Impact of COVID-19 Outbreak on Influenza and Pneumococcal Vaccination Uptake: A Multi-Center Retrospective Study.

During the coronavirus disease 2019 (COVID-19) pandemic, global vaccination efforts declined due to the burden on health systems and community resistance to epidemic control measures. Influenza and pneumococcal vaccines have been recommended for vulnerable populations to prevent severe pneumonia. We investigated community response towards influenza and pneumococcal vaccines (pneumococcal conjugate vaccine and pneumococcal polysaccharide vaccine) after the COVID-19 outbreak in Taiwan. We retrospectively included adults who visited Chang Gung Memorial Hospital (CGMH) institutions for influenza or pneumococcal vaccination from January 2018 to December 2021. The first case of COVID-19 in Taiwan was detected in January 2020; therefore, in this study, hospitalized cases from January 2018 to December 2019 were defined as "before COVID-19 outbreak," and hospitalized cases from January 2020 to December 2021 were defined as "after COVID-19 outbreak". A total of 105,386 adults were enrolled in the study. An increase in influenza vaccination (n = 33,139 vs. n = 62,634) and pneumococcal vaccination (n = 3035 vs. n = 4260) were observed after the COVID-19 outbreak. In addition, there was an increased willingness to receive both influenza and pneumococcal vaccinations among women, adults without underlying disease and younger adults. The COVID-19 pandemic may have increased awareness of the importance of vaccination in Taiwan.

Outcomes and eye care knowledge in rhegmatogenous retinal detachment patients with a history of laser refractive surgery for myopia.

Purpose: To investigate the surgical outcomes and eye care knowledge of patients with rhegmatogenous retinal detachment (RRD) who had previously undergone laser refractive surgery (LRS) for myopia in a myopia epidemic area. Methods: This retrospective study included patients with primary RRD who underwent surgery and had a history of LRS for myopia at a tertiary medical center. Data were reviewed from medical charts to analyse the surgical outcomes. Questions about eye care knowledge and attitude toward myopia and LRS were obtained. Results: A total of 774 patients underwent RRD surgery, among whom 341 (44%) had myopia > -3 dioptres, 66% of whom had high myopia. Thirty eyes of 26 patients had a history of LRS for myopia. The mean age of patients with a history of LRS was significantly lower than that of those without a history of LRS (45.7 ± 2.9 years vs. 53.8 ± 1.0, p < 0.001). The mean pre-LRS spherical equivalent was -8.66 ± 0.92 (range: -3.00--12.00) dioptres. In more than half the patients (n = 15, 57.7%), the interval between LRS and RRD was more than 10 years. The primary retinal reattachment rate was only 60%, whereas the final retinal reattachment rate was 93%. The mean final visual acuity (VA) improved from a 20/286 to 20/105 (p = 0.006). Linear mixed model analysis showed factors of male sex and macular detachment were significant with poor visual outcome (p = 0.046 and 0.008) Eye care knowledge obtained from the 19 RRD patients with history of LRS, 47% of patients (9/19) mistakenly thought that LRS could cure myopia and its complications, and 63% of patients were less willing to visit an ophthalmologist because uncorrected VA improvement after LRS. Eighty-four percent thought that proper knowledge and more education about LRS and myopia for the public are important. Conclusion: In the RRD patients with a history of LRS for myopia, their age was relative younger. Male sex and macular detachment were associated with poor visual outcome. More education with proper knowledge of LRS, myopia and RRD is recommended for the patients to prevent or early detect the occurrence of RRD.

Evaluation of the Oncomine Pan-Cancer Cell-Free Assay for Analyzing Circulating Tumor DNA in the Cerebrospinal Fluid in Patients with Central Nervous System Malignancies.

Available tools to evaluate patients with central nervous system (CNS) tumors such as magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) cytology, and brain biopsies, have significant limitations. MRI and CSF cytology have poor specificity and sensitivity, respectively, and brain biopsies are invasive. Circulating tumor DNA in CSF (CSF-ctDNA) could be used as a biomarker in patients with CNS tumors, but studies in this area are limited. We evaluated four CSF-ctDNA extraction methods and analyzed mutations in CSF-ctDNA with the Oncomine Pan-Cancer cell-free assay. CSF-ctDNA was extracted from 38 patients with primary or metastatic CNS tumors and 10 patients without CNS malignancy. Commercial ctDNA controls were used for assay evaluation. CSF-ctDNA yields ranged from 3.65 to 3120 ng. Mutations were detected in 39.5% of samples. TP53 was the most commonly mutated gene and copy number alterations were detected in CCND1, MYC, and ERBB2/HER2. Twenty-five percent of CSF-cytology-negative samples showed mutations in CSF-ctDNA. There was good concordance between mutations in CSF-ctDNA and matching tumors. The QIAamp Circulating Nucleic Acid Kit was the optimal method for extraction of CSF-ctDNA and the Oncomine cell-free DNA assay is suitable for detection of mutations in CSF-ctDNA. Analysis of CSF-ctDNA is more sensitive than CSF-cytology and has the potential to improve the diagnosis and monitoring of patients with CNS tumors.

Mesonephric-like Carcinoma of the Endometrium: A Subset of Endometrial Carcinoma With an Aggressive Behavior.

Endometrial mesonephric-like carcinomas (MLCa) are uncommon with <50 reported cases thus far. Previous studies have characterized the histologic, immunohistochemical, and molecular features of MLCa; however, there is limited information with respect to outcome. This single-institution study of 23 uterine MLCas characterizes the behavior of such a neoplasm. Uterine MLCas (2004-present) had review of histologic features, immunohistochemical results, molecular profile, and clinical information (stage, treatment, follow-up). The behavior of MLCa was compared with low-grade endometrioid carcinomas (ECas) and uterine serous carcinomas (USCs) treated at our institution from 2004 to present. All MLCas had a mixture of previously described architectural and cytologic features most notably ductal and/or tubular architecture (21/23), nuclei resembling those of papillary thyroid carcinoma (18/23), and at least focal intraluminal eosinophilic secretions (20/23). Immunoperoxidase studies facilitated diagnosis in 22 cases: CD10, 10/10; calretinin, 5/15; estrogen receptor (≥10% nuclei), 6/21; progesterone receptor, 1/15; GATA-3, 15/16; TTF-1, 11/16. Fourteen of 17 tested cases had a KRAS mutation (7 as the only alteration; 7 with additional mutations including PIK [n=5]; PTEN [n=2], CTNNB1 [n=1]).One case had mutations in PTEN, PIK, and CTNNB1 without KRAS; 2 cases had no detectable somatic mutation. Overall, 48% of patients presented with International Federation of Gynecology and Obstetrics (FIGO) stage 3 or 4 disease with the following uterine risk factors: >50% myometrial invasion, 20/23; lymphovascular space invasion, 16/23; cervical stromal invasion, 7/23. Twenty patients had adjuvant therapy (7 radiation only; 13 chemotherapy±radiation), whereas 3 patients had either unknown or declined therapy. Follow-up was known for 21 patients: 17 patients had recurrences or never achieved remission with the lung being the most common recurrence site (n=9); 7 patients died of disease. The median progression-free survival was 18.2 months for MLCa compared with 183 months for ECa and 67.1 months for USC. The median overall survival for MLCa was 70.6 months compared with 139.1 months for USC (median survival for ECa not reached). Uterine MLCa is uncommon with most tumors recognized by architectural heterogeneity, vesicular, overlapping nuclei with grooves, and eosinophilic luminal secretions. The typical immunoprofile includes low to absent expression of hormone receptors but at least focal expression of GATA-3 and/or TTF-1. Most tested cases had a KRAS mutation although genetic mutations typically associated with ECa are not uncommon. Compared with more commonly encountered types of ECa, MLCa is more aggressive with a tendency towards earlier and distant recurrence.

Prognostic significance of beta-catenin and topoisomerase IIalpha in de novo acute myeloid leukemia.

The Wnt/beta-catenin signaling is important for controlling self-renewal of hematopoietic stem cells and its constitutive activation has recently been documented in a significant proportion of acute myeloid leukemia (AML) cases. Topoisomerase IIalpha (Topo IIalpha) is a marker of cell proliferation and a crucial target for anthracycline cytotoxicity, the mainstay of management employed in AML. We retrospectively investigated the prognostic roles of beta-catenin and topo IIalpha in a cohort of 59 patients with newly diagnosed AML by immunohistochemistry. Aberrant beta-catenin expression was demonstrated in 13 patients (22%), and it was more likely to occur in those with unfavorable karyotypes. Advanced age and poor performance status adversely influenced the achievement of complete remission, while neither aberrant beta-catenin expression nor enhanced topo IIalpha activity did. On multivariate survival analysis, four factors independently predicted a shortened overall survival: aberrant beta-catenin expression, high topo IIalpha activity, poor-risk cytogenetics, and presence of at least one comorbidity factor. Our results suggest that both beta-catenin and topo IIalpha independently predicted an adverse prognosis and might serve as new markers for risk stratification in AML patients.

Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells.

The triggering of gemcitabine (GEM) drug resistance in pancreatic cancer by the receptor for advanced glycation end products (RAGE) has been demonstrated. Hence, finding a safe and effective adjuvant for preventing pancreatic cancer progression is imperative. Quercetin is a flavonoid that is abundant in apples, grapes, red raspberry, and onions and has been reported to inhibit RAGE. This research aimed to investigate the mechanisms of quercetin in regulating cell death and enhancing drug effects through RAGE reduction, especially in GEM-resistant pancreatic cancer cells. Our results showed that silencing RAGE expression by RAGE-specific siRNA transfection significantly increased cell death by apoptosis, autophagy and GEM-induced cytotoxicity by suppressing the PI3K/AKT/mTOR axis in MIA Paca-2 and MIA Paca-2 GEMR cells (GEM-resistant cells). Notably, quercetin showed a dramatic effect similar to RAGE silencing that effectively attenuated RAGE expression to facilitate cell cycle arrest, autophagy, apoptosis, and GEM chemosensitivity in MIA Paca-2 GEMR cells, suggesting that an additional reaction occurred under combined quercetin and GEM treatment. In conclusion, the results demonstrated that the molecular mechanisms of quercetin in regulating apoptosis and autophagy-related pathways and increasing GEM chemosensitivity in pancreatic cancer cells involved inhibition of RAGE expression.

Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease.

Circulating tumor DNA (ctDNA) refers to tumor-derived cell-free DNA that circulates in body fluids. Fluid samples are easier to collect than tumor tissue, and are amenable to serial collection at multiple time points during the course of a patient's illness. Studies have demonstrated the feasibility of performing mutation profiling from blood samples in cancer patients. However, detection of ctDNA in the blood of patients with brain tumors is suboptimal. Cerebrospinal fluid (CSF) can be obtained via lumbar puncture or intraventricular catheter, and may be a suitable fluid to assess ctDNA in patients with brain tumors. We detected melanoma-associated mutations by droplet-digital PCR (ddPCR) and next-generation sequencing in ctDNA obtained from the CSF (CSF-ctDNA) of melanoma patients with leptomeningeal disease. There is a strong correlation between mutation detection by ddPCR, the presence of circulating tumor cells in CSF and abnormalities in the MRI. However, approximately 30% of CSF samples that were negative or indeterminate for the presence of tumor cells by microscopic examination were positive for CSF-ctDNA by ddPCR. Our results demonstrate that CSF is a suitable fluid for evaluating ctDNA and ddPCR is superior to CSF-cytology for analysis of CSF in melanoma patients with leptomeningeal disease.

erb-b2 amplification by fluorescence in situ hybridization in breast cancer specimens read as 2+ in immunohistochemical analysis.

We conducted this study to ascertain the prevalence of erb-b2 gene amplification in breast cancer specimens read as 2+ in immunohistochemical analysis. Slides from patients with metastatic or recurrent breast cancer were eligible for fluorescent in situ hybridization (FISH) study if they were read as 2+ immunohistochemically for erb-b2 by a certified pathologist. The PathVysion kit (Vysis, Downers Grove, IL) was used for FISH studies. Amplification of the erb-b2 gene was defined as an erb-b2/CEP17 (chromosome 17 centromere) ratio of 2 or more in 30 tumor cells counted. From May 2003 to June 2004, 221 slides were submitted from 24 hospitals around the island. Of 216 successful hybridizations, 96 (44.4%) were determined to be erb-b2 amplified. In addition, the topoisomerase IIa gene was coamplified in 11 (21%) of 53 and deleted in 8 (15%) of 53 erb-b2 amplified cases. The erb-b2 gene amplification rate was very high in cases determined to be 2+ by immunohistochemical analysis; therefore, determination of erb-b2 status by FISH in cases scored 2+ immunohistochemically is strongly recommended.

Phase II and pharmacokinetic study of GL331 in previously treated Chinese gastric cancer patients.

PURPOSE: A phase II and pharmacokinetic study was designed to assess the efficacy and toxicity profile of an epidophyllotoxin analogue, GL331, in previously treated Chinese gastric cancer patients, with concurrent pharmacokinetic evaluation of the drug's metabolism. MATERIAL AND METHODS: GL331 was given at 200 mg/m(2) as a daily 3-h infusion for 5 days every 4 weeks. RESULTS: Enrolled in the study were 15 patients. One patient died from neutropenic sepsis before evaluation, one patient did not receive the full dose for reasons unrelated to GL331, nine patients had progressive disease with a median survival of 80 days, and five had stable disease with a median survival of 240 days. Grade 3 and 4 myelosuppression occurred in 10 of the 15 patients, with one death from neutropenic sepsis. This patient's peak GL331 concentration was 16.8 microg/ml, which was high compared to the mean peak drug concentration of 6+/-4.1 microg/ml. The mean systemic GL331 clearance was 12.1+/-7.2 l/h per m(2), much lower than 23.3+/-8.2 l/h per m(2) found in the phase I trial. Topoisomerase IIalpha was determined by immunohistochemistry and overexpression was detected in 3 of 11 specimens. CONCLUSIONS: GL331 was ineffective at this dose and schedule in this group of patients in spite of adequate blood levels of the drug.

Palliative MEFLEP therapy in advanced pancreatic cancer: excellent response in a patient with Her-2/neu amplification.

INTRODUCTION: Patients with pancreatic cancer often present initially in advanced disease with many compromising factors, and yet they may still be responsive to chemotherapy. AIMS: The response of 23 patients with advanced pancreatic cancer to continuous infusion therapy was investigated. METHODOLOGY: From September 1995 to February 1998, 23 patients with advanced pancreatic cancer, many with compromising factors, were treated with a MEFLEP regimen: biweekly 24-hour infusions of etoposide, 5-fluorouracil, leucovorin, epirubicin, and cisplatin, all given through an infusion pump, plus megestrol acetate, 160 mg/d, taken daily. A total of 145 courses were given. Overall response rate was 21% (4/19) for assessable chemo-naive patients; median survival for all 23 patients was 6 months; 22% of patients were alive at 1 year; and a clinical response benefit was attained in 35%. RESULTS: Toxicity was manageable; grade 3 or 4 leukopenia occurred in 1 patient each, 1 patient had fever and grade 3 infection, and grade 3 and 4 hyperammonemic encephalopathy developed in 3 and 1 patients, respectively. All four of the latter patients recovered uneventfully within 2 days of initiation of therapy. Nine patients were evaluated by fluorescence in situ hybridization for the Her-2/neu oncogene, but for only one patient did amplification of the gene occur. She attained complete remission with treatment and lived for 26.7 months after diagnosis. CONCLUSION: Biweekly MEFLEP is an active and manageable regimen for patients with advanced pancreatic cancer with compromised clinical status.

Clinical significance of ESR1 gene copy number changes in breast cancer as measured by fluorescence in situ hybridisation.

AIMS: The ESR1 gene encodes for oestrogen receptor (ER) α, which plays a crucial role in mammary carcinogenesis and clinical outcome in patients with breast cancer. However, the clinical significance of the ESR1 gene copy number change for breast cancer has not been clarified. METHODS: ESR1 gene copy number was determined by fluorescence in situ hybridisation (FISH) on tissue sections. A minimum of 20 tumour cells were counted per section, and a FISH ratio of ESR1 gene to CEP6 ≥ 2.0 was considered ESR1 amplification. A ratio >1.2 but <2.0 was considered ESR1 gain. The ESR1 copy number was further measured by quantitative real-time PCR (Q-PCR) with ASXL2 as a reference. RESULTS: FISH revealed ESR1 amplification in six cases (4.0%) and ESR1 gain in 13 cases (8.7%) from a total of 150 cases. ESR1 gain and amplification were more common in older patients (p<0.001), and correlated well with ER protein expression (p=0.03) measured by immunohistochemistry, and ESR1 copy number (p<0.001) measured by Q-PCR. Furthermore, the multivariate analysis revealed that ESR1 amplification was associated with a shorter disease-free survival (HR=5.56, p=0.03) and a shorter overall survival (HR=5.11, p=0.04). CONCLUSIONS: In general, the frequency of ESR1 amplification in breast cancer is low when measured by FISH in large sections. ESR1 gain and amplification in breast cancer may be associated with older age and poorer outcomes.

Molecular subtypes of breast cancer emerging in young women in Taiwan: evidence for more than just westernization as a reason for the disease in Asia.

BACKGROUND: In the past two decades, the incidence of breast cancer in young Taiwanese females has been rapidly increasing, approaching the risk level of western countries. As a first step to investigate the possible etiology, we examined the molecular subtypes of female breast cancer in Taiwan. METHODS: This study included 1,028 consecutive patients with breast cancer diagnosed in National Taiwan University Hospital between 2004 and 2006. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2, cytokeratin 5/6, and epidermal growth factor receptor expression and/or gene amplification were analyzed. RESULTS: Younger (50 years) patients. The higher prevalence of luminal A subtype was mainly attributed to a higher ER (75% versus 63%; P < 0.001) and PR (47% versus 33%; P < 0.001) expression rate in younger patients than older patients. Tumors with histologic grade 3 were less prevalent in younger patients than in older patients (23% versus 30%; P = 0.01). For very young (<35 years) patients, the molecular subtype distribution, ER and/or PR expression rate, and histologic grade were not significantly different from those of less young (35-50 years) patients. CONCLUSIONS: Young breast cancer patients in Taiwan are characterized by a high prevalence of luminal A subtype and low prevalence of histologic grade 3 tumor and/or basal-like subtype. These features are distinct from young breast cancer patients in western countries.

Comprehensive breast cancer adjuvant digital summary.

BACKGROUND: Patients with breast cancer often fail to recall the details of their original diagnosis and adjuvant therapy with the passage of time. Subsequent follow-up and treatment at a later time and a different institution wastes valuable time and effort to retrieve the original data. PATIENTS AND METHODS: Twenty-five consecutive patients with breast cancer of all stages admitted for adjuvant/neoadjuvant treatment and surgical excision were entered on study. An individualized comprehensive visual evaluation summary sheet (VESS) was created that detailed initial diagnosis, preceding relevant investigations, drug scheduling, and dosages of adjuvant therapy. Completion of a VESS required a computer, a digital camera with connection to a microscope, and radiology images over the PACS system. The completed one-page summary can be printed or stored. RESULTS: A VESS takes up an average of 4.4 MB (1.24-8 MB), each containing 11.5 images (range, 4-23 images), spanning a time period of around 216 days (range, 125-558 days). CONCLUSIONS: Patients received a complete summary of pertinent information concerning their diagnosis and adjuvant therapy.

Prognostic implications of the expression of erbB2, topoisomerase II alpha and thymidylate synthase in metastatic gastric cancer after fluorouracil-based therapy.

OBJECTIVE: This retrospective study aimed to ascertain the expression of erbB2 in relation to topoisomerase II alpha (T2 alpha) and thymidylate synthase (TS) markers in 30 consecutive metastatic gastric cancer patients with a specimen available for study. METHODS: All patients had been entered on consecutive chemotherapeutic clinical trials that were all 5-fluorouracil based. The specimens were evaluated by fluorescence in situ hybridization to ascertain erbB2 and T2 alpha gene amplification, and by immunohistochemical staining for T2 alpha and TS protein expression. RESULTS: erbB2 amplification was detected in 16.7% of specimens, with co-amplification of the T2 alpha gene in 40%, and 44% had undetectable TS protein expression. Kaplan-Meier survival curves showed significantly prolonged overall survival in patients with erbB2 and T2 alpha gene amplification, T2 alpha protein overexpression and absence of TS protein expression (P = 0.0011, P = 0.0048, P = 0.0061 and P = 0.0267, respectively, by log rank test). There was a positive correlation between erbB2 amplification and T2 alpha amplification, T2 alpha protein overexpression, and a trend towards absence of TS expression (P = 0.0001, P = 0.003 and P = 0.066 by Fisher's exact test). CONCLUSION: High dose fluorouracil/leucovorin-based chemotherapy may have the potential to reverse the adverse effects resulting from erbB2 gene amplification in gastric cancer.