Tertiary prevention strategies for micrometastatic lymph node cervical cancer: A systematic review and a prototype of an adapted model of care.

PURPOSE: We found a need for balancing the application of clinical guidelines and tailored approaches to follow-up of cervical cancer (CC) patients in the lymph node micrometastatic (MICs) setting. This review aimed to determine the current knowledge of management of MIC-positive CC cases. METHODOLOGY: We addressed prognostic and risk of recurrence monitoring impacts associated with MIC+ cases. The electronic databases for literature and relevant articles were analysed. RESULTS: Fifteen studies, (4882 patients), were included in our systematic review. While the results show that MICs significantly worsen prognosis in early CC. A tertiary prevention algorithm for low volume lymph node disease may stratify follow-up according to the burden of nodal disease and provide data that helps improve follow-up performance. CONCLUSION: MICs worsen prognosis and should be managed as suggested by the algorithm. However, this algorithm must be externally validated. The clinical impact of isolated tumor cells (ITC) remains unclear.

Case report: lipoprotein apheresis reduces the risk of cardiovascular events and prolongs pregnancy in a woman with severely elevated lipoprotein(a), cardiovascular disease, and a high risk of preeclampsia.

Background: Preeclampsia is a common and serious pregnancy-induced disease, with potential severe maternal and fetal complications. Recently, an increased lipoprotein (a) (Lp[a]) concentration, an important factor in cardiovascular diseases (CVDs) pathogenesis, has been identified as a sensitive and specific marker of preeclampsia severity. Although lipoprotein apheresis (LA) is currently used in patients with hyperlipoproteinemia(a) and CVD, real-life data on its efficacy among pregnant women with an increased risk of preeclampsia are limited. Case presentation: We present the case of a pregnant woman with severely elevated Lp(a), two previous episodes of the acute coronary syndrome and multivessel coronary disease treated with long-term LA before pregnancy, and a high risk of preeclampsia (as assessed using combined test screening). An increased pulsatility index and early diastolic notch were observed on Doppler interrogation at 18 weeks' gestation. Biweekly LA therapy was re-initiated at 21 weeks' gestation. The LA safely removed 70% of the serum Lp(a) concentration and reduced low-density lipoprotein-cholesterol (LDL-C) levels by 60%. We also observed an improvement in her urine protein/creatinine ratio, a reduction in the pulsatility index, and a notch on Doppler interrogation. The pregnancy lasted until week 36, when severe preeclampsia prompted an emergency cesarean delivery. Conclusion: Pregnancy in women with elevated Lp(a), CVD, and a high risk of preeclampsia can present challenges in clinical management. Our case report indicates the benefits of LA in preventing atherosclerotic CVD progression during pregnancy, its potential influence on uteroplacental circulation, and prolongation of pregnancy for the best possible intrauterine fetus development. LA may be considered as a treatment option during pregnancy in such conditions. In addition, in pregnant women with CVD, we suggest screening using a combined test and measurement of Lp(a) as a marker of preeclampsia severity.

Prognostic value of ALK overexpression and molecular abnormalities in high-grade serous ovarian carcinoma.

BACKGROUND: ALK receptor tyrosine kinase (ALK) aberrations have an established role in pathogenesis of many neoplasms, but their clinical significance in high grade serous ovarian carcinoma (HGSOC) is unclear. OBJECTIVE: To analyse the frequency of ALK overexpression, molecular abnormalities of ALK, and their impact on the progression-free survival (PFS) and overall survival (OS) in HGSOC. METHODS: Protein expression was examined by immunohistochemistry (IHC) using three different clones of anti-ALK antibody. The presence of translocations was analysed using fluorescent in situ hybridization. Next-generation sequencing was used for studying the copy number variation, as well as point mutation and translocations involving other commonly rearranged genes. RESULTS: ALK overexpression was demonstrated in up to 52% of tumours, whereas ALK copy gains in 8.2%, with no clear impact on survival. ALK point mutations were identified in 13 tumours (8.9%), with 3 belonging to the class IV showing significantly better OS. A trend suggesting better PFS was also noticed in these cases. Additionally, three gene fusions were found: ERBB2-GRB7, PRKCA-BRCA1 and SND1-BRAF, none of which has been previously described in HGSOC. CONCLUSIONS: HGSOC harbouring activating ALK mutations might be associated with a better survival, while ALK overexpression and ALK amplification does not impact the prognosis.

Analysis of BRCA1 and BRCA2 alternative splicing in predisposition to ovarian cancer.

BACKGROUND: The mRNA splicing is regulated on multiple levels, resulting in the proper distribution of genes' transcripts in each cell and maintaining cell homeostasis. At the same time, the expression of alternative transcripts can change in response to underlying genetic variants, often missed during routine diagnostics. AIM: The main aim of this study was to define the frequency of aberrant splicing in BRCA1 and BRCA2 genes in blood RNA extracted from ovarian cancer patients who were previously found negative for the presence of pathogenic alterations in the 25 most commonly analysed ovarian cancer genes, including BRCA1 and BRCA2. MATERIAL AND METHODS: Frequency and spectrum of splicing alterations in BRCA1 and BRCA2 genes were analysed in blood RNA from 101 ovarian cancer patients and healthy controls (80 healthy women) using PCR followed by gel electrophoresis and Sanger sequencing. The expression of splicing events was examined using RT-qPCR. RESULTS: We did not identify any novel, potentially pathogenic splicing alterations. Nevertheless, we detected six naturally occurring transcripts, named BRCA1ΔE9-10, BRCA1ΔE11, BRCA1ΔE11q, and BRCA2ΔE3, BRCA2ΔE12 and BRCA2ΔE17-18 of which three (BRCA1ΔE11q, BRCA1ΔE11 and BRCA2ΔE3) were significantly higher expressed in the ovarian cancer cohort than in healthy controls (p ≤ 0.0001). CONCLUSIONS: This observation indicates that the upregulation of selected naturally occurring transcripts can be stimulated by non-genetic mechanisms and be a potential systemic response to disease progression and/or treatment. However, this hypothesis requires further examination.

The analysis of the therapeutic decisions in a patient with gigantic ovarian leiomyoma.

Complicated or unusual cases appear in clinical practice. It's important to know how to react when we face clinical difficulty. The more unusual the case, the longer or more demanding the decision-making process is. In this case we present a patient with a gigantic ovarian tumor whose diagnosis was overturned, and the choice of the surgical procedure changed, which makes this case a very educative example of why we should consult our patients, whenever we may encounter doubts or difficulties in a therapeutic process.

Protocol of Breast Cancer Prevention Model with Addition of Breast Ultrasound to Routine Gynecological Visits as a Chance for an Early Diagnosis and Treatment in 25 to 49-Year-Old Polish Females.

The low attendance rate for cancer screening tests in Poland is a major healthcare concern that requires specific analysis and the development of implementation recommendations for prevention, and both actions are likely to benefit culturally similar countries. Four female cancers account for approximately 20% of all cancer cases-breast cancer, cervical cancer, endometrial cancer, and ovarian cancer-suggesting that gynecologists have a significant preventative role. Of the four, breast cancer and cervical cancer are among the 10 most common malignant neoplasms globally, regardless of gender, occur only in women and are known to have effective screening measures. Our research aims to create a screening model that combines cervical cancer and breast cancer to maximize health outcomes for women at risk of both cancers. In the study protocol, we have created a model that maximizes benefits for patients with minimal additional costs to the health care system. To achieve the set goal, instead of regular clinical breast exams as recommended by the gynecological societies, we proposed an ultrasound examination, during which palpation may also be performed (in the absence of elastography). We present a scheme for such a protocol that takes into consideration all types of prevention in both cancers, and that emphasizes breast ultrasound as the most frequently missing element. Our study includes a discussion of the strengths and weaknesses of our strategy, and the crucial need for infrastructure and education for the successful implementation of the program. We conclude that our model merits consideration and discussion among health-care decision makers, as the screening changes we propose have significant potential benefits for the female population.

Hemoptysis during pregnancy: a comprehensive review of literature and an unprecedented case report of oropharyngeal carcinoma.

OBJECTIVES: Hemoptysis in pregnancy is a very rare finding causing diagnostic and therapeutic difficulties. The case report of hemoptysis by a 29 years old patient in the 31st week of pregnancy is presented and discussed along with the diagnostic process and treatment provided.Upon pharyngeal cancer occurrence in a pregnant patient a multidisciplinary medical team performed appropriate treatment along with delivery of a healthy newborn at term. Patients and fetal conditions and outcomes were analyzed and compared to available literature in this newly created literature review. MATERIAL AND METHODS: After MEDLINE database analysis using formula "hemoptysis" AND "pregnancy" more than 125 results were found published during the period 2002-2022. Almost 30 papers about hemoptysis were found and included for full analysis. CONCLUSIONS: The literature review offers a detailed description of previously reported incidents of hemoptysis in pregnancy to gain understanding of the etiology, differential diagnosis, available treatment and predicted future outcomes for both patient and fetus.

Incorporation of Tumor-Free Distance and Other Alternative Ultrasound Biomarkers into a Myometrial Invasion-Based Model Better Predicts Lymph Node Metastasis in Endometrial Cancer: Evidence and Future Prospects.

Myometrial invasion (MI) is a parameter currently used in transvaginal ultrasound (TVS) in endometrial cancer (EC) to determine local staging; however, without molecular diagnostics, it is insufficient for the selection of high-risk cases, i.e., those with a high risk of lymph node metastases (LNM). The study's objective was to answer the question of which TVS markers, or their combination, reflecting the molecular changes in EC, can improve the prediction of LNM. Methods: The TVS examination was performed on 116 consecutive EC patients included in this prospective study. The results from the final histopathology were a reference standard. Univariate and multivariate logistic models of analyzed TVS biomarkers (tumor [T] size, T area [AREA], T volume [SPE-VOL], MI, T-free distance to serosa [TFD], endo-myometrial irregularity, [EMIR], cervical stromal involvement, CSI) were evaluated to assess the relative accuracy of the possible LNM predictors., Spline functions were applied to avoid a potential bias in assuming linear relations between LNM and continuous predictors. Calculations were made in R using libraries splines, glmulti, and pROC. Results: LNM was found in 20 out of the 116 (17%) patients. In univariate analysis, only uMI, EMIR, uCSI and uTFD were significant predictors of LNM. The accuracy was 0.707 (AUC 0.684, 95% CI 0.568−0.801) for uMI (p < 0.01), 0.672 (AUC 0.664, 95% CI 0.547−0.781) for EMIR (p < 0.01), 0.776 (AUC 0.647, 95% CI 0.529−0.765) for uCSI (p < 0.01), and 0.638 (AUC 0.683, 95% CI 0.563−0.803) for uTFD (p < 0.05). The cut-off value for uTFD was 5.2 mm. However, AREA and VOL revealed a significant relationship by nonlinear analysis as well. Among all possible multivariate models, the one comprising interactions of splines of uTFD with uMI and splines of SPE-VOL with uCSI showed the most usefulness. Accuracy was 0.802 (AUC 0.791, 95% CI 0.673−0.91) Conclusions: A combination of uTFD for patients with uMI > 50%, and SPE-VOL for patients with uCSI, allows for the most accurate prediction of LNM in EC, rather than uMI alone.

Thousands of Women's Lives Depend on the Improvement of Poland's Cervical Cancer Screening and Prevention Education as Well as Better Networking Strategies Amongst Cervical Cancer Facilities.

Proper targeted cancer prophylaxis reduces the incidence of cancer in all forms; this includes cancers with significant progression potential and poor prognosis. Based on the assumption that one of the risk factors of cervical cancer is the avoidance of screening tests, we analyzed the current scenario of cervical cancer (CC) screening and recommendations in Poland (country with a well-off socioeconomic status). Based on the comprehensive literature review concerning documents of guidelines and recommendations of various bodies, including national ones, data on the implementation of CC screening in Poland, and different models for medium-to-high-income countries, we proposed how the CC screening strategy could be improved. Finally, the new strategy was further developed for those who are prone to not being screened. The proposal on how to improve the Polish CC screening program is the following: refinement of the public education on CC risk factors, popularization of CC screening incentives amongst the public, and improvement of networking strategies between CC screening facilities ("cervical screening clinical"), allowing screenings to be more efficient and rapid. We believe that, to enhance the future quality of life of those with rapid CC progression by catching the disease preemptively and limiting the sequelae of the disease, we have to improve education and access to medical services.

Perioperative and Long-Term Anatomical and Subjective Outcomes of Laparoscopic Pectopexy and Sacrospinous Ligament Suspension for POP-Q Stages II-IV Apical Prolapse.

The aim of this paper was to analyze perioperative and long-term outcomes in 114 women undergoing surgery for POP-Q ≥ 2 apical prolapse: sacrospinous ligament colpo/hysteropexy (SSLF/SSHP)­61; laparoscopic pectopexy (LP)­53. Validated questionnaires (PGI-I, ISI, #35 EPIQ, PFIQ-7, PFDI-20) were completed at baseline and follow-up. POP-Q stages II, III and IV were diagnosed in 1 (0.9%), 84 (73.7%) and 29 (25.4%) patients, respectively. Mean operative time and hospital stay were 151.8 ± 36.2 min/2.6 ± 1.1 days for LP and 69 ± 20.4 min (p < 0.001)/2.7 ± 1.0 days for SSLF. Severe intraoperative complications occurred in two (1.8%) patients. Mean follow-up was 26.9 ± 12 and 37.3 ± 17.5 months for LP and SSLF, respectively. At follow-up, significant improvement for all POP-Q points was observed in both groups (p < 0.001). Shortening of total vaginal length was found in both groups, but predominantly in SSLF patients (p = 0.01). The sensation of vaginal bulge (EPIQ) was reduced, and total PFDI-20 and PFIQ-7 scores improved (p < 0.04) in both groups. Subjective success was reported by 40 (75.5%) LP and 44 (72.1%) SSLF patients. ISI detected no deterioration in urinary incontinence. PGI-I, PFDI-20, #35 EPIQ, PFIQ-7 and ISI did not differ between the groups. In conclusion both, SSLF and LP for apical prolapse generate good anatomical and subjective outcomes, with protective effect on the anterior compartment observed for LP.

Colpocleisis as an obliterative surgery for pelvic organ prolapse: is it still a viable option in the twenty-first century? Narrative review.

INTRODUCTION AND HYPOTHESIS: The aims were to review the literature from the last two decades and analyze treatment efficacy and findings of the studies on colpocleisis. METHODS: A systematic search was conducted within the MEDLINE/PubMed and ClinicalTrials.gov databases, using the following keywords: pelvic organ prolapse (POP), colpocleisis, obliterative, and LeFort. All English full-text prospective and retrospective observational and interventional studies were included. Anatomical and subjective success, surgical techniques, concomitant procedures, complication rates, anesthesia methods, and decision regret were analyzed. RESULTS: A total of 237 papers were identified and 49 met the inclusion criteria. Mean patient age was 69.0 ± 8.0 to 84 ± 3.1. Over 90.2% of patients undergoing colpocleisis were diagnosed with POP stage ≥ 3. The follow-up ranged from 30 days to a median of 5 years. Anatomical success, defined as POP-Q stage ≤ 1 and no prolapse beyond the hymen, was achieved in 62.5 to 100% and 87.5 to 100% of all patients respectively. Subjective success ranged from 88% to 100%. Regret over the loss of coital ability ranged from 0% in many studies to 12.9%, general decision regret from 0% to 13.8%. After concomitant midurethral sling surgery, 86.8% to 94% of all patients were continent, with a 0-14% sling revision rate due to urinary retention. Urinary tract infection was the most common postoperative complication (4.3 to 9% confirmed with urine culture, 34.7% based on symptom definition). Bowel (0 to 2.7%) and urinary tract (0 to 9.1%) injuries were the consequences of concomitant procedures. The mortality rates were up to 1.3%. CONCLUSIONS: Colpocleisis is a heterogeneous procedure, characterized by high subjective and objective success, low coital ability regret, and a low risk of complications.

Challenges in lower limb lymphoedema assessment based on limb volume change: Lessons learnt from the SENTIX prospective multicentre study.

BACKGROUND: Lower limb lymphoedema (LLL) is the most disabling adverse effect of surgical staging of pelvic lymph nodes. However, the lack of standardisation of volumetric LLL assessment hinders direct comparison between the studies and makes LLL reporting unreliable. The aim of our study is to report outcomes from a prospective trial that have implications for LLL assessment standardisation. METHODS: In the prospective international multicentre trial SENTIX, a group of 150 patients with stage IA1-IB2 cervical cancer treated by uterine surgery with bilateral sentinel lymph node biopsy was prospectively evaluated by objective LLL assessment, based on limb volume change (LVC) using circumferrential limb measurements and subjective patient-reported swelling. The assessments were conducted in six-month periods over 24 months post-surgery. RESULTS: Patient LVC substantially fluctuated in both positive and negative directions, which were comparable in frequency up to ±14% change. Thirty-eight patients experienced persistent LVC increase >10% classified as LLL, with nine months median time to onset. Some 34.2% of cases experienced onset later than one year after the surgery. Thirty-three patients (22%) experienced transient oedema characterised as LVC >10%, which resolved without intervention between two consequent follow-up visits. No significant correlation between LVC >10% and a patient-reported swelling was observed. CONCLUSIONS: Given that we observed comparable fluctuations of the the lower-limb volumes after surgical treatment of cervical cancer in both positive and negative direction up to ±14%, the diagnostic threshold for LLL diagnosis based on LVC should be increased to >15% LVC. The distinction of transient oedema from persistent LLL requires repeated measurements. Also, as one-third of LLL cases are diagnosed >1-year post-surgery, a sufficient follow-up duration needs to be ensured. Patient-reported swelling correlated poorly with LVC and should only be used as an adjunct to objective LLL assessment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02494063.

Variant Identification in BARD1, PRDM9, RCC1, and RECQL in Patients with Ovarian Cancer by Targeted Next-generation Sequencing of DNA Pools.

Several ovarian cancer susceptibility genes have been discovered, but more are likely to exist. In this study, we aimed to analyze knowledge-based selected genes, that is, BARD1, PRDM9, RCC1, and RECQL, in which pathogenic germline variants have been reported in patients with breast and/or ovarian cancer. As deep sequencing of DNA samples remains costly, targeted next-generation sequencing of DNA pools was utilized to screen the exons of BARD1, PRDM9, RCC1, and RECQL in approximately 400 Polish ovarian cancer cases. A total of 25 pools of 16 samples (including several duplicated samples with known variants) were sequenced on the NovaSeq6000 and analyzed with SureCall (Agilent) application. The set of variants was filtrated to exclude spurious variants, and, subsequently, the identified rare genetic variants were validated using Sanger sequencing. No pathogenic mutation was found within the analyzed cohort of patients with ovarian cancer. Validation genotyping of filtered rare silent and missense variants revealed that the majority of them were true alterations, especially those with a higher mutation quality value. The high concordance (R2 = 0.95) of population allele frequency for 44 common SNPs in the European control population (gnomAD) and our experiment confirmed the reliability of pooled sequencing. Mutations in BARD1, PRDM9, RCC1, and RECQL do not contribute substantially to the risk of ovarian cancer. Pooled DNA sequencing is a cost-effective and reliable method for the initial screening of candidate genes; however, it still requires validation of identified rare variants. PREVENTION RELEVANCE: BARD1, PRDM9, RCC1, and RECQL are not high/moderate-risk ovarian cancer susceptibility genes. Pooled sequencing is a reliable and cost-effective method to detect rare variants in candidate genes.

Clinical impact of low-volume lymph node metastases in early-stage cervical cancer: A comprehensive meta-analysis.

OBJECTIVE: In order to define the clinical significance of low-volume metastasis, a comprehensive meta-analysis of published data and individual data obtained from articles mentioning micrometastases (MIC) and isolated tumor cells (ITC) in cervical cancer was performed, with a follow up of at least 3 years. METHODS: We performed a systematic literature review and meta-analysis, following Cochrane's review methods guide and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcome was the disease-free survival (DFS), and the secondary outcome was the overall survival (OS). The hazard ratio (HR) was taken as the measure of the association between the low-volume metastases (MIC+ITC and MIC alone) and DFS or OS; it quantified the hazard of an event in the MIC (+/- ITC) group compared to the hazard in node-negative (N0) patients. A random-effect meta-analysis model using the inverse variance method was selected for pooling. Forest plots were used to display the HRs and risk differences within individual trials and overall. RESULTS: Eleven articles were finally retained for the meta-analysis. In the analysis of DFS in patients with low-volume metastasis (MIC + ITC), the HR was increased to 2.60 (1.55-4.34) in the case of low-volume metastasis vs. N0. The presence of MICs had a negative prognostic impact, with an HR of 4.10 (2.71-6.20) compared to N0. Moreover, this impact was worse than that of MIC pooled with ITCs. Concerning OS, the meta-analysis shows an HR of 5.65 (2.81-11.39) in the case of low-volume metastases vs. N0. The presence of MICs alone had a negative effect, with an HR of 6.94 (2.56-18.81). CONCLUSIONS: In conclusion, the presence of MIC seems to be associated with a negative impact on both the DFS and OS and should be treated as MAC.

Ultrasound Measurement of Tumor-Free Distance from the Serosal Surface as the Alternative to Measuring the Depth of Myometrial Invasion in Predicting Lymph Node Metastases in Endometrial Cancer.

BACKGROUND: Ultrasonography's usefulness in endometrial cancer (EC) diagnosis consists in its roles in staging and prediction of metastasis. Ultrasound-measured tumor-free distance from the tumor to the uterine serosa (uTFD) is a promising marker for these diagnostic and prognostic variables. The aim of the study was to determine the usefulness of this biomarker in locoregional staging, and thus in the prediction of lymph node metastasis (LNM). METHODS: We conducted a single-institutional, prospective study on 116 consecutive patients with EC who underwent 2D transvaginal ultrasound examination. The uTFD marker was compared with the depth of ultrasound-measured myometrial invasion (uMI). Univariable and multivariable logit models were evaluated to assess the predictive power of the uTFD and uMI in regard to LNM. The reference standard was a final histopathology result. Survival was assessed by the Kaplan-Meier method. RESULTS: LNM was found in 17% of the patients (20/116). In the univariable analysis, uMI and uTFD were significant predictors of LNM. The accuracy was 70.7%, and the NPV was 92.68% (OR 4.746, 95% CI 1.710-13.174) for uMI (p = 0.002), and they were 63.8% and 89.02% (OR 0.842, 95% CI 0.736-0.963), respectively, for uTFD (p = 0.01). The cutoff value for uTFD in the prediction of LNM was 5.2 mm. The association between absence of LNM and biomarker values of uMI < 1/2 and uTFD ≥ 5.2 mm was greater than that between the presence of metastases and uMI > 1/2 and uTFD values <5.2 mm. In the multivariable analysis, the accuracy of the uMI-uTFD model was 74%, and its NPV was 90.24% (p = non-significant). Neither uMI nor uTFD were surrogates for overall and recurrence-free survivals in endometrial cancer. CONCLUSIONS: Both uMI and uTFD, either alone or in combination, were valuable tools for gaining additional preoperative information on expected lymph node status. Negative lymph nodes status was better described by ultrasound biomarkers than a positive status. It was easier to use the uTFD rather than the uMI measurement as a biomarker of EC invasion, and the former still maintained a similar predictive value for lymph node metastases to the latter at diagnosis.