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KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors - nejm.org
Original Article from The New England Journal of Medicine — KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors
From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); DanaFarber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.). Address reprint requests to Dr. Hong at the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, or at [email protected]; or to Dr. Li at the Thoracic Oncology and Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY 10065, or at [email protected].
Humoral Immune Response to SARS-CoV-2 in Iceland | NEJM - nejm.org
Original Article from The New England Journal of Medicine — Humoral Immune Response to SARS-CoV-2 in Iceland
Specificity of SARS-CoV-2 Antibody Assays Both assays measuring pan-Ig antibodies had low numbers of false positives among samples collected in 2017: there were 0 and 1 false positives for the two assays among 472 samples, results that compared favorably with those obtained with the single IgM anti-N and IgG anti-N assays (Table S3). Because of the low prevalence of SARS-CoV-2 infection in Iceland, we required positive results from both pan-Ig antibody assays for a sample to be considered seropositive (see Supplementary Methods in Supplementary Appendix 1). None of the samples collected in early 2020 group were seropositive, which indicates that the virus had not spread widely in Iceland before February 2020. SARS-CoV-2 Antibodies among qPCR-Positive Persons Figure 2. Figure 2. Antibody Prevalence and Titers among qPCR-Positive Cases as a Function of Time since Diagnosis by qPCR.Shown are the percentages of samples positive for both pan-Ig antibody assays and the antibody titers. Red denotes the count or percentage of samples among persons during their hospitalization (249 samples from 48 persons), and blue denotes the count or percentage of samples among persons after they were declared recovered (1853 samples from 1215 persons). Vertical bars denote 95% confidence intervals. The dashed lines indicated the thresholds for a test to be declared positive. OD denotes optical density, and RBD receptor binding domain. Table 1. Table 1. Prevalence of SARS-CoV-2 Antibodies by Sample Collection as Measured by Two Pan-Ig Antibody Assays.Twenty-five days after diagnosis by qPCR, more than 90% of samples from recovered persons tested positive with both pan-Ig antibody assays, and the percentage of persons testing positive remained stable thereafter (Figure 2 and Fig. S2). Hospitalized persons seroconverted more frequently and quickly after qPCR diagnosis than did nonhospitalized persons (Figure 2 and Fig. S3). Of 1215 persons who had recovered (on the basis of results for the most recently obtained sample from persons for whom we had multiple samples), 1107 were seropositive (91.1%; 95% confidence interval [CI], 89.4 to 92.6) (Table 1 and Table S4). Since some diagnoses may have been made on the basis of false positive qPCR results, we determined that 91.1% represents the lower bound of sensitivity of the combined pan-Ig tests for the detection of SARS-CoV-2 antibodies among recovered persons. Table 2. Table 2. Results of Repeated Pan-Ig Antibody Tests among Recovered qPCR-Diagnosed Persons.Among the 487 recovered persons with two or more samples, 19 (4%) had different pan-Ig antibody test results at different time points (Table 2 and Fig. S4). It is notable that of the 22 persons with an early sample that tested negative for both pan-Ig antibodies, 19 remained negative at the most recent test date (again, for both antibodies). One person tested positive for both pan-Ig antibodies in the first test and negative for both in the most recent test. The longitudinal changes in antibody levels among recovered persons were consistent with the cross-sectional results (Fig. S5); antibody levels were higher in the last sample than in the first sample when the antibodies were measured with the two pan-Ig assays, slightly lower than in the first sample when measured with IgG anti-N and IgG anti-S1 assays, and substantially lower than in the first sample when measured with IgM anti-N and IgA anti-S1 assays. IgG anti-N, IgM anti-N, IgG anti-S1, and IgA anti-S1 antibody levels were correlated among the qPCR-positive persons (Figs. S5 and S6 and Table S5). Antibody levels measured with both pan-Ig antibody assays increased over the first 2 months after qPCR diagnosis and remained at a plateau over the next 2 months of the study. IgM anti-N antibody levels increased rapidly soon after diagnosis and then fell rapidly and were generally not detected after 2 months. IgA anti-S1 antibodies decreased 1 month after diagnosis and remained detectable thereafter. IgG anti-N and anti-S1 antibody levels increased during the first 6 weeks after diagnosis and then decreased slightly. SARS-CoV-2 Infection in Quarantine Table 3. Table 3. SARS-CoV-2 Infection among Quarantined Persons According to Exposure Type and Presence of Symptoms.Of the 1797 qPCR-positive Icelanders, 1088 (61%) were in quarantine when SARS-CoV-2 infection was diagnosed by qPCR. We tested for antibodies among 4222 quarantined persons who had not tested qPCR-positive (they had received a negative result by qPCR or had simply not been tested). Of those 4222 quarantined persons, 97 (2.3%; 95% CI, 1.9 to 2.8) were seropositive (Table 1). Those with household exposure were 5.2 (95% CI, 3.3 to 8.0) times more likely to be seropositive than those with other types of exposure (Table 3); similarly, a positive result by qPCR for those with household exposure was 5.2 (95% CI, 4.5 to 6.1) times more likely than for those with other types of exposure. When these two sets of results (qPCR-positive and seropositive) were combined, we calculated that 26.6% of quarantined persons with household exposure and 5.0% of quarantined persons without household exposure were infected. Those who had symptoms during quarantine were 3.2 (95% CI, 1.7 to 6.2) times more likely to be seropositive and 18.2 times (95% CI, 14.8 to 22.4) more likely to test positive with qPCR than those without symptoms. We also tested persons in two regions of Iceland affected by cluster outbreaks. In a SARS-CoV-2 cluster in Vestfirdir, 1.4% of residents were qPCR-positive and 10% of residents were quarantined. We found that none of the 326 persons outside quarantine who had not been tested by qPCR (or who tested negative) were seropositive. In a cluster in Vestmannaeyjar, 2.3% of residents were qPCR-positive and 13% of residents were quarantined. Of the 447 quarantined persons who had not received a qPCR-positive result, 4 were seropositive (0.9%; 95% CI, 0.3 to 2.1). Of the 663 outside quarantine in Vestmannaeyjar, 3 were seropositive (0.5%; 95% CI, 0.1 to 0.2%). SARS-CoV-2 Seroprevalence in Iceland None of the serum samples collected from 470 healthy Icelanders between February 18 and March 9, 2020, tested positive for both pan-Ig antibodies, although four were positive for the pan-Ig anti-N assay (0.9%), a finding that suggests that the virus had not spread widely in Iceland before March 9. Of the 18,609 persons tested for SARS-CoV-2 antibodies through contact with the Icelandic health care system for reasons other than Covid-19, 39 were positive for both pan-Ig antibody assays (estimated seroprevalence by weighting the sample on the basis of residence, sex, and 10-year age category, 0.3%; 95% CI, 0.2 to 0.4). There were regional differences in the percentages of qPCR-positive persons across Iceland that were roughly proportional to the percentage of people quarantined (Table S6). However, after exclusion of the qPCR-positive and quarantined persons, the percentage of persons who tested positive for SARS-CoV-2 antibodies did not correlate with the percentage of those who tested positive by qPCR. The estimated seroprevalence in the random sample collection from Reykjavik (0.4%; 95% CI, 0.3 to 0.6) was similar to that in the Health Care group (0.3%; 95% CI, 0.2 to 0.4) (Table S6). We calculate that 0.5% of the residents of Iceland have tested positive with qPCR. The 2.3% with SARS-CoV-2 seroconversion among persons in quarantine extrapolates to 0.1% of Icelandic residents. On the basis of this finding and the seroprevalence from the Health Care group, we estimate that 0.9% (95% CI, 0.8 to 0.9) of the population of Iceland has been infected by SARS-CoV-2. Approximately 56% of all SARS-CoV-2 infections were therefore diagnosed by qPCR, 14% occurred in quarantine without having been diagnosed with qPCR, and the remaining 30% of infections occurred outside quarantine and were not detected by qPCR. Deaths from Covid-19 in Iceland In Iceland, 10 deaths have been attributed to Covid-19, which corresponds to 3 deaths per 100,000 nationwide. Among the qPCR-positive cases, 0.6% (95% CI, 0.3 to 1.0) were fatal. Using the 0.9% prevalence of SARS-CoV-2 infection in Iceland as the denominator, however, we calculate an infection fatality risk of 0.3% (95% CI, 0.2 to 0.6). Stratified by age, the infection fatality risk was substantially lower in those 70 years old or younger (0.1%; 95% CI, 0.0 to 0.3) than in those over 70 years of age (4.4%; 95% CI, 1.9 to 8.4) (Table S7). Age, Sex, Clinical Characteristics, and Antibody Levels Table 4. Table 4. Association of Existing Conditions and Covid-19 Severity with SARS-CoV-2 Antibody Levels among Recovered Persons.SARS-CoV-2 antibody levels were higher in older people and in those who were hospitalized (Table 4, and Table S8 [described in Supplementary Appendix 1 and available in Supplementary Appendix 2]). Pan-Ig antiS1-RBD and IgA anti-S1 levels were lower in female persons. Of the preexisting conditions, and after adjustment for multiple testing, we found that body-mass index, smoking status, and use of antiinflammatory medication were associated with SARS-CoV-2 antibody levels. Body-mass index correlated positively with antibody levels; smokers and users of antiinflammatory medication had lower antibody levels. With respect to clinical characteristics, antibody levels were most strongly associated with hospitalization and clinical severity, followed by clinical symptoms such as fever, maximum temperature reading, cough, and loss of appetite. Severity of these individual symptoms, with the exception of loss of energy, was associated with higher antibody levels.
Natural History of Asymptomatic SARS-CoV-2 Infection | NEJM - nejm.org
Correspondence from The New England Journal of Medicine — Natural History of Asymptomatic SARS-CoV-2 Infection
Information on the natural history of asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains scarce.1-3 The outbreak of coronavirus disease 2019 (Covid-19) on the cruise ship Diamond Princess led to 712 persons being infected with SARS-CoV-2 among the 3711 passengers and crew members, and 410 (58%) of these infected persons were asymptomatic at the time of testing (see the Supplementary Appendix, available with the full text of this letter at NEJM.org).4,5 Here, we report the natural history of asymptomatic SARS-CoV-2 infection in part of this cohort. A total of 96 persons infected with SARS-CoV-2 who were asymptomatic at the time of testing, along with their 32 cabinmates who tested negative on the ship, were transferred from the Diamond Princess to a hospital in central Japan between February 19 and February 26 for continued observation. Clinical signs and symptoms of Covid-19 subsequently developed in 11 of these 96 persons, a median of 4 days (interquartile range, 3 to 5; range, 3 to 7) after the first positive polymerase-chain-reaction (PCR) test, which meant that they had been presymptomatic rather than asymptomatic. The risk of being presymptomatic increased with increasing age (odds ratio for being presymptomatic with each 1-year increase in age, 1.08; 95% confidence interval [CI], 1.01 to 1.16). Eight of 32 cabinmates with a negative PCR test on the ship had a positive PCR test within 72 hours after arrival in the hospital but remained asymptomatic. In total, data on 90 persons with asymptomatic SARS-CoV-2 infection, defined as persons who were asymptomatic at the time of the positive PCR test and remained so until the resolution of infection (as determined by two consecutive negative PCR tests), were available for analysis (Fig. S1 in the Supplementary Appendix). Figure 1. Figure 1. Crossing-Point Values in RT-PCR Testing of Asymptomatic Persons with SARS-CoV-2 Infection.Included in the analysis are persons who had at least one positive polymerase-chain-reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the hospital. With fluorescence-based real-time reverse-transcriptase PCR (RT-PCR), the number of cycles at which the fluorescence signal from amplification exceeds the background fluorescence level is determined as the crossing point (Cp), threshold cycle, or other measures by different instrument manufacturers. A lower value correlates with a higher copy number of the target nucleotide sequence. The group of persons with asymptomatic SARS-CoV-2 infection consisted of 58 passengers and 32 crew members, with median age of 59.5 years (interquartile range, 36 to 68; range, 9 to 77). A total of 24 of these persons (27%) had coexisting medical conditions, including hypertension (in 20%) and diabetes (9%). The first PCR test at the hospital was performed a mean of 6 days after the initial positive PCR test on the ship. The median number of days between the first positive PCR test (either on the ship or at the hospital) and the first of the two serial negative PCR tests was 9 days (interquartile range, 6 to 11; range, 3 to 21), and the cumulative percentages of persons with resolution of infection 8 and 15 days after the first positive PCR test were 48% and 90%, respectively. The risk of delayed resolution of infection increased with increasing age (mean delay in resolution for an increase in age from 36 to 68 years, 4.41 days; 95% CI, 2.28 to 6.53) (Figure 1). In this cohort, the majority of asymptomatically infected persons remained asymptomatic throughout the course of the infection. The time to the resolution of infection increased with increasing age. Aki Sakurai, M.D.Toshiharu Sasaki, M.D.Fujita Health University, Aichi, Japan Shigeo Kato, Pharm.B.Ministry of Health, Labor, and Welfare Nagoya Quarantine Station, Aichi, Japan Masamichi Hayashi, M.D., Ph.D.Sei-ichiro Tsuzuki, M.D.Fujita Health University, Aichi, Japan Takuma Ishihara, M.S.Gifu University Hospital, Gifu, Japan Mitsunaga Iwata, M.D., Ph.D.Zenichi Morise, M.D., Ph.D.Yohei Doi, M.D., Ph.D.Fujita Health University, Aichi, Japan [email protected] Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on June 12, 2020, at NEJM.org. 5 References
- 1. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. N Engl J Med 2020;382:2081-2090.
- 2. Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020;323:1406-1407.
- 3. Kimball A, Hatfield KM, Arons M, et al. Asymptomatic and presymptomatic SARS-CoV-2 infections in residents of a long-term care skilled nursing facility King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep 2020;69:377-381.
- 4. Field briefing: Diamond Princess COVID-19 cases, 20 Feb update. Tokyo: National Institute of Infectious Diseases, February 21, 2020 (https://www.niid.go.jp/niid/en/2019-ncov-e/9417-covid-dp-fe-02.html).
- 5. Ministry of Health, Labour and Welfare. Official report on the cruise ship Diamond Princess. March 5, 2020 (https://www.mhlw.go.jp/stf/newpage_09997.html).