Cervical cancer is a common gynecological malignancy often caused by high-risk human papillomavirus. There is a paucity of human-derived culture systems to study the cervical epithelium and the ...cancers derived thereof. Here we describe a long-term culturing protocol for ecto- and endocervical epithelia that generates 3D organoids that stably recapitulate the two tissues of origin. As evidenced for HSV-1, organoid-based cervical models may serve to study sexually transmitted infections. Starting from Pap brush material, a small biobank of tumoroids derived from affected individuals was established that retained the causative human papillomavirus (HPV) genomes. One of these uniquely carried the poorly characterized HPV30 subtype, implying a potential role in carcinogenesis. The tumoroids displayed differential responses to common chemotherapeutic agents and grew as xenografts in mice. This study describes an experimental platform for cervical (cancer) research and for future personalized medicine approaches.
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•Establishment of long-term organoid cultures from human ecto- and endocervix•Promising platform for modeling STIs, as evidenced for HSV-1•Pap brush collection as a successful method for cervical tumoroid derivation•Cervical tumoroids display disease hallmarks, such as causative HPV infection
Human-based model systems that faithfully recapitulate cervical cancer and causative HPV infection are scarce and often inadequate. With the advances in organoid technology, Lõhmussaar et al. have now extended this knowledge to the cervix, describing a successful derivation of endo- and ectocervical organoids as well as tumoroids from the associated malignancies.
For adult granulosa cell tumors (aGCTs), the preferred treatment modality is surgery. Chemotherapy and anti-hormonal therapy are also frequently used in patients with recurrent aGCT. We aimed to ...review the existing literature on the response to chemotherapy and anti-hormonal therapy in patients with aGCT. Embase and MEDLINE were searched from inception to November 2021 for eligible studies. Objective response rate (ORR) was calculated as the total number of cases with a complete response (CR) or a partial response (PR). Disease control rate (DCR) was defined as the sum of cases with CR, PR or stable disease (SD). A total of 10 studies were included that reported on chemotherapy and 13 studies were included that reported on anti-hormonal therapy. The response rates of the 56 chemotherapy regimens that could be evaluated resulted in an ORR of 30% and DCR of 58%. For anti-hormonal therapy, the results of 73 regimens led to an ORR of 11% and a DCR of 66%. Evidence on systemic therapy in aGCT only is limited. For both chemotherapy and anti-hormonal therapy, the ORR is limited, but the response is considerably higher when patients achieving SD are included. New approaches are needed to provide more evidence and standardize treatment in aGCT.
Non-genetic healthcare professionals can provide pre-test counseling and order germline genetic tests themselves, which is called mainstream genetic testing. In this systematic review, we determined ...whether mainstream genetic testing was feasible in daily practice while maintaining quality of genetic care.
PubMed, Embase, CINAHL, and PsychINFO were searched for articles describing mainstream genetic testing initiatives in cancer care.
Seventeen articles, reporting on 15 studies, met the inclusion criteria. Non-genetic healthcare professionals concluded that mainstream genetic testing was possible within the timeframe of a routine consultation. In 14 studies, non-genetic healthcare professionals completed some form of training about genetics. When referral was coordinated by a genetics team, the majority of patients carrying a pathogenic variant were seen for post-test counseling by genetic healthcare professionals. The number of days between cancer diagnosis and test result disclosure was always lower in the mainstream genetic testing pathway than in the standard genetic testing pathway (e.g., pre-test counseling at genetics department).
Mainstream genetic testing seems feasible in daily practice with no insurmountable barriers. A structured pathway with a training procedure is desirable, as well as a close collaboration between genetics and other clinical departments.
Recently, the safety of laparoscopic radical hysterectomy (LRH) has been called into question in early-stage cervical cancer. This study aimed to evaluate overall survival (OS) and disease-free ...survival (DFS) in patients treated with abdominal radical hysterectomy (ARH) and LRH for early-stage cervical cancer and to provide a literature review.
Patients diagnosed between 2010 and 2017 with International Federation of Gynaecology and Obstetrics (2009) stage IA2 with lymphovascular space invasion, IB1 and IIA1, were identified from the Netherlands Cancer Registry. Cox regression with propensity score, based on inverse probability treatment weighting, was applied to examine the effect of surgical approach on 5-year survival and calculate hazard ratios (HR) and 95% confidence intervals (CIs). Literature review included observational studies with (i) analysis on tumours ≤4 cm (ii) median follow-up ≥30 months (iii) ≥5 events per predictor parameter in multivariable analysis or a propensity score.
Of the 1109 patients, LRH was performed in 33%. Higher mortality (9.4% vs. 4.6%) and recurrence (13.1% vs. 7.3%) were observed in ARH than LRH. However, adjusted analyses showed similar DFS (89.4% vs. 90.2%), HR 0.92 95% CI: 0.52–1.60) and OS (95.2% vs. 95.5%), HR 0.94 95% CI: 0.43–2.04). Analyses on tumour size (<2/≥2 cm) also gave similar survival rates. Review of nine studies showed no distinct advantage of ARH, especially in tumours <2 cm.
After adjustment, our retrospective study showed equal oncological outcomes between ARH and LRH for early-stage cervical cancer – also in tumours <2 cm. This is in correspondence with results from our literature review.
•Oncological outcome is equal after abdominal and laparoscopic radical hysterectomy.•Disease-free survival and overall survival are equal in tumours <2 cm.•The exact role of laparoscopy should be examined in prospective randomised trials.
Abstract Objective To evaluate the sensitivity of sentinel node (SN) ultrastaging and to define parameters that may reduce the overall false-negative rate in women with early-stage cervical cancer. ...Methods We analyzed data from a large retrospective multicenter cohort group with FIGO stages IA–IIB cervical cancer in whom at least one SN was identified and systematic pelvic lymphadenectomy was uniformly performed. All who were SN negative by initial evaluation were subjected to ultrastaging. Results In all, 645 patients were evaluable. SN were detected bilaterally in 72% of cases and unilaterally in 28%. Patients with optimal bilateral SN detection were significantly more likely to have any metastasis detected (33.3% vs. 19.2%; P < 0.001) as well as micrometastasis detected in their SN (39.6% vs. 11.4%). SN ultrastaging resulted in a low overall false-negative rate of 2.8% (whole group) and an even lower false-negative rate of 1.3% for patients with optimal bilateral mapping. Patients with false-negative SN after ultrastaging had a higher prevalence of LVSI and more frequent unilateral SN detection. Sensitivity of SN ultrastaging was 91% (95% CI: 86%–95%) for the whole group and 97% (95% CI: 91%–99%) in the subgroup with bilateral SN detection. Conclusion These data confirm previous observations that optimal bilateral SN detection substantially decreases the false negative rate of SN ultrastaging and increases detection of micrometastasis. In patients with bilateral SN detection, the sensitivity of SN ultrastaging is not reduced in more advanced stages of the disease. SN mapping and ultrastaging should become standard practice in the surgical management of early-stage cervical cancer.
Intra-tumor heterogeneity is a hallmark of many cancers and may lead to therapy resistance or interfere with personalized treatment strategies. Here, we combined topographic mapping of somatic ...breakpoints and transcriptional profiling to probe intra-tumor heterogeneity of treatment-naïve stage IIIC/IV epithelial ovarian cancer. We observed that most substantial differences in genomic rearrangement landscapes occurred between metastases in the omentum and peritoneum versus tumor sites in the ovaries. Several cancer genes such as NF1, CDKN2A, and FANCD2 were affected by lesion-specific breakpoints. Furthermore, the intra-tumor variability involved different mutational hallmarks including lesion-specific kataegis (local mutation shower coinciding with genomic breakpoints), rearrangement classes, and coding mutations. In one extreme case, we identified two independent TP53 mutations in ovary tumors and omentum/peritoneum metastases, respectively. Examination of gene expression dynamics revealed up-regulation of key cancer pathways including WNT, integrin, chemokine, and Hedgehog signaling in only subsets of tumor samples from the same patient. Finally, we took advantage of the multilevel tumor analysis to understand the effects of genomic breakpoints on qualitative and quantitative gene expression changes. We show that intra-tumor gene expression differences are caused by site-specific genomic alterations, including formation of in-frame fusion genes. These data highlight the plasticity of ovarian cancer genomes, which may contribute to their strong capacity to adapt to changing environmental conditions and give rise to the high rate of recurrent disease following standard treatment regimes.
To investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic
-pathogenic variant (PV) ...carriers.
We included
-PV carriers who underwent RRSO between 1995 and 2018 from the Hereditary Breast and Ovarian cancer in the Netherlands study. All pathology reports were screened, and histopathology reviews were performed for RRSO specimens with epithelial abnormalities or where HGSC developed after normal RRSO. We then compared clinical characteristics, including parity and oral contraceptive pill (OCP) use, for women with and without HGSC at RRSO.
Of the 2,557 included women, 1,624 had
, 930 had
, and three had both
-PV. The median age at RRSO was 43.0 years (range: 25.3-73.8) for
-PV and 46.8 years (27.6-77.9) for
-PV carriers. Histopathologic review confirmed 28 of 29 HGSCs and two further HGSCs from among 20 apparently normal RRSO specimens. Thus, 24 (1.5%)
-PV and 6 (0.6%)
-PV carriers had HGSC at RRSO, with the fallopian tube identified as the primary site in 73%. The prevalence of HGSC in women who underwent RRSO at the recommended age was 0.4%. Among
PV carriers, older age at RRSO increased the risk of HGSC and long-term OCP use was protective.
We detected HGSC in 1.5% (
-PV) and 0.6% (
-PV) of RRSO specimens from asymptomatic
-PV carriers. Consistent with the fallopian tube hypothesis, we found most lesions in the fallopian tube. Our results highlight the importance of timely RRSO with total removal and assessment of the fallopian tubes and show the protective effects of long-term OCP.
Ovarian cancer mortality rates have not decreased significantly in the past years. As most women are still diagnosed in an advanced stage, there is a need for new treatment strategies for recurrent ...disease. A potentially new developing targeted approach, theranostics, combines diagnostics and treatment using radiopharmaceuticals. Through target receptors, imaging and treatment of malignant tissue can be achieved. For ovarian malignancy, the follicle-stimulating hormone (FSH) receptor may serve as a possible target since expression appears to be limited to ovarian cells. In this systematic review, we aim to gather all available literature on the expression of the FSH receptor in ovarian tumors. Pubmed, Embase and the Cochrane databases were searched until December 2023 for eligible studies. The search yielded 41 studies, mostly regarding serous carcinomas, sex cord-stromal tumors (SCSTs) and cell lines of serous and SCSTs. Various techniques were used to analyze the expression of the FSH receptor. For serous carcinomas, conflicting results on the expression of the FSH receptor were found. Studies on SCSTs, mainly studying the subtype of granulosa cell tumors, all showed positive expression of the FSH receptor. In the cell lines studies, the KGN cell line derived from a granulosa cell tumor shows positive expression in all studies. Available studies show that SCSTs express the FSH receptor. A theranostic approach targeting the FSH receptor may, therefore, provide a useful new approach for this malignancy with limited therapeutic options in recurrent disease.
Accurate staging of para-aortic nodal status in cervical cancer is of great importance for individualizing treatment and impacting outcomes. Three-dimensional imaging (i.e. PET, CT, MRI) may miss ...para-aortic lymph node (PALN) metastases. The aim of this study was to systematically review and meta-analyze the proportion of upstaging by PALN dissection in patients with locally advanced cervical cancer without suspicious PALNs on imaging.
PubMed/MEDLINE and Embase were systematically searched. The analysis included diagnostic studies that reported on 3D imaging and pre-therapeutic surgical assessment of PALN status in patients with cervical cancer. An overall pooled upstaging rate was calculated using a random-effects model.
The search identified 16 eligible studies including 18 cohorts with a total of 1530 patients. Pooling of 12 cohorts demonstrated an upstaging rate of 12% (95% confidence interval CI 10–15%) by PALN dissection after negative PET or PET-CT. Pooling of 6 cohorts demonstrated a pooled upstaging rate of 11% (95% CI: 8–16%) by PALN dissection after negative MRI or CT. No significant heterogeneity in upstaging proportions across cohorts was observed (I2 = 0% and 27%, respectively). In 7 cohorts including only patients with pelvic nodal metastases on imaging (but no suspicion of PALN involvement) a pooled upstaging rate by PALN dissection of 21% (95% CI: 17–26%) was found (I2 = 0%).
This meta-analysis demonstrates that in case of no suspicious PALN on PET-CT or MRI, PALN dissection still identifies lymph node metastases in a considerable amount of patients with locally advanced cervical cancer and especially in those patients with confirmed pelvic nodal metastases.
•Para-aortic lymph node (PALN) status in locally advanced cervical cancer has therapeutic and prognostic implications.•Reported proportions in literature of upstaging by PALN dissection after negative PALN imaging were meta-analyzed.•After negative PET or PET-CT, PALN dissection yielded pathologic PALNs in 12% of all patients.•After negative MRI or CT, PALN dissection yielded pathologic PALNs in 11% of all patients.•After PET-CT showed pelvic nodal (but no PALN) involvement, PALN dissection yielded pathologic PALNs in 21% of patients.
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