Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA in settings of low tumor burden is limited by the number of mutations analyzed and the plasma volume available. We used a whole-genome sequencing (WGS) approach for ctDNA detection in patients with urothelial carcinoma. METHODS: We used a tumor-informed WGS approach for ctDNA-based detection of MRD and evaluation of treatment responses. We analyzed 916 longitudinally collected plasma samples from 112 patients with localized muscle-invasive bladder cancer who received neoadjuvant chemotherapy (NAC) before radical cystectomy. Recurrence-free survival (primary endpoint), overall survival, and ctDNA dynamics during NAC were assessed. KEY FINDINGS AND LIMITATIONS: We found that WGS-based ctDNA detection is prognostic for patient outcomes with a median lead time of 131 d over radiographic imaging. WGS-based ctDNA assessment after radical cystectomy identified recurrence with sensitivity of 91% and specificity of 92%. In addition, genomic characterization of post-treatment plasma samples with a high ctDNA level revealed acquisition of platinum therapy-associated mutational signatures and copy number variations not present in the primary tumors. The sequencing depth is a limitation for studying tumor evolution. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our results support the use of WGS for ultrasensitive ctDNA detection and highlight the possibility of plasma-based tracking of tumor evolution. WGS-based ctDNA detection represents a promising option for clinical use owing to the low volume of plasma needed and the ease of performing WGS, eliminating the need for personalized assay design. PATIENT SUMMARY: Detection of tumor DNA in blood samples from patients with cancer of the urinary tract is associated with poorer outcomes. Disease recurrence after surgery can be identified by the presence of tumor DNA in blood before it can be detected on radiography scans.

The second empty nest: The lived experience of older women whose intensive 'grandmotherhood' has ended.

Grandmothers are the major nonparental unpaid source of childcare in Western societies. Intensive caring for grandchildren may pose challenges to some grandmothers, but also offers an opportunity to refill the 'empty nest' often experienced in mid-life. When grandmothers' intensive involvement in their grandchildren's care decreases significantly or ceases altogether, they may experience a recurrence of the empty nest syndrome. This may be particularly powerful in the familial and pro-natalist Israeli society, where caring for children is a central tenet of femininity. Despite the growing numbers of grandmothers whose intensive involvement in caring for their grandchildren has ended, this transition has been overlooked socially and rarely examined empirically. To fill this void, the present study examined the lived experience of these grandmothers and the relevance of the concept of the 'second empty nest' in this context. Within a phenomenological study, in-depth interviews were conducted with 11 Israeli women whose intensive 'grandmotherhood' (childcare occurring at least three times per week, for at least two hours each day, for a minimum of two years) has ended. These interviews were analyzed according to Moustakas' phenomenological analysis. The analysis revealed four themes: the circumstances of the cessation of intensive childcare involvement; difficulties and challenges experienced; positive aspects associated with it; and behavioral and cognitive strategies utilized to cope with the void in grandmothers' lives. The grandmothers' experiences reveal a significant similarity to that reported by mothers undergoing the empty nest syndrome. Hence, we offer the term 'the second empty nest' to represent the phenomenon of grandmothers' cessation of intensive childcare. Alongside the similarities between the two empty nests, the challenges of the second transition seem more intense than those posed by the first. This is due to the different locations of mothers and grandmothers across the lifespan and the intersection between sexism and ageism that underlies Western societies. Possible practices to assist grandmothers undergoing the second empty nest are suggested.