Our purpose was to assess the feasibility, safety, and efficacy of stereotactic ablative radiation therapy (SAbR) as an alternative for intracavitary/interstitial brachytherapy boost for locally ...advanced cervical cancer (LACC) after initial chemoradiation.
A single arm institutional phase II study of SAbR as a boost for LACC was conducted. Eligible patients had LACC FIGO 2009 stage IB2-IVB, performance status 0 to 3, and one of the following: medically unfit or refused intracavitary or tumor extent required interstitial brachytherapy for coverage. The cervix planning target volume boost (PTV
) received 28 Gy in 4 fractions.
The study was closed with 15 of 21 patients completed owing to concern for toxicity. Median follow-up for this cohort was 19 months. Patients had predominantly advanced stage (III-IV, 53%) with median Charlson comorbidity score of 4. Most tumors were large with a median SAbR boost PTV size of 139 cc (range, 51-268 cc). Tumor size and patient comorbidities probably contributed to the lower-than-expected 2-year local control, progression free, and overall survival of 70.1%, 46.7%, and 53.3%, respectively. The SAbR boost 2 year cumulative grade ≥ 3 toxicity of 26.7% was predominantly rectal (ulcer/fistula).The median SAbR PTV volume was 225 cc versus 95 cc for patients with and without grade ≥ 3 toxicity. On dosimetric analysis, only the percentage of rectal circumference receiving 15 Gy (PRC
) for the SAbR boost was associated with development of grade 3 ulcer or rectovaginal fistula (P = .04), with PRC
> 62.7% being the strongest predictor of toxicity (AUC, 0.93; sensitivity, 100%; specificity, 90%).
In this SAbR boost series suboptimal outcomes were probably related to patient selection and very large tumor volume. This approach may still be considered in patients with smaller tumors unable to undergo standard brachytherapy for cervix cancer.
Radical hysterectomy is the mainstay of treatment for early-stage cervical cancer. Urinary tract dysfunction is one of the most common complications after radical hysterectomy, and prolonged ...catheterization has previously been defined as a significant risk factor for catheter–associated urinary tract infections.
This study aimed to determine the rate of catheter–associated urinary tract infections after radical hysterectomy for cervical cancer, and to identify additional risk factors for developing catheter–associated urinary tract infections in this population.
We reviewed patients who underwent radical hysterectomy for cervical cancer from 2004 to 2020 after institutional review board approval. All patients were identified from institutional Gynecologic Oncology surgical and tumor databases. The inclusion criterion was radical hysterectomy for early-stage cervical cancer. Exclusion criteria included inadequate hospital follow-up, insufficient records of catheter use in the electronic medical record, urinary tract injury, and preoperative chemoradiation. Catheter–associated urinary tract infection was defined as an infection diagnosed in a catheterized patient or within 48 hours of catheter removal, with significant bacteriuria (>103 cfu/mL) and symptoms or signs attributable to the urinary tract. Data analysis was performed using comparative analysis and univariate and multivariable logistic regression using Excel, GraphPad Prism, and IBM SPSS Statistics.
Of the 160 included patients, 12.5% developed catheter–associated urinary tract infections. In univariate analysis, catheter–associated urinary tract infection was significantly associated with current smoking history (odds ratio, 3.76; 95% confidence interval, 1.39–10.08), minimally invasive surgical approach (odds ratio, 5.24; 95% confidence interval, 1.91–16.87), estimated surgical blood loss >500 mL (odds ratio, 0.18; 95% confidence interval, 0.04–0.57), operative time >300 minutes (odds ratio, 2.92; 95% confidence interval, 1.07–9.36), and increased duration of catheterization (odds ratio, 18.46; 95% confidence interval, 3.67–336). After adjusting for interactions and controlling for potential confounders with multivariable analysis, current smoking history and catheterization for >7 days were identified as independent risk factors for development of catheter–associated urinary tract infections (adjusted odds ratio, 3.94; 95% confidence interval, 1.28–12.37; adjusted odds ratio, 19.49; 95% confidence interval, 2.78–427).
Preoperative smoking cessation interventions for current smokers should be implemented to decrease risk for postoperative complications, including catheter–associated urinary tract infections. In addition, catheter removal within 7 postoperative days should be encouraged in all women undergoing radical hysterectomy for early-stage cervical cancer in an effort to decrease infection risk.
Defects in translation lead to changes in the expression of proteins that can serve as drivers of cancer formation. Here, we show that cytosolic NAD+ synthesis plays an essential role in ovarian ...cancer by regulating translation and maintaining protein homeostasis. Expression of NMNAT-2, a cytosolic NAD+ synthase, is highly upregulated in ovarian cancers. NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal proteins. Depletion of NMNAT-2 or PARP-16 leads to inhibition of MARylation, increased polysome association and enhanced translation of specific mRNAs, aggregation of their translated protein products, and reduced growth of ovarian cancer cells. Furthermore, MARylation of the ribosomal proteins, such as RPL24 and RPS6, inhibits polysome assembly by stabilizing eIF6 binding to ribosomes. Collectively, our results demonstrate that ribosome MARylation promotes protein homeostasis in cancers by fine-tuning the levels of protein synthesis and preventing toxic protein aggregation.
Display omitted
•The cytosolic NAD+ synthase NMNAT-2 is highly upregulated in ovarian cancers•Ribosome MARylation requires NAD+ from NMNAT-2, as well as the MART PARP-16•Site-specific MARylation of ribosomes inhibits polysome assembly and mRNA loading•It also inhibits translation, maintains proteostasis, and supports cancer cell growth
Challa et al. study ribosome MARylation and proteostasis in cancer. They find that cytosolic NAD+ supports ribosome MARylation by PARP-16, leading to reduced translation and increased proteostasis to support ovarian cancer cell proliferation, which is associated with poorer outcomes in patients.
PARP-7 (TiPARP) is a mono(ADP-ribosyl) transferase whose protein substrates and biological activities are poorly understood. We observed that
mRNA levels are lower in ovarian cancer patient samples ...compared to non-cancerous tissue, but PARP-7 protein nonetheless contributes to several cancer-related biological endpoints in ovarian cancer cells (e.g. growth, migration). Global gene expression analyses in ovarian cancer cells subjected to PARP-7 depletion indicate biological roles for PARP-7 in cell-cell adhesion and gene regulation. To identify the MARylated substrates of PARP-7 in ovarian cancer cells, we developed an NAD
analog-sensitive approach, which we coupled with mass spectrometry to identify the PARP-7 ADP-ribosylated proteome in ovarian cancer cells, including cell-cell adhesion and cytoskeletal proteins. Specifically, we found that PARP-7 MARylates α-tubulin to promote microtubule instability, which may regulate ovarian cancer cell growth and motility. In sum, we identified an extensive PARP-7 ADP-ribosylated proteome with important roles in cancer-related cellular phenotypes.
Cervical cancer continues to be a significant cause of cancer-related deaths in women. The most common treatment for cervical cancer involves the use of the drug cisplatin in conjunction with other ...therapeutics. However, the development of cisplatin resistance in patients can hinder the efficacy of these treatments, so alternatives are needed. In this study, we found that PARP inhibitors (PARPi) could attenuate the growth of cells representing cervical adenocarcinoma and cervical squamous cell carcinoma. Moreover, a combination of PARPi with cisplatin increased cisplatin-mediated cytotoxicity in cervical cancer cells. This was accompanied by a dramatic alteration of the transcriptome. The FOS gene, which encodes the transcription factor Fos, was one of the most highly upregulated genes in the dual treatment condition, leading to increased Fos protein levels, greater Fos binding to chromatin, and the subsequent induction of Fos target genes. Increased expression of Fos was sufficient to hinder cervical cancer growth, as shown by ectopic expression of Fos in cervical cancer cells. Conversely, Fos knockdown enhanced cell growth. Collectively, these results indicate that by inducing FOS expression, PARPi treatment in combination with cisplatin leads to inhibition of cervical cancer proliferation, likely through a Fos-specific gene expression program.
Our observations, which link the gene regulatory effects of PARPi + cisplatin to the growth inhibitory effects of FOS expression in cervical cancer cells, strengthen the rationale for using PARPi with cisplatin as a therapy for cervical cancer.
Surgical evaluation of lymph node metastasis is paramount in the treatment of cervical cancer. We sought to explore the outcomes of patients with and without para-aortic lymphadenectomy undergoing ...curative-intent radical hysterectomy for stage IA-IIA cervical cancer.
Institutional data were retrospectively reviewed to identify women undergoing curative-intent radical hysterectomy with concurrent lymphadenectomy for stage IA-IIA cervical carcinoma from 2004 to 2021. Any carcinoma histology was allowed. Clinical risk stratification was performed according to GOG 92 and GOG 109 protocols. Disease outcomes, patterns of recurrence, and survival were analyzed with Chi square, t-test, Kaplan-Meier, and Cox proportional hazards multivariable statistics.
300 patients were identified, 265 met inclusion criteria. Median follow up was 56 months. Pelvic lymphadenectomy (PLND) was performed in 71%, with the remainder undergoing combined para-aortic dissection (PPaLND). Baseline patient demographics and presence of clinical risk factors were well balanced between groups. PPaLND was more common in patients undergoing open surgery (OR 10.58, p <.0001), and tumors were larger in this group (2.96 vs 2.12 cm, p = .0002) and more likely non-squamous histology (OR 2.02, p = .017). Recurrence of disease was present in 13% of cases, with no difference between PLND and PPaLND regardless of histology. There were zero cases of isolated PaLN recurrence in either group. Neither progression free nor overall survival was different between groups. Prophylactic extended field radiation (EFRT) was not prescribed.
Omission of PaLN dissection, in the absence of suspicious nodes, did not decrease survival. There were no isolated PaLN recurrences after PLND alone.
•Omission of routine para-aortic lymphadenectomy did not worsen survival for surgically managed early stage cervical cancer.•Patients undergoing combined PPaLND had higher pre-operative risk factors.•There were no isolated PaLN recurrences in patients omitting PaLND.
Patients with cervical cancer who are diagnosed with venous thromboembolism (VTE) have worse outcomes compared to those not affected. There has yet to be a reliable method to predict or prevent VTE ...in cervical cancer patients. Our objective is to describe the incidence of VTE in patients with recurrent and metastatic (r/mCC) and determine risk factors that may predict VTE in this setting.
We performed an observational cohort study of 386 patients with r/mCC who received at least one line of systemic chemotherapy. We collected demographic, clinical, histologic data and Khorana scores for all patients. Inclusion and exclusion criteria were applied before analysis. Statistical analysis was performed using Pearson chi-square, Student's t-test, and Wilcoxon rank-sum.
232 patients were included for evaluation. Mean age was 49 years (range 20–83). The majority (167, 72%) of patients had squamous cell histology. 169 (72.8%) patients received treatment for recurrent disease and 63 (27.2%) for metastatic, stage IVB disease. 180 (78%) patients received prior radiation and 134 (58%) received bevacizumab. VTE was diagnosed in 89 (38%) patients. There were no statistically significant differences amongst clinical and pathologic characteristics between patients who developed VTE and those who did not. There was no significant association between BMI, Khorana score, radiation, bevacizumab, or immunotherapy and the development of VTE.
Approximately 40% of patients with r/mCC experienced a new VTE. There were no independent risk factors that could predict VTE in this population. Due to the overwhelmingly high incidence of VTE, prophylactic anticoagulation could be strongly considered in patients with r/mCC.
•Venous thromboembolisms (VTEs) are associated with increased morbidity and mortality in cervical cancer patients.•Almost 40% of patients with metastatic and recurrent cervical cancer were diagnosed with a VTE.•Current risk-stratification tools, alone and in combination with other known risk factors, could not predict VTE.•Thromboprophylaxis should be considered for patients with metastatic and recurrent cervical cancer.
Vulvar squamous cell carcinoma pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics ...remain ambiguous across studies. In this study, we present a retrospective cohort analysis of 36 patients with invasive vulvar squamous cell carcinoma where HPV status was determined using RNA in situ hybridization and PCR. Clinical annotation, p16 immunohistochemistry, PD-L1 immunohistochemistry, HPV16 circular E7 RNA detection, and RNA sequencing of the cases were performed. A combination of in situ hybridization and PCR identified 20 cases (55.6%) as HPV positive. HPV status did not impact overall survival (hazard ratio: 1.36, 95% confidence interval = 0.307–6.037, P = 0.6857) or progression-free survival (hazard ratio: 1.12, 95% confidence interval = 0.388–3.22, P = 0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n = 23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs, including several circular RNAs that have previously been implicated in the pathogenesis of other cancers.
Stage IVA cervical cancer is an uncommon diagnosis. The course of the disease and the complications of treatment are not well characterized. The goal of this study was to report treatment outcomes of ...patients with stage IVA cervical cancer.
A single institution retrospective review was carried out of all patients treated for stage IVA cervical cancer from January 2008 to July 2017. Patients were clinically staged using the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging criteria for cervical cancer. Inclusion criteria were patients with stage IVA cervical cancer of any histologic subtype, including patients with evidence of para-aortic lymph node involvement, treated at the institution during this time period. Overall survival and progression free survival were calculated using the Kaplan-Meyer method. Comparisons between survival were done using the Cox proportional hazards regression model and the log rank test.
We identified 25 patients with stage IVA cervical cancer. Mean age at diagnosis was 54 years (range 27-77). Squamous cell carcinoma was the histologic diagnosis in 24 of 25 patients (96%), with 1 case of small cell carcinoma (4%). 21 patients completed a full course of radiation. The median overall survival for patients who completed their treatment was 60 months (range 3-136), with a 2 year overall survival of 63%. The median progression free survival was 27 months (range 0-125), with a 2 year progression free survival of 40%. 11 of 25 patients (44%) developed fistulas during the course of their disease, and 55% of these were complex fistulas. 19 of 25 (76%) patients had a percutaneous nephrostomy for either hydronephrosis or diversion of vesicovaginal fistula. 111 unplanned admissions occurred among the 25 patients, and infections of the urinary tract was implicated in 46 (41%) of these. The cohort had a total of 92 emergency department visits, with pain control (36%) and medication refills (15%) being the most common presentations.
Patients with stage IVA cervical cancer may have substantial long term survival, although the sequelae of disease and treatment is associated with significant morbidity. Symptoms of fistula, percutaneous nephrostomy complications, and chronic pain present unique issues that require extensive supportive care.
PDF
