H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours.

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

Window of opportunity with PD1 blockade before chemoradiotherapy for an advanced stage clear cell carcinoma of the cervix.

Clear cell carcinoma is a rare and very aggressive subset of cervical cancer, with poor outcome if diagnosed at advanced stage. There are few data available on the optimal management of this histotype, and treatment recommendations that include surgery and chemoradiotherapy, are essentially based on those for squamous cell carcinoma. Here we report the case of a young patient newly diagnosed with advanced stage (FIGO IIB) clear cell carcinoma of the uterine cervix who received a window of opportunity one injection of nivolumab followed by standard chemoradiotherapy. She showed a persistent complete remission after 28 months of follow-up, but developed hypothyroidism, as a consequence of immunotherapy, and required lifelong thyroid hormone replacement.

Knowledge of cytology results affects the performance of colposcopy: a crossover study.

OBJECTIVE: To determine whether knowledge of cytology affects the colposcopist's diagnostic accuracy in the identification of cervical intraepithelial neoplasia grade 2 and worse (≥ CIN2). METHOD: In this cross-over study, healthcare professionals interpreted colposcopy images from 80 patient cases with known histological diagnoses. For each case, 2 images taken with a colposcope were provided (native and after acetic acid application). Inclusion criteria consisted of women with a transformation zone type 1 or 2, who had both a cytological and histological diagnosis. Cases were distributed across two online surveys, one including and one omitting the cytology. A wash-out period of six weeks between surveys was implemented. Colposcopists were asked to give their diagnosis for each case as < CIN2 or ≥ CIN2 on both assessments. Statistical analysis was conducted to compare the two interpretations. RESULTS: Knowledge of cytology significantly improved the sensitivity when interpreting colposcopic images, from 51.1% [95%CI: 39.3 to 62.8] to 63.7% [95%CI: 52.1 to 73.9] and improved the specificity from 63.5% [95%CI: 52.3 to 73.5] to 76.6% [95%CI: 67.2 to 84.0]. Sensitivity was higher by 38.6% when a high-grade cytology (ASC-H, HSIL, AGC) was communicated compared to a low-grade cytology (inflammation, ASC-US, LSIL). Specificity was higher by 31% when a low-grade cytology was communicated compared to a high-grade. CONCLUSIONS: Our data suggests that knowledge of cytology increases sensitivity and specificity for diagnosis of ≥ CIN2 lesions at colposcopy. Association between cytology and histology may have contributed to the findings.

Statement of the AGO Kommission Ovar, AGO Study Group, NOGGO, AGO Austria, Swiss AGO, BGOG, CEEGOG, GEICO, and SFOG regarding the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in epithelial ovarian cancer.

An international joint statement about the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer was published in 2016, warning about the uncritical use of HIPEC outside controlled studies. This statement has now been updated after the most recent literature was reviewed by the participating study groups and societies. HIPEC became a treatment option in patients with advanced colon cancer after positive results of a randomized trial comparing surgery and HIPEC versus palliative treatment alone. Although this trial did not compare the added value of HIPEC to surgery alone, HIPEC for the treatment of peritoneal metastases was in the subsequent years generalized to many other cancer types associated with peritoneal carcinomatosis including epithelial ovarian cancer (EOC). In the meantime, new evidence from prospective randomized trials specifically for EOC-patients emerged, with however contradicting results and several quality aspects that made the interpretation of their findings critical. Moreover, three additional trials in colorectal cancer failed to confirm the previously presumed survival benefit through the implementation of HIPEC in peritoneally disseminated colorectal cancers. Based on a still unclear and inconsistent landscape, the authors conclude that HIPEC should remain within the remit of clinical trials for EOC-patients. Available evidence is not yet sufficient to justify its broad endorsement into the routine clinical practice.

Gastric-type adenocarcinoma of the endocervix: Potentially overcoming resistant behavior with surgery.

Objective: Gastric-type adenocarcinoma of the endocervix (GAS) is a rare form of human papillomavirus-independent cervical cancer commonly described as an insidious disease bearing a poor prognosis. Based on scarce data, uncertainty persists pertaining to its oncologic management. Method: All cases of well-differentiated GAS treated at our institution from 2010 to 2021 were reviewed. Clinical characteristics, diagnostic tests results and oncologic outcomes were recorded and analyzed. Kaplan-Meier curves and log rank test were performed to compare survival curves between patients with tumors confined to the cervix (group 1: up to stage IB3) versus locally advanced or metastatic (group 2: stages II to IV). Results: Cervical cytologies and biopsies yielded low detection rates (38 and 42% respectively) leading to 87% of patients with locally advanced or metastatic disease at diagnosis. Median overall survival (OS) was 40.0 ± 15.9 months with a clear dichotomy in survival when comparing patients with disease confined to the cervix to those with higher stages (respectively 59.0 vs 12.0 months, p = 0.047). None of the 5 patients initially managed with concurrent chemoradiotherapy (CCRT) responded to treatment but fortunately 3 of the latter achieved remission after surgery. Conclusion: Well-differentiated GAS did not show favorable response to chemotherapy and radiation. Surgical resection seems to be a cornerstone in the management of this disease, as all patients who achieved remission were treated with surgery, either upfront or after suboptimal response to CCRT. We suggest considering aggressive upfront surgery when feasible. If CCRT is selected to avoid upfront exenterative procedures, rapid evaluation of tumor response is recommended.

Nab-PIPAC: a phase IB study protocol of intraperitoneal cisplatin and nab-paclitaxel administered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of advanced malignancies confined to the peritoneal cavity.

INTRODUCTION: Intraperitoneal dissemination is a major problem resulting in very poor prognosis and a rapid marked deterioration in the quality of life of patients. Pressurised intraperitoneal aerosol chemotherapy (PIPAC) is an emergent laparoscopic procedure aiming to maximise local efficacy and to reduce systemic side effects. METHODS AND ANALYSIS: Nab-PIPAC, a bicentre open-label phase IB, aims to evaluate safety of nab-paclitaxel and cisplatin association using in patients with peritoneal carcinomatosis (PC) of gastric, pancreatic or ovarian origin as ≥1 prior line of systemic therapy. Using a 3+3 design, sequential intraperitoneal laparoscopic application of nab-paclitaxel (7.5, 15, 25, 37.5, 52.5 and 70 mg/m2) and cisplatin (10.5 mg/m2) through a nebuliser to a high-pressure injector at ambient temperature with a maximal upstream pressure of 300 psi. Treatment maintained for 30 min at a pressure of 12 mm Hg and repeated4-6 weeks intervals for three courses total.A total of 6-36 patients are expected, accrual is ongoing. Results are expected in 2024.The primary objective of Nab-PIPAC trial is to assess tolerability and safety of nab-paclitaxel and cisplatin combination administered intraperitoneally by PIPAC in patients with PC of gastric, pancreatic or ovarian origin. This study will determine maximum tolerated dose and provide pharmacokinetic data. ETHIC AND DISSEMINATION: Ethical approval was obtained from the ethical committees of Geneva and Vaud (CCER-2018-01327). The study findings will be published in an open-access, peer-reviewed journal and presented at relevant conferences and research meetings. TRIAL REGISTRATION NUMBER: NCT04000906.

[Intraperitoneal therapy for carcinomatosis in ovarian cancer: proposed treatment algorithm]. / Traitements intrapéritonéaux de la carcinose ovarienne : proposition d'algorithmes décisionnels.

Ovarian cancer is the first cause of death by gynecological cancer. Most of the patients are diagnosed with peritoneal carcinomatosis that represents a therapeutic challenge. Its management implies maximal cytoreductive surgery with survival benefit. Over the last three decades, several strategies of intra-peritoneal chemotherapy have been investigated. This includes intra-peritoneal adjuvant chemotherapy that is used mainly in North America, hyperthermic intraperitoneal chemotherapy (HIPEC) and more recently pressurized intraperitoneal aerosol chemotherapy (PIPAC). In the current article, we review the evidence in favor of each therapeutic approach, and we propose treatment algorithms depending on the clinical situation of ovarian cancer patients: upfront, platinum-sensitive and platinum-resistant relapse.

Le cancer de l'ovaire est la première cause de décès par cancer gynécologique. La plupart des patientes sont diagnostiquées au stade de carcinose péritonéale qui représente un défi thérapeutique. Sa prise en charge chirurgicale implique une cytoréduction maximaliste. Au cours des 30 dernières années, plusieurs stratégies de chimiothérapie intrapéritonéale ont été testées afin d'améliorer le contrôle de la carcinose péritonéale. Il s'agit des chimiothérapies intrapéritonéale adjuvante utilisée surtout en Amérique du Nord, hyperthermique intrapéritonéale (CHIP) et intrapéritonéale pressurisée en aérosols (PIPAC). Dans cet article, nous reprenons les données de la littérature sur chacune de ces trois approches thérapeutiques et proposons des algorithmes décisionnels selon la situation clinique des patientes traitées pour un cancer de l'ovaire : au diagnostic, récidive platine-sensible et platine-résistante.

Study protocol for a two-site clinical trial to validate a smartphone-based artificial intelligence classifier identifying cervical precancer and cancer in HPV-positive women in Cameroon.

INTRODUCTION: Cervical cancer remains a major public health challenge in low- and middle-income countries (LMICs) due to financial and logistical issues. WHO recommendation for cervical cancer screening in LMICs includes HPV testing as primary screening followed by visual inspection with acetic acid (VIA) and treatment. However, VIA is a subjective procedure dependent on the healthcare provider's experience. Its accuracy can be improved by computer-aided detection techniques. Our aim is to assess the performance of a smartphone-based Automated VIA Classifier (AVC) relying on Artificial Intelligence to discriminate precancerous and cancerous lesions from normal cervical tissue. METHODS: The AVC study will be nested in an ongoing cervical cancer screening program called "3T-study" (for Test, Triage and Treat), including HPV self-sampling followed by VIA triage and treatment if needed. After application of acetic acid on the cervix, precancerous and cancerous cells whiten more rapidly than non-cancerous ones and their whiteness persists stronger overtime. The AVC relies on this key feature to determine whether the cervix is suspect for precancer or cancer. In order to train and validate the AVC, 6000 women aged 30 to 49 years meeting the inclusion criteria will be recruited on a voluntary basis, with an estimated 100 CIN2+, calculated using a confidence level of 95% and an estimated sensitivity of 90% +/-7% precision on either side. Diagnostic test performance of AVC test and two current standard tests (VIA and cytology) used routinely for triage will be evaluated and compared. Histopathological examination will serve as reference standard. Participants' and providers' acceptability of the technology will also be assessed. The study protocol was registered under ClinicalTrials.gov (number NCT04859530). EXPECTED RESULTS: The study will determine whether AVC test can be an effective method for cervical cancer screening in LMICs.

Using Dynamic Features for Automatic Cervical Precancer Detection.

Cervical cancer remains a major public health concern in developing countries due to financial and human resource constraints. Visual inspection with acetic acid (VIA) of the cervix was widely promoted and routinely used as a low-cost primary screening test in low- and middle-income countries. It can be performed by a variety of health workers and the result is immediate. VIA provides a transient whitening effect which appears and disappears differently in precancerous and cancerous lesions, as compared to benign conditions. Colposcopes are often used during VIA to magnify the view of the cervix and allow clinicians to visually assess it. However, this assessment is generally subjective and unreliable even for experienced clinicians. Computer-aided techniques may improve the accuracy of VIA diagnosis and be an important determinant in the promotion of cervical cancer screening. This work proposes a smartphone-based solution that automatically detects cervical precancer from the dynamic features extracted from videos taken during VIA. The proposed solution achieves a sensitivity and specificity of 0.9 and 0.87 respectively, and could be a solution for screening in countries that suffer from the lack of expensive tools such as colposcopes and well-trained clinicians.

Laparoscopic Management of Giant Ovarian Cysts Using the Alexis Laparoscopic System®: A Case Series.

Objective: The aim of this study was to review the characteristics of patients who underwent laparoscopic removal of giant ovarian cysts using the Alexis Laparoscopic System® and confirm the safety and feasibility of this technique. Method: We conducted a retrospective review of data of women undergoing the procedure from March 2014 to February 2019. Inclusion criteria were ovarian cysts of at least 15 cm. Exclusion criteria were the presence of solid components and suspicion of neoplasia on imaging. Results: Six patients were included in the series. Median size of the cysts at imaging was 22.8 cm (range 15-30 cm), while median volume was 5.9 L (range 1.9-15.6 L). Mean age of operated women was 59 years (range 21-88 years). All patients underwent exclusive laparoscopic management except one patient who underwent a conversion into midline laparotomy. The size of the skin incision initially performed to puncture the cyst ranged from 2.5 to 4 cm. On final pathological reports, two cysts were mucinous cystadenomas, and four were serous cystadenomas. There was no epithelial ovarian cancer or borderline tumor in any of the specimen operated. Conclusion: Laparoscopic management of giant ovarian cysts using the Alexis Laparoscopic System® is safe and feasible in well-selected cases. Midline laparotomy can thus be avoided, decreasing the risk of post-operative complications and increasing quality of life of patients.

User perception of endocervical sampling: A randomized comparison of endocervical evaluation with the curette vs cytobrush.

OBJECTIVES: To evaluate whether the endocervical brush (ECB) is better accepted by patients and health care providers for endocervical evaluation when compared to the endocervical curette (ECC), without a decrease in the quality of sampling. METHODS: Two hundred patients with cervical dysplasia were randomized at the colposcopy clinic of the University Hospital of Geneva into two groups according to technique. Patients and physicians' preference regarding the technique as well as the quality of samples were assessed. ECB samples were analyzed using both cytological (cell block) and histologic analysis, while ECC samples were analyzed using standard histologic analysis. RESULTS: Of the 200 patients, 89 were randomized to ECC, 101 to ECB and 10 were excluded due to incomplete information or cervical stenosis. Physicians preferred ECB against ECC, classifying it more frequently as an easy technique (94.1% vs.61.4%, p<0.001). Physicians more frequently evaluated the ECB as little or not uncomfortable for patients (28.7% vs.10.2%, p<0.001), though patients themselves didn't express a preference for either technique. From a quality standpoint, the brush allowed for a better quality of samples, with a lower rate of inadequate samples (2.0% vs 14.3%, p = 0.002) and greater amount of material. CONCLUSION: Endocervical sampling using ECB seems to be easier to perform and provides better quality samples. ECB can therefore be an acceptable alternative to ECC in standard practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT01435590.

A Smartphone-Based Approach for Triage of Human Papillomavirus-Positive Sub-Saharan African Women: A Prospective Study.

BACKGROUND: Sub-Saharan African countries are marked by a high incidence of cervical cancer. Madagascar ranks 11th among the countries with the highest cervical cancer incidence worldwide. OBJECTIVE: The aim of the study was to evaluate the performances of digital smartphone-based visual inspection with acetic acid (D-VIA) and Lugol's iodine (D-VILI) for diagnosing cervical precancer and cancer. METHODS: Human papillomavirus (HPV)-positive women recruited through a cervical screening campaign had D-VIA and D-VILI examinations with endocervical curettage (ECC) and cervical biopsy. Three images were captured for each woman (native, D-VIA, D-VILI) using a smartphone camera. The images were randomly coded and distributed on 2 online databases (Google Forms). The D-VIA form included native and D-VIA images, and the D-VILI form included native and D-VILI images. Pathological cases were defined as cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Physicians rated the images as non-pathological or pathological. Using the ECC and cervical biopsy results as references, the sensitivity and specificity of D-VIA and D-VILI examinations for each and all physicians were calculated. RESULTS: Altogether, 15 clinicians assessed 240 images. Sensitivity was higher for the D-VIA interpretations (94.1%; 95% CI 81.6-98.3) than for the D-VILI interpretations (78.8%; 95% CI 54.1-92.1; P=.009). In contrast, the specificity was higher for the D-VILI interpretations (56.4%; 95% CI 38.3-72.9) than for the D-VIA interpretations (50.4%; 95% CI 35.9-64.8; P=.005). CONCLUSION: Smartphone-based image for triage of HPV-positive women is more accurate for detecting CIN2+ lesions with D-VIA than D-VILI, although with a small loss of specificity.

Is imaging relevant for treatment choice in early stage cervical uterine cancer?

BACKGROUND: Improvement in the selection of patients with early cervical cancer eligible for different therapeutic options is expected from imaging. OBJECTIVE: We examined key tumoral features such as tumor diameter cut-off values of 2 cm or 4 cm in largest dimension, distance between tumor and internal os, outer third stromal cervical invasion, parametrial invasion and lymph node invasion. SEARCH STRATEGY: We conducted a literature search to identify all relevant studies based on imaging that evaluated these parameters. SELECTION CRITERIA: Articles were only considered when data of imaging modalities were compared with histopathological findings of the surgical specimens, considered as the gold standard. DATA COLLECTION AND ANALYSIS: We examined series that included more than 30 patients with primary untreated biopsy-confirmed cervical cancer. When numerous articles were obtained for one investigational modality, only series that included more than fifty patients were taken into account. MAIN RESULTS: Data is lacking for the diagnostic value of imaging for assessing tumor diameter cut-off values of 2 cm or 4 cm, and distance between tumor and internal os. There is a high negative predictive value of MRI for complete stromal invasion. Accurate assessment of lymph node status in patients with early cervical cancer is still lacking. PET-CT role is promising, but the diagnostic value of normal-sized hypermetabolic lymph nodes needs further investigation. CONCLUSION: Based on imaging, accurate selection of patients for treatment choice is still lacking in patients with early cervical cancer.

Non-invasive modalities for predicting lymph node spread in early stage endometrial cancer?

BACKGROUND: Lymph node status in EC determines the staging and has important prognostic and therapeutic implications. OBJECTIVES: We have examined the diagnostic value of preoperative and intraoperative non-invasive methods to determine the lymph node status in endometrial cancer, or, indirectly, for identification of patients at increased risk of lymph node involvement. SEARCH STRATEGY: We conducted a literature search to identify all relevant reports that evaluated lymph node spread in EC. SELECTION CRITERIA: Articles were only considered when data of investigational modalities were compared with histopathological findings of the surgical specimens, considered as the gold standard. DATA COLLECTION AND ANALYSIS: When numerous relevant articles were identified for one investigational modality, only series including more than 50 patients were considered. MAIN RESULTS: Sensitivity of CT and MRI for diagnosis metastatic lymph node is limited. TVS performs as well as MRI in predicting deep myometrial invasion. It is unclear whether intraoperative gross visual examination and frozen section perform better than preoperative methods to predict deep myometrial invasion. There is a limited sensitivity of intraoperative frozen section for predicting poorly differentiated EC. CONCLUSION: Accurate non-invasive assessment of lymph node status in patients with EC remains challenging. SYNOPSIS: Despite imaging advances in the past 20 years, accurate non-invasive assessment of lymph node status in patients with EC remains challenging.

Early-stage cervical cancer: is surgery better than radiotherapy?

Patients with early-stage cervical cancer may be treated appropriately with either radical surgery or radiation therapy. As most patients will be cured of their disease, side-effects of therapy and quality of life become of great importance. Individualization of treatment to reduce therapy-associated morbidity should be the main goal in cervical cancer management. Recent developments in surgical techniques, such as laparoscopy, nerve-sparing radical hysterectomy, sentinel lymph node biopsy, trachelectomy and 'less radical' hysterectomy, have contributed to reduce the morbidity of the surgical treatment. The use of postoperative radiotherapy or chemoradiation leads to more pronounced side effects than after either surgery or irradiation alone. Therefore, prognostic factors should be used to select patients for either surgery or radiotherapy alone to minimize the increased toxicities associated with the combination. The objectives of this review are to discuss the evidence supporting radical surgery, 'less radical' surgery and radiotherapy with regard to complication rate and quality of life.

Magnetic resonance imaging to identify risk of lymph node metastasis in patients with endometrial cancer.

OBJECTIVE: To assess the value of magnetic resonance imaging (MRI) to identify endometrial cancer patients at risk of lymph node metastasis. METHODS: Retrospective review of data from 108 patients with clinical stage I endometrial cancer who underwent preoperative MRI and were treated surgically. Patients at risk of lymph node metastasis were defined as those who had more than 50% myometrial infiltration or cervical invasion. Preoperative MRI reports were compared with final pathologic results. RESULTS: The mean age of the patients was 69.5 years and most patients had endometrioid cancer. On final pathologic analysis, 59 patients had deep myometrial infiltration or cervical invasion. For diagnosis of deep myometrial infiltration, cervical invasion, or both, MRI sensitivity and specificity were 56% and 85%; 47% and 83%; and 67% and 77%, respectively. CONCLUSION: MRI has limited value in identifying patients with endometrial cancer who are at risk of lymph node metastasis. Minimally invasive laparoscopic lymph node staging should be undertaken when it is feasible.