CONTEXT The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer ...susceptibility, the family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing. OBJECTIVE To apply whole-genome sequencing to a patient without any significant family history of cancer but with suspected increased cancer susceptibility because of multiple primary tumors to identify rare or novel germline variants in cancer susceptibility genes. DESIGN, SETTING, AND PARTICIPANT Skin (normal) and bone marrow (leukemia) DNA were obtained from a patient with early-onset breast and ovarian cancer (negative for BRCA1 and BRCA2 mutations) and therapy-related acute myeloid leukemia (t-AML) and analyzed with the following: whole-genome sequencing using paired-end reads, single-nucleotide polymorphism (SNP) genotyping, RNA expression profiling, and spectral karyotyping. MAIN OUTCOME MEASURES Structural variants, copy number alterations, single-nucleotide variants, and small insertions and deletions (indels) were detected and validated using the described platforms. RESULTS Whole-genome sequencing revealed a novel, heterozygous 3-kilobase deletion removing exons 7-9 of TP53 in the patient's normal skin DNA, which was homozygous in the leukemia DNA as a result of uniparental disomy. In addition, a total of 28 validated somatic single-nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient's leukemia genome. CONCLUSION Whole-genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome.
Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using ...single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.
The resistance to β-lactam and non-β-lactam antibiotics of 133 nasopharyngeal isolates of Streptococcus pneumoniae recovered from December 1995 to February 1996 from children attending seven day-care ...centers in southwestern Greece was studied. Reduced susceptibility to one or more antimicrobial agents was found in 70 isolates (53%), as follows: penicillin, 17% intermediate, 12% resistant; cefotaxime, 10.5% intermediate, 1.5% resistant; trimethoprim-sulfamethoxazole, 8% intermediate, 35% resistant; chloramphenicol, 27% resistant; tetracycline, 29% resistant; and erythromycin/ clindamycin, 19% resistant. Eighty-seven percent of penicillin-intermediate or -resistant strains belonged to serogroups/serotypes 19, 21, and 23. Fifty-six percent of the antibiotic-resistant pneumococci were multiply resistant, including serogroup 6 strains that were penicillin-susceptible but resistant to all non-β-lactam drugs tested, as well as serogroup 23 strains resistant to penicillin, chloramphenicol, tetracycline, and trimethoprim-sulfamethoxazole. The high incidence of antibiotic-resistant pneumococci and the divergent and unique resistance patterns found in this study underline the need for global surveillance of S. pneumoniae to document the evolution and spread of resistant strains and to guide therapy.
The mechanism of resistance was investigated in 39 macrolide-resistant clinical isolates of
Streptococcus pneumoniae isolated from January 1997 to July 1999 in Santiago, Chile. Our results showed ...that 22 (56.5%) were macrolide-resistant, clindamycin-susceptible isolates (M phenotype) and 17 (43.5%) were macrolide and clindamycin resistant (MLS
B phenotype).
mefE gene was detected in all M phenotype, while
ermB gene was detected in all MLS
B-phenotype strains. Serotype 14 was the most frequent serotype among M-phenotype strains, and serotypes 19 and 23F were the most frequent serotypes in MLS
B strains. These results demonstrate that both phenotypes of macrolide-resistant
S. pneumoniae are found in Santiago, Chile, with the M phenotype predominating.
The associations of cytogenetics with complete remission (CR) rates, overall survival (OS), and outcomes after CR were studied in 609 previously untreated AML patients younger than 56 years old in a ...clinical trial comparing 3 intensive postremission therapies: intensive chemotherapy, autologous transplantation (ABMT), or allogeneic bone marrow transplantation (alloBMT) from matched related donors. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes. CR rates varied significantly (P < .0001) among the 4 groups: favorable, 84% (95% confidence interval CI, 77%-90%); intermediate, 76% (CI, 71%-81%); unfavorable, 55% (CI, 48%-63%); and unknown, 54% (CI, 33%-74%). There was similar significant heterogeneity of OS (P < .0001), with the estimated relative risk of death from any cause being 1.50 (CI, 1.10-2.05), 3.33 (CI, 2.43-4.55), and 2.66 (CI, 1.59-4.45) for the intermediate, unfavorable, and unknown risk groups, respectively, compared with the favorable group. In multivariate analyses, the effects of cytogenetic risk status on CR rate and OS could not be explained by other patient or disease characteristics. Among postremission patients, survival from CR varied significantly among favorable, intermediate, and unfavorable groups (P = .0003), with significant evidence of interaction (P = .017) between the effects of treatment and cytogenetic risk status on survival. Patients with favorable cytogenetics did significantly better following ABMT and alloBMT than with chemotherapy alone, whereas patients with unfavorable cytogenetics did better with alloBMT. Cytogenetic risk status is a significant factor in predicting response of AML patients to therapy; however, to tighten treatment correlates within genetically defined AML subsets, a significantly larger leukemia cytogenetic database is warranted.
We conducted a prospective cohort study testing the noninferiority of survival of ablative intravenous busulfan (IV-BU) vs ablative total body irradiation (TBI)-based regimens in myeloid ...malignancies. A total of 1483 patients undergoing transplantation for myeloid malignancies (IV-BU, N = 1025; TBI, N = 458) were enrolled. Cohorts were similar with respect to age, gender, race, performance score, disease, and disease stage at transplantation. Most patients had acute myeloid leukemia (68% IV-BU, 78% TBI). Grafts were primarily peripheral blood (77%) from HLA-matched siblings (40%) or well-matched unrelated donors (48%). Two-year probabilities of survival (95% confidence interval CI), were 56% (95% CI, 53%-60%) and 48% (95% CI, 43%-54%, P = .019) for IV-BU (relative risk, 0.82; 95% CI, 0.68-0.98, P = .03) and TBI, respectively. Corresponding incidences of transplant-related mortality (TRM) were 18% (95% CI, 16%-21%) and 19% (95% CI, 15%-23%, P = .75) and disease progression were 34% (95% CI, 31%-37%) and 39% (95% CI, 34%-44%, P = .08). The incidence of hepatic veno-occlusive disease (VOD) was 5% for IV-BU and 1% with TBI (P < .001). There were no differences in progression-free survival and graft-versus-host disease. Compared with TBI, IV-BU resulted in superior survival with no increased risk for relapse or TRM. These results support the use of myeloablative IV-BU vs TBI-based conditioning regimens for treatment of myeloid malignancies.
•Compared with TBI, IV-BU resulted in superior survival with no increased risk for relapse or TRM.•The results support the use of myeloablative IV-BU vs TBI-based conditioning regimens for treatment of myeloid malignancies.
Investigators from the Seattle Cancer Care Alliance describe their implementation of a Death with Dignity program in compliance with Washington State law.
In 1997, Oregon became the first state in ...the United States to pass legislation that offered a “physician-assisted” approach to dying for adults with poor short-term prognoses.
1
The Washington State legislature followed Oregon more than a decade later, passing an almost identical law, the Washington Death with Dignity Act, in November 2008.
2
Under the law, competent adults residing in Washington who have a life expectancy of 6 months or less because of a diagnosed medical condition may request and self-administer lethal medication prescribed by a physician (Table 1).
As of December 2011, a total of 255 patients had participated in . . .
Gemtuzumab ozogamicin (GO) improves outcomes when added to intensive AML chemotherapy. A meta-analysis suggested the greatest benefit when combining fractionated doses of GO (GO3) with 7 + 3. To test ...whether GO3 can be safely used with high intensity chemotherapy, we conducted a phase 1/2 study of cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone (CLAG-M) in adults with newly diagnosed AML or other high-grade myeloid neoplasm (NCT03531918). Sixty-six patients with a median age of 65 (range: 19–80) years were enrolled. Cohorts of six and twelve patients were treated in phase 1 with one dose of GO or three doses of GO (GO3) at 3 mg/m2 per dose. Since a maximum-tolerated dose was not reached, the recommended phase 2 dose (RP2D) was declared to be GO3. At RP2D, 52/60 (87%) patients achieved a complete remission (CR)/CR with incomplete hematologic recovery (CRi), 45/52 (87%) without flow cytometric measurable residual disease (MRD). Eight-week mortality was 0%. Six- and twelve-month event-free survival (EFS) were 73% and 58%; among favorable-risk patients, these estimates were 100% and 95%. Compared to 186 medically matched adults treated with CLAG-M alone, CLAG-M/GO3 was associated with better survival in patients with favorable-risk disease (EFS: p = 0.007; OS: p = 0.030). These data indicate that CLAG-M/GO3 is safe and leads to superior outcomes than CLAG-M alone in favorable-risk AML/high-grade myeloid neoplasm.
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