activation can cause adverse effects on the host and contributes to the pathogenesis of type I IFN-related autoimmune diseases. Here, we show that heparin interacts with the human pDCs-specific blood dendritic cell antigen 2 (BDCA-2) but not with related lectins such as DCIR or dectin-2. Importantly, BDCA-2-heparin interaction depends on heparin sulfation and receptor glycosylation and results in inhibition of TLR9-driven type I IFN production in primary human pDCs and the pDC-like cell line CAL-1. This inhibition is mediated by unfractionated and low-molecular-weight heparin, as well as endogenous heparin from plasma, suggesting that the local blood environment controls the production of IFN-α in pDCs. Additionally, we identified an activation-dependent soluble form of BDCA-2 (solBDCA-2) in human plasma that functions as heparin antagonist and thereby increases TLR9-driven IFN-α production in pDCs. Of importance, solBDCA-2 levels in the serum were increased in patients with scrub typhus (an acute infectious disease caused by Orientia tsutsugamushi) compared to healthy control subjects and correlated with anti-dsDNA antibodies titers. In contrast, solBDCA-2 levels in plasma from patients with bullous pemphigoid or psoriasis were reduced. In summary, this work identifies a regulatory network consisting of heparin, membrane-bound and solBDCA-2 modulating TLR9-driven IFN-α production in pDCs. This insight into pDCs function and regulation may have implications for the treatment of pDCs-related autoimmune diseases.

ctDNA improves prognostic prediction for patients with relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone.

ABSTRACT: It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.

Period prevalence of uveitis in human T-lymphotropic virus 1 carriers versus noncarriers in a highly endemic area: The Nagasaki Islands Study.

The magnitude of the effect of human T-lymphotropic virus 1 (HTLV-1) infection on uveitis remains unclear. We conducted a cross-sectional study in a highly endemic area of HTLV-1 in Japan. The study included 4265 residents (men, 39.2%), mostly middle-aged and older individuals with a mean age of 69.9 years, who participated in our surveys between April 2016 and September 2022. We identified HTLV-1 carriers by screening using chemiluminescent enzyme immunoassays and confirmatory tests, and the proportion of carriers was 16.1%. Participants with uveitis were determined from the medical records of all hospitals and clinics where certified ophthalmologists practiced. We conducted logistic regression analyses in an age- and sex-adjusted model to compute the odds ratio (OR) and 95% confidence interval (CI) of uveitis according to HTLV-1 infection status. Thirty-two (0.8%) participants had uveitis. For HTLV-1 carriers, the age- and sex-adjusted OR (95% CI) of uveitis was 3.27 (1.57-6.72) compared with noncarriers. In conclusion, HTLV-1 infection was associated with a higher risk of uveitis among mostly middle-aged and older Japanese residents in a highly endemic HTLV-1 area. Our findings suggest that physicians who treat HTLV-1 carriers should assess ocular symptoms, and those who diagnose patients with uveitis should consider HTLV-1 infection.

Small medial proximal tibial angle is a radiographic finding strongly associated with less coronal alignment correction under valgus stress in medial knee osteoarthritis.

PURPOSE: The degree to which varus knees can be corrected manually is important when considering total versus unicompartmental knee arthroplasty (UKA). The primary aim was to clarify the relationship between the degree of coronal alignment correction and radiographic parameters involved in UKA prognosis using preoperative full-length lower extremity valgus stress radiography. The secondary aim was to identify the factors affecting alignment correction. METHODS: This retrospective observational study included 115 knees with medial osteoarthritis that underwent knee osteotomy or arthroplasty. Percent mechanical axis without valgus stress (%MA: neutral, 50%; varus, <50% and valgus, >50%), mechanical lateral distal femoral angle, lateral bowing femoral angle, medial proximal tibial angle (MPTA), joint line convergence angle, medial and lateral joint space width (LJSW) and medial femoral and tibial joint osteophyte size were measured using preoperative full-length weight-bearing radiographs. Correlation and multiple linear regression analyses were used to assess associations between parameters and %MA with valgus stress or amount of %MA change (%MA with valgus stress minus %MA without valgus stress). RESULTS: %MA with valgus stress was correlated with all radiographic parameters. %MA change was correlated with parameters except for MPTA and LJSW. Multiple regression analyses showed that %MA without valgus stress and MPTA were associated with both %MA with valgus stress and %MA change. When %MA with valgus stress was set at 30%, 40% and 50%, MPTA cutoff values were 81.6°, 83.5° and 84.9°, and cutoffs for %MA without valgus stress were 10.7%, 17.1% and 25.1%, respectively. CONCLUSION: Small MPTA is strongly associated with less alignment correction under valgus stress in varus knees. The finding is useful in surgical planning, especially to avoid undercorrection with UKA when valgus stress radiographs are unavailable. LEVEL OF EVIDENCE: Level III.

Preoperative radiographs underdiagnose the severity of lateral femoral and medial trochlear cartilage damage in varus osteoarthritis knees.

OBJECTIVE: This study evaluated whether preoperative radiographs accurately predicted intra-articular cartilage damage in varus knees. METHODS: The study assessed 181 knees in 156 patients who underwent total knee arthroplasty. Cartilage damage was graded by two examiners with the International Cartilage Repair Society classification; one used knee radiographs and the other used intraoperative photographs. It was then determined if this radiographic cartilage assessment over- or underestimated the actual damage severity. Knee morphological characteristics affecting radiographic misestimation of damage severity were also identified. RESULTS: The concordance rate between radiographic and intraoperative assessments of the medial femoral condyle was high, at around 0.7. Large discrepancies were found for the lateral femoral condyle and medial trochlear groove. Radiographic assessment underestimated cartilage damage on the medial side of the lateral femoral condyle due to a large lateral tibiofemoral joint opening and severe varus alignment {both r = -0.43}. Medial trochlear damage was also underdiagnosed, in cases of residual medial tibiofemoral cartilage and shallow medial tibial slope {r = -0.25 and -0.21, respectively}. CONCLUSIONS: Radiographic evaluation of knee osteoarthritis was moderately practical using International Cartilage Repair Society grades. Lateral femoral condyle and medial trochlear cartilage damage tended to be misestimated, but considering morphologic factors might improve the diagnostic rate.

[Acute myeloid leukemia with type I CBFB::MYH11 fusion gene not detected by screening test for leukemia-related chimeric genes].

A 27-year-old woman with pancytopenia was admitted to our hospital. Bone marrow aspiration revealed 52.2% myeloperoxidase-positive myeloblasts, leading to a diagnosis of acute myeloid leukemia. While a screening test for chimeric genes related to leukemia initially yielded negative results, including for the CBFB::MYH11 fusion gene, G-banded karyotyping uncovered the presence of inv (16)(p13.1q22). Further investigation by fluorescence in situ hybridization (FISH) confirmed the split signals for CBFB. A second screening test for leukemia-related chimeric genes with different PCR primers revealed the elusive CBFB::MYH11 fusion gene. Subsequently, the type I CBFB::MYH11 fusion gene was identified through exhaustive exploration using RNA sequencing for fusion gene discovery. This exceptional case highlights the existence of a distinctive subtype of CBFB::MYH11 that may yield false-negative results in conventional chimeric fusion screening, thus emphasizing the indispensable utility of PCR primer modification, FISH, and RNA sequencing in the investigative process.

Residual Deformity of the Trochlea After Non-displaced Supracondylar Fracture in a Child: A Case Report.

Residual deformity of the trochlea after fractures of the distal end of the humerus in children is well known and is referred to as fishtail deformity. Despite numerous reports on this entity, the reason for various types of fractures with the same results remains unknown. Fishtail deformities after non-displaced supracondylar fractures are very rare. A 7-year-old boy with a non-displaced supracondylar fracture was treated conservatively. Three years later, the patient returned to our hospital complaining of mild elbow pain. Radiography revealed a fishtail deformity of the trochlea due to the premature fusion of the epiphysis. At the latest follow-up at the age of 17 years, only a marginal limitation at the excursion of the elbow was observed, and no additional treatment was needed. Fishtail deformities can occur even after a non-displaced supracondylar fracture. Long-term follow-ups are required in children with distal humeral fractures.

A Comparison of the Effects of Alcohol Abstinence and Drinking Habit on the Survival of Patients with Alcohol-related Cirrhosis: A Retrospective Observational Study.

Objective Abstaining from alcohol improves the outcome of alcohol-related cirrhosis. This study evaluated the effect of alcohol abstinence on the outcomes of patients with alcohol-related cirrhosis recruited from a core hospital in Boso Peninsula, Japan. Methods This single-center retrospective study recruited 116 patients with alcohol-related cirrhosis who were admitted to our department between April 2014 and October 2022. Taking the day of discharge as day 0, the patients were divided into two groups based on their subsequent behavior (abstinence/non-abstinence from alcohol). The study analysis included 98 patients after excluding 13 who died during hospitalization and 5 for whom follow-up at our hospital ended after discharge. We evaluated differences in the patient survival between the abstaining and drinking groups. Results The abstaining and drinking groups comprised 57 and 41 patients, respectively. We excluded from the analysis 10 and 6 patients with viable hepatocellular carcinoma in the abstaining and drinking groups, respectively. The findings revealed that the survival rate plateaued in the abstaining group from the third year onward, whereas the survival rate in the drinking group gradually decreased with time. Conclusion Our findings suggest that at least two years of alcohol abstinence is required to sustain the survival of patients with alcohol-related cirrhosis. The data collected by our hospital retrospectively demonstrated the importance of abstinence on a timescale of years of sustained abstinence.

Seven draft genome sequences of Streptococcus canis strains, revealing reduced penicillin-G susceptibility.

We report seven draft genome sequences of Streptococcus canis strains revealing reduced penicillin-G susceptibility. The genomes measured 2.054-2.385 Mbp, with G+C contents of 38.8%-39.6%. Amino acid substitutions in penicillin-binding proteins were characterized as compared with those of NCTC 12191(T) genome sequence (GenBank accession number NZ_LR134293.1).

Finite element analysis of mechanical stress in a cementless tapered-wedge short stem in the varus position.

BACKGROUND: In recent years, the use of tapered-wedge short stems has increased due to their ability to preserve bones and tendons. Surgical techniques occasionally result in a varus position of the stem, which is particularly pronounced in short stems. Although the varus position is not clinically problematic, there are reports of an increased incidence of stress shielding and cortical hypertrophy. Thus, we evaluated and examined the acceptable range of varus angles using finite element analysis. METHODS: Patients diagnosed with osteoarthritis of the hip joint who had undergone arthroplasty were selected and classified into three types [champagne-flute (type A), intermediate (type B), and stovepipe (type C)]. Finite element analysis was performed using Mechanical Finder. The model was created using a Taperloc microplasty stem with the varus angle increased by 1° from 0° to 5° from the bone axis and classified into seven zones based on Gruen's zone classification under loading conditions in a one-leg standing position. The volume of interest was set, the mean equivalent stress for each zone was calculated. RESULTS: A significant decrease in stress was observed in zone 2, and increased stress was observed in zones 3 and 4, suggesting the emergence of a distal periosteal reaction, similar to the results of previous studies. In zone 2, there was a significant decrease in stress in all groups at a varus angle ≥ 3°. In zone 3, stress increased from ≥ 3° in type B and ≥ 4° in type C. In zone 4, there was a significant increase in stress at varus angles of ≥ 2° in types A and B and at ≥ 3° in type C. CONCLUSION: In zone 2, the varus angle at which stress shielding above Engh classification grade 3 may appear is expected to be ≥ 3°. Distal cortical hypertrophy may appear in zones 3 and 4; the narrower the medullary cavity shape, the smaller the allowable angle of internal recession, and the wider the medullary cavity shape, the wider the allowable range. Long-term follow-up is required in patients with varus angles > 3°.

Draft genome sequence of emm103/ST1363 Streptococcus pyogenes strain AB1, isolated from the blood of a woman with peritonitis and toxic shock syndrome.

We report the draft genome sequence of Streptococcus pyogenes strain AB1 isolated from the blood of a woman with peritonitis-toxic shock syndrome. The genome measured 1.855 Mbp, with a G + C content of 38.3%. Sequences unmapped to the reference genome sequence of M1 SF370 (GenBank accession number AE004092.2) were characterized.

Initial real-world experience of clazosentan for subarachnoid hemorrhage in Japan.

BACKGROUND: Cerebral vasospasm (CVS) is one of the most critical factors associated with clinical outcomes of patients with subarachnoid hemorrhage (SAH). Clazosentan has been investigated worldwide as a prophylactic agent to prevent CVS. We evaluated a new CVS management protocol which included clazosentan. METHODS: Consecutive 138 patients with SAH, hospitalized in our institution between January 2017 and December 2022, were included in this study. Baseline characteristics, clinical findings, and operative records were analyzed retrospectively. From May 2022, 10 mg/h clazosentan was co-administered with fasudil to all patients according to the indication in the Japanese label. Patients admitted before this date received the conventional combined protocol using the fasudil hydrochloride, nicardipine, and ozagrel. RESULTS: Eighteen (13.0%) patients received the new protocol during the CVS period (defined as day 1 up to day 14 after SAH onset). There were 54 (39.1%) elderly patients aged 75 years or older. Seventy-two (52.2%) patients underwent neurosurgical clipping, whereas 55 (39.9%) patients received endovascular coiling. Among the patients with new protocol, only one patient (5.6%) had symptomatic CVS, compared with 18 patients (15.0%) in those with conventional protocol. More patients who received the new protocol had fluid retention compared with control group (38.9% [7/18] vs. 8.3% [10/120]). Other results did not differ between the two groups. CONCLUSIONS: Clinical outcomes of the new protocol were comparable to those of conventional protocol. Clazosentan may simplify anti-vasospasm treatment. Fluid retention was a specific side-effect of clazosentan, which requires attention especially in the first half of the CVS period.

Genetic organization of an M protein trans-acting positive regulator (Mga) orthologue and its adjacent M-like protein (SCM) alleles in Streptococcus canis.

OBJECTIVE: The purpose of this study was to identify the M protein trans-acting positive regulator (Mga) orthologue and its adjacent M-like protein (SCM) alleles in Streptococcus canis. RESULTS: Using the 39 SCM allele isolates and polymerase chain reaction-based amplification and sequencing, we obtained the deduced Mga amino acid (AA) sequences. The 22 Mga sequences in whole-genome sequences were obtained by searching the National Collection of Type Cultures 12,191(T) Mga sequence into the database. The percentage identity to the type-strain Mga sequence was examined along with its size. The presence of the Mga-specific motifs was confirmed. Of the 62 strains, we identified 59 Mga sequences with an AA size of 509 (except for four different sizes). Percentage identity ranged from 96.66 to 100% with the confirmed Mga-specific motifs and diverse SCM allele populations. Our findings support the presence of an Mga orthologue and diverse SCM allele populations.

Association between atherosclerosis and height loss among older individuals.

Atherosclerosis and height loss are each reportedly associated with cardiovascular disease. However, no studies have found an association between atherosclerosis and height loss. A retrospective study of 2435 individuals aged 60-89 years who underwent annual health check-ups was conducted. Atherosclerosis was defined as carotid intima-media thickness (CIMT) ≥ 1.1 mm. Height loss was defined as being in the highest quintile of height decrease per year, as in our previous studies. Among study participants, 555 were diagnosed as having atherosclerosis. Independent of known cardiovascular risk factors, atherosclerosis was positively associated with height loss. The adjusted odds ratio (OR) was 1.46 (95% confidence interval, 1.15, 1.83). Essentially the same associations were observed for men and women. The adjusted OR (95% CI) was 1.43 (1.01, 2.04) for men and 1.46 (1.07, 1.99) for women. Among older individuals, atherosclerosis is associated with height loss. This result can help clarify the mechanism underlying the association between height loss and cardiovascular disease.

Antimicrobial resistance patterns of Streptococcus uberis isolates from bovine milk in Chiba prefecture, Japan: association between multidrug resistance and clonal complex 996.

Streptococcus uberis is one of major pathogens causing bovine mastitis. However, there is poor information on antimicrobial resistance (AMR) among the Japanese isolates. To provide treatment information for the mastitis caused by S. uberis in Japan, we aimed to clarify AMR patterns of the isolates from bovine milk mainly in Chiba. AMR phenotyping/genotyping [blaZ-erm(A)-erm(B)-mef(A)-linB-lnuD-tet(M)-tet(O)-tet(K)-tet(L)-tet(S)] and multilocus sequence typing were performed to analyze relationships between AMR patterns and clonal complexes (CCs). Resistance to tetracycline-, macrolide-, and lincosamide-classes was mainly associated with possession of tet(O), tet(S), erm(B), linB, and lnuD genes. CC996 was significantly associated with multidrug resistance (P<0.0001). These findings will aid Chiba farm animal clinics in treating bovine mastitis.

Association between eating speed and atherosclerosis in relation to growth differentiation factor-15 levels in older individuals in a cross-sectional study.

Although fast eating speed has been associated with cardiovascular risk factors, no studies have reported an association between fast eating speed and atherosclerosis as evaluated by carotid intima-media thickness (CIMT). Rapid glucose ingestion is known to cause glucose spikes, which may accelerate atherogenesis and increase levels of growth differentiation factor 15 (GDF-15). Therefore, GDF-15 levels may influence the association between fast eating speed and atherosclerosis. To evaluate the association between eating speed and atherosclerosis in relation to GDF-15, this cross-sectional study analyzed 742 Japanese aged 60-69 years. They were required to have normal thyroid hormone levels, because both GDF-15 levels and atherosclerosis (CIMT ≥ 1.1 mm) can be influenced by thyroid dysfunction. Participants were stratified by the median GDF-15 level. A significant positive association was observed between fast eating speed and atherosclerosis, but only among participants with a high GDF-15 level: the sex- and age-adjusted odds ratios (95% confidence intervals) were 1.95 (1.09, 3.48) in participants with a high GDF-15 level, and 0.83 (0.37, 1.88) in those with a low GDF-15 level. This association remained even after further adjustment for thyroid function and metabolic factors. Serum concentrations of GDF-15 may mediate the association between fast eating speed and atherosclerosis.

Platypnoea-orthodeoxia syndrome in COVID-19 pneumonia patients: An observational study.

This retrospective observational study aimed to assess the clinical characteristics of platypnea-orthodeoxia syndrome in patients with coronavirus disease 2019 (COVID-19) treated using mechanical ventilation or high-flow nasal canula. We analyzed 42 consecutive patients with COVID-19 from January 2020 to March 2022. The primary outcomes were the incidence of platypnea-orthodeoxia syndrome, the time with required long-term oxygen therapy, and short-term prognosis. Additionally, we examined the relationships between platypnea-orthodeoxia syndrome and COVID-19 severity, the time with long-term oxygen therapy, and short-term prognosis. Of the 42 included patients, 15 (35.7 %) had platypnea-orthodeoxia syndrome. Although mortality was not significantly different between both groups, the oxygen withdrawal rate in the platypnea-orthodeoxia syndrome group was significantly lower than that in the group without this syndrome. Clinical staff should be aware of the possibility of platypnea-orthodeoxia syndrome during positional changes in patients with COVID-19. Recognizing POS can improve early detection, countermeasures, and safety during physiotherapy.

Successful treatment of streptococcal toxic shock syndrome complicated by primary peritonitis and bilateral empyema in a healthy young woman: Identification of uncommon clone emm103 and novel sequence type 1363.

Streptococcal toxic shock syndrome (STSS) has a dramatic clinical course and high mortality rate. Here, we report a case of STSS complicated by primary peritonitis and bilateral empyema. A previously healthy young woman was diagnosed with STSS complicated by primary peritonitis and bilateral empyema. Blood culture results on admission were negative. Sever shock, respiratory failure, systemic inflammation, thrombocytopenia, renal failure, ascites, and pleural effusion occurred, mimicking thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure and organomegaly (TAFRO) syndrome. Retesting blood cultures identified Streptococcus pyogenes. Gram staining of ascites and pleural fluid indicated gram-positive cocci in chains. Antibiotics, immunoglobulins, and surgical intervention led to recovery without complications. Ex-post genotypic analyses showed uncommon emm103.0 (cluster E3) of emm long sequence (784 base) and novel sequence type 1363. STSS diagnosis can be difficult as it mimics other systemic inflammatory diseases. Therefore, it is crucial for clinicians to perform microbiological examinations from infection foci, even if the initial culture is negative.

The RNA helicases DDX19A/B modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export in leukemia cells.

Selinexor, a first-in-class exportin1 (XPO1) inhibitor, is an attractive anti-tumor agent because of its unique mechanisms of action; however, its dose-dependent toxicity and lack of biomarkers preclude its wide use in clinical applications. To identify key molecules/pathways regulating selinexor sensitivity, we performed genome-wide CRISPR/Cas9 dropout screens using two B-ALL lines. We identified, for the first time, that paralogous DDX19A and DDX19B RNA helicases modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export. While single depletion of either DDX19A or DDX19B barely altered MCL1 protein levels, depletion of both significantly attenuated MCL1 mRNA nuclear export, reducing MCL1 protein levels. Importantly, combining selinexor treatment with depletion of either DDX19A or DDX19B markedly induced intrinsic apoptosis of leukemia cells, an effect rescued by MCL1 overexpression. Analysis of Depmap datasets indicated that a subset of T-ALL lines expresses minimal DDX19B mRNA levels. Moreover, we found that either selinexor treatment or DDX19A depletion effectively induced apoptosis of T-ALL lines expressing low DDX19B levels. We conclude that XPO1 and DDX19A/B coordinately regulate cellular MCL1 levels and propose that DDX19A/B could serve as biomarkers for selinexor treatment. Moreover, pharmacological targeting of DDX19 paralogs may represent a potential strategy to induce intrinsic apoptosis in leukemia cells.

Impact of Genomic Alterations on Efficacy of Trastuzumab Deruxtecan Against Human Epidermal Growth Factor Receptor-2-Positive Advanced Gastric Cancer.

PURPOSE: The impact of genomic alterations on response and resistance to trastuzumab deruxtecan (T-DXd) has not been elucidated. Thus, we sought to identify factors predicting sensitivity to T-DXd in gastric or gastroesophageal junction (G/GEJ) cancer. METHODS: We conducted a retrospective study using real-world clinical data and next-generation sequencing-based comprehensive genomic profiling (CGP) data from patients with advanced G/GEJ cancers, collected by the nationwide database in Japan. We analyzed the associations between genomic alterations and the patients' survivals after T-DXd treatment. RESULTS: In 114 patients with human epidermal growth factor receptor-2 (HER2)-positive G/GEJ cancer treated with T-DXd, the most frequently altered genes were TP53 (82%), ERBB2 (80%), and CCNE1 (36%). Multivariate Cox regression analysis revealed CCNE1 amplification to be a significant predictor of shorter progression-free survival (PFS) after T-DXd treatment among 91 patients whose CGP samples were obtained before T-DXd (median PFS, 131 days v 189 days; hazard ratio [HR], 1.90 [95% CI, 1.02 to 3.53]; P = .044). Analyses of 1,450 G/GEJ cancers revealed significant CCNE1/ERBB2 coamplification (41% relative to 11% CCNE1 amplification in ERBB2-nonamplified tumors; P < .0001). ERBB2-activating mutations were also detected in 3.7% of G/GEJ cancers and in 8.8% of HER2-positive G/GEJ cancers treated with T-DXd. Patients with ERBB2-mutated tumors showed shorter PFS than those without ERBB2 mutations after T-DXd treatment (mPFS, 105 v 180 days; P = .046). CONCLUSION: CCNE1 amplification may confer primary resistance to T-DXd in HER2-positive G/GEJ cancer, suggesting that the cell cycle could be a potential therapeutic target in CCNE1/ERBB2 coamplified tumors. ERBB2-activating mutation may also attenuate T-DXd efficacy in HER2-positive G/GEJ cancer.