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.

Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer.

Although immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. We investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly available database, we found that the intratumoral expression of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which regenerates inactive glucocorticoids into active glucocorticoids, was associated with poor clinical outcome and correlated with immunosuppressive gene signatures in patients with renal cell carcinoma (RCC). HSD11B1 was mainly expressed in tumor-infiltrating immune myeloid cells as seen by immunohistochemistry in RCC patient samples. Using peripheral blood mononuclear cells from healthy donors or immune cells isolated from the tumor of RCC patients, we showed that the pharmacological inhibition of HSD11B1 improved the response to the immune checkpoint inhibitor anti-PD-1. In a subcutaneous mouse model of renal cancer, the combination of an HSD11B1 inhibitor with anti-PD-1 treatment increased the proportion of tumor-infiltrating dendritic cells. In an intrarenal mouse tumor model, HSD11B1 inhibition increased the survival of mice treated with anti-PD-1. In addition, inhibition of HSD11B1 sensitized renal tumors in mice to immunotherapy with resiquimod, a Toll-like receptor 7 agonist. Mechanistically, we demonstrated that HSD11B1 inhibition combined with resiquimod increased T cell-mediated cytotoxicity to tumor cells by stimulating the antigen-presenting capacity of dendritic cells. In conclusion, these results support the use of HSD11B1 inhibitors to improve the outcome of immunotherapy in renal cancer and highlight the role of the endogenous glucocorticoid metabolism in the efficacy of immunotherapy.

Practical guidelines of the EOTTD for pathological and genetic diagnosis of hydatidiform moles.

Hydatidiform moles are rare and thus most pathologists and geneticists have little experience with their diagnosis. It is important to promptly and correctly identify hydatidiform moles given that they are premalignant disorders associated with a risk of persistent gestational trophoblastic disease and gestational trophoblastic neoplasia. Improvement in diagnosis can be achieved with uniformization of diagnostic criteria and establishment of algorithms. To this aim, the Pathology and Genetics Working Party of the European Organisation for Treatment of Trophoblastic Diseases has developed guidelines that describe the pathological criteria and ancillary techniques that can be used in the differential diagnosis of hydatidiform moles. These guidelines are based on the best available evidence in the literature, professional experience and consensus of the experts' group involved in its development.

Clonal expansion of intra-epithelial T cells in breast cancer revealed by spatial transcriptomics.

The spatial distribution of tumor-infiltrating lymphocytes (TIL) predicts breast cancer outcome and response to systemic therapy, highlighting the importance of an intact tissue structure for characterizing tumors. Here, we present ST-FFPE, a spatial transcriptomics method for the analysis of formalin-fixed paraffin-embedded samples, which opens the possibility of interrogating archival tissue. The method involves extraction, exome capture and sequencing of RNA from different tumor compartments microdissected by laser-capture, and can be used to study the cellular composition of tumor microenvironment. Focusing on triple-negative breast cancer (TNBC), we characterized T cells, B cells, dendritic cells, fibroblasts and endothelial cells in both stromal and intra-epithelial compartments. We found a highly variable spatial distribution of immune cell subsets among tumors. This analysis revealed that the immune repertoires of intra-epithelial T and B cells were consistently less diverse and more clonal than those of stromal T and B cells. T-cell receptor (TCR) sequencing confirmed a reduced diversity and higher clonality of intra-epithelial T cells relative to the corresponding stromal T cells. Analysis of the top 10 dominant clonotypes in the two compartments showed a majority of shared but also some unique clonotypes both in stromal and intra-epithelial T cells. Hyperexpanded clonotypes were more abundant among intra-epithelial than stromal T cells. These findings validate the ST-FFPE method and suggest an accumulation of antigen-specific T cells within tumor core. Because ST-FFPE is applicable for analysis of previously collected tissue samples, it could be useful for rapid assessment of intratumoral cellular heterogeneity in multiple disease and treatment settings.

Third International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions).

The heterogeneous group of B3 lesions in the breast harbors lesions with different malignant potential and progression risk. As several studies about B3 lesions have been published since the last Consensus in 2018, the 3rd International Consensus Conference discussed the six most relevant B3 lesions (atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), classical lobular neoplasia (LN), radial scar (RS), papillary lesions (PL) without atypia, and phyllodes tumors (PT)) and made recommendations for diagnostic and therapeutic approaches. Following a presentation of current data of each B3 lesion, the international and interdisciplinary panel of 33 specialists and key opinion leaders voted on the recommendations for further management after core-needle biopsy (CNB) and vacuum-assisted biopsy (VAB). In case of B3 lesion diagnosis on CNB, OE was recommended in ADH and PT, whereas in the other B3 lesions, vacuum-assisted excision was considered an equivalent alternative to OE. In ADH, most panelists (76%) recommended an open excision (OE) after diagnosis on VAB, whereas observation after a complete VAB-removal on imaging was accepted by 34%. In LN, the majority of the panel (90%) preferred observation following complete VAB-removal. Results were similar in RS (82%), PL (100%), and FEA (100%). In benign PT, a slim majority (55%) also recommended an observation after a complete VAB-removal. VAB with subsequent active surveillance can replace an open surgical intervention for most B3 lesions (RS, FEA, PL, PT, and LN). Compared to previous recommendations, there is an increasing trend to a de-escalating strategy in classical LN. Due to the higher risk of upgrade into malignancy, OE remains the preferred approach after the diagnosis of ADH.

Relative Quantification of Proteins in Formalin-Fixed Paraffin-Embedded Breast Cancer Tissue Using Multiplexed Mass Spectrometry Assays.

The identification of clinically relevant biomarkers represents an important challenge in oncology. This problem can be addressed with biomarker discovery and verification studies performed directly in tumor samples using formalin-fixed paraffin-embedded (FFPE) tissues. However, reliably measuring proteins in FFPE samples remains challenging. Here, we demonstrate the use of liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM/MS) as an effective technique for such applications. An LC-MRM/MS method was developed to simultaneously quantify hundreds of peptides extracted from FFPE samples and was applied to the targeted measurement of 200 proteins in 48 triple-negative, 19 HER2-overexpressing, and 20 luminal A breast tumors. Quantitative information was obtained for 185 proteins, including known markers of breast cancer such as HER2, hormone receptors, Ki-67, or inflammation-related proteins. LC-MRM/MS results for these proteins matched immunohistochemistry or chromogenic in situ hybridization data. In addition, comparison of our results with data from the literature showed that several proteins representing potential biomarkers were identified as differentially expressed in triple-negative breast cancer samples. These results indicate that LC-MRM/MS assays can reliably measure large sets of proteins using the analysis of surrogate peptides extracted from FFPE samples. This approach allows to simultaneously quantify the expression of target proteins from various pathways in tumor samples. LC-MRM/MS is thus a powerful tool for the relative quantification of proteins in FFPE tissues and for biomarker discovery.

ABCD criteria to improve visual inspection with acetic acid (VIA) triage in HPV-positive women: a prospective study of diagnostic accuracy.

OBJECTIVES: A simple system for visual inspection with acetic acid assessment, named ABCD criteria, has been developed to increase accuracy for triaging of high-risk human papillomavirus (HPV)-positive women. This study aimed to determine the accuracy of ABCD criteria for the detection of histologically confirmed cervical intraepithelial neoplasia grade two or worse (CIN2+) in HPV-positive women living in a low-resource setting. DESIGN: Prospective study of diagnostic accuracy. SETTING: Cervical cancer screening programme based on a 3T-Approach (test, triage and treat) in the Health District of Dschang, West Cameroon. PARTICIPANTS: Asymptomatic non-pregnant women aged 30-49 years were eligible to participate. Exclusion criteria included history of CIN treatment, anogenital cancer or hysterectomy. A total of 1980 women were recruited (median age, 40 years; IQR 35-45 years), of whom 361 (18.4%) were HPV-positive and 340 (94.2%) completed the trial. INTERVENTIONS: HPV-positive women underwent a pelvic examination for visual assessment of the cervix according to ABCD criteria. The criteria comprised A for acetowhiteness, B for bleeding, C for colouring and D for diameter. The ABCD criteria results were codified as positive or negative and compared with histological analysis findings (reference standards). PRIMARY OUTCOME MEASURE: Diagnostic performance of ABCD criteria for CIN2+, defined as sensitivity, specificity, negative and positive predictive values. RESULTS: ABCD criteria had a sensitivity of 77.5% (95% CI 61.3% to 88.2%), specificity of 42.0% (95% CI 36.5% to 47.7%), positive predictive value of 15.1% (95% CI 10.8% to 20.8%), and negative predictive value of 93.3% (95% CI 87.6% to 96.5%) for detection of CIN2 +lesions. Most (86.7%) of the ABCD-positive women were treated on the same day. CONCLUSIONS: ABCD criteria can be used in the context of a single-visit approach and may be the preferred triage method for management of HPV-positive women in a low-income context. TRIAL REGISTRATION NUMBER: NCT03757299.

Substaging of pT1 Urothelial Bladder Carcinoma Predicts Tumor Progression and Overall Survival.

INTRODUCTION: Limitations in tumor staging and the heterogeneous natural evolution of pT1 urothelial bladder carcinoma (UBC) make the choice of treatment challenging. We evaluated if histopathological substaging (pT1a, pT1b, and pT1c) helps predict disease recurrence, progression, and overall survival following transurethral resection of the bladder (TURB). METHODS: We included 239 consecutive patients diagnosed with pT1 UBC at TURB in a single institution since 2001. Each sample was interpreted by our specialized uropathologists trained to subclassify pT1 stage. Three groups were distinguished according to the degree of invasion: T1a (up to the muscularis mucosae [MM]), T1b (into the MM), and T1c (beyond the MM). RESULTS: T1 substaging was possible in 217/239 (90%) patients. pT1a, b, and c occurred in 124 (57), 59 (27), and 34 (16%), respectively. The median follow-up was 3.1 years, with a cumulative recurrence rate of 52%, progression rate of 20%, and survival rate of 54%. Recurrence was not significantly associated with tumor substage (p = 0.61). However, the Kaplan-Meier survival analysis showed a significantly higher progression rate among T1b (31) and T1c (26%) tumors than T1a (13%) (log-rank test: p = 0.001) stages. In a multivariable model including gender, age, ASA score, smoking, tumor grade, and presence of carcinoma in situ, T1 substage was the single variable significantly associated with progression-free survival (HR 1.7, p = 0.005). Nineteen patients (9%) needed radical cystectomy; among them, 12/19 (63%) had an invasive tumor. Overall survival was significantly associated with tumor substaging (p = 0.001). CONCLUSION: Histopathological substaging of pT1 UBC is significantly associated with tumor progression and overall survival and therefore appears to be a useful prognostic tool to counsel patients about treatment options.

Pelvic splenosis mimicking a suspicious adnexal mass.

A 58-year-old asymptomatic woman was referred to our gynecologic oncology unit for the management of a left adnexal mass found during a routine gynecologic examination. Her personal history included an emergency splenectomy at the age of 4 years old, following traumatic splenic laceration after a car accident. The patient's work-up (including transvaginal ultrasound and MRI) confirmed a pelvic solid mass, which was reported as suspicious for malignancy and classified as Ovarian-Adnexal Reporting & Data System-MRI 5. An exploratory laparoscopy was performed, showing a reddish blue lesion located at the left broad ligament. Histologic analysis showed the presence of splenic tissue and normal adnexa. The postoperative follow-up was uneventful.Pelvic splenosis is a challenging diagnosis rarely made preoperatively due to concern for malignancy. In the presence of a pelvic mass, the collection of a detailed patient's history, including information about previous splenic rupture, might raise suspicion for pelvic splenosis.

Ovarian cancer with high-level focal ERBB2 amplification responds to trastuzumab and pertuzumab.

Epithelial ovarian cancer (EOC) is usually diagnosed at an advanced stage and significantly contributes to cancer mortality in women. Despite multimodal treatment associating chemotherapy and surgery, most patients ultimately progress and require palliative systemic therapy. In EOC, the efficacy of anti-HER2 agents is minimal even after selecting patients for HER2 expression. ERBB2 gene amplification is observed in 3-10% of patients, depending on the specific method of detection and cutoffs. We report the case of a young woman with a FIGO stage IV high-grade serous ovarian cancer with an amplification of ERBB2. She was treated with the association of trastuzumab - pertuzumab after two lines of standard treatment and presented an excellent long-lasting partial response after 36 months of treatment. The association of trastuzumab and pertuzumab, without chemotherapy, has not been previously tested in this context and could be more efficacious than monotherapy with either agent. In addition, the significant benefit observed in this case could be attributed to the presence of a high-level focal amplification that is relatively rare and probably more specific than an increase in HER2 expression. In conclusion, prospective trials of the trastuzumab and pertuzumab combination should be considered in an appropriately selected EOC patient population.

A cross-sectional study exploring triage of human papillomavirus (HPV)-positive women by visual assessment, manual and computer-interpreted cytology, and HPV-16/18-45 genotyping in Cameroon.

BACKGROUND: High-risk human papillomavirus (HPV)-positive women require triage to identify those at higher risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). We aimed to compare visual assessment of the cervix, manual cytology and automated cytology as triage tests to screen HPV-positive women, and to assess over-treatment rates after visual assessment and over-referral rates to colposcopy after cytology. METHODS: The present cross-sectional study is nested in a large prospective screening trial in Cameroon. Evaluations of the tests have been conducted individually and in combination with HPV-16/HPV-18/45 genotyping. For the evaluation of over-treatment and colposcopic over-referral, we simulated two screening scenarios: (1) one-visit scenario (test-triage-and-treatment); and (2) two-visit scenario (test-triage-and-colposcopy). RESULTS: 1582 women with a median age of 40 years (IQR 35-45) performed self-sampling for HPV testing, of which 294 (18.6%) were HPV-positive, and 12.2% had CIN2+. Sensitivities for CIN2+ detection were 77.1% for visual assessment, 80.0% for manual cytology, and 84.8% for automated cytology. Sensitivity of combined tests was higher compared with single tests. The highest sensitivity was obtained by the combination of genotyping and automated cytology (91.2%). In the one-visit scenario, the over-treatment rate was 83.9% in referred women, with a ratio of 6.2 treated women per CIN2+. In the two-visit scenario, the lowest over-referral rate would have been under manual cytology (45.0%), with a ratio of 1.8 referred women per CIN2+. Single and combined triage strategies by automated cytology gave rise to over-referral rates of 69.2% and 76.7%, respectively, and a ratio of 3.2 and 4.3 referred women per CIN2+, respectively. DISCUSSION: Triage of HPV-positive women using a combination of genotyping and automated cytology for CIN2+ detection may provide public benefits in low- and middle-income countries.

Gestational trophoblastic disease in Switzerland: retrospective study of the impact of a regional reference centre.

AIMS OF THE STUDY: The European Society of Medical Oncology (ESMO) recommends that countries should have reference centres to provide adequate diagnosis and treatment of gestational trophoblastic disease. A trophoblastic disease centre in the French-speaking part of Switzerland was inaugurated in 2009. The objectives of this study were to report the activity of the centre during the last 10 years and analyse gestational trophoblastic disease outcomes. METHODS: This was a retrospective study with data collected from all cases of gestational trophoblastic disease referred to the centre from 2009 to 2018. All histological specimens as well as data for treatment and follow-up of gestational trophoblastic disease and neoplasia were reviewed. Clinical features, including age, prognostic score and International Federation of Gynecology and Obstetrics (FIGO) stages (in the case of gestational trophoblastic neoplasia), human chorionic gonadotropin (hCG) follow-up, treatment and outcome were reported. RESULTS: The centre registered 354 patients, and these patients presented 156 cases of partial hydatidiform moles, 163 cases of complete hydatidiform moles and 14 cases of gestational trophoblastic neoplasia. During follow-up, 35 gestational trophoblastic neoplasms were diagnosed after hCG persistence. After pathology review, the overall agreement rates between our centre and a participating provider hospital was 82%. Methotrexate was the first line of single-agent chemotherapy for most patients, with resistance rates of 23%. Multi-agent chemotherapy was used as first-line treatment for five patients. None of the patients followed up by the centre died from gestational trophoblastic disease. CONCLUSIONS: This study reflects the activity of the Swiss trophoblastic disease centre from the French-speaking part of Switzerland created in 2009, and its role as local and national reference centre, in terms of global health, for women with gestational trophoblastic disease.

Immunologic Clearance of a BK Virus-associated Metastatic Renal Allograft Carcinoma.

BACKGROUND: Metastatic carcinoma of a renal allograft is a rare but life threatening event with a difficult clinical management. Recent reports suggested a potential role of BK polyomavirus (BKPyV) in the development of urologic tract malignancies in kidney transplant recipients. METHODS: We investigated a kidney-pancreas female recipient with an history of BKPyV nephritis who developed a rapidly progressive and widely metastatic donor-derived renal carcinoma 9 years after transplantation. RESULTS: Histology and fluorescence in situ hybridization analysis revealed a donor-derived (XY tumor cells) collecting (Bellini) duct carcinoma. The presence of BKPyV oncogenic large tumor antigen was identified in large amount within the kidney tumor and the bowel metastases. Whole genome sequencing of the tumor confirmed multiple genome BKPyV integrations. The transplanted kidney was removed, immunosuppression was withdrawn, and recombinant interleukin-2 (IL-2) was administered for 3 months, inducing a complete tumor clearance, with no evidence of disease at 6-year follow-up. The immunological profiling during IL-2 therapy revealed the presence of donor-specific T cells and expanded cytokine-producing bright natural killer cells but no donor-specific antibodies. Finally, we found persistently elevated anti-BK virus IgG titers and a specific anti-BKPyV T cell response. CONCLUSIONS: This investigation showed evidence for the potential oncogenic role of BKPyV in collecting duct carcinoma in renal allografts and demonstrated that immunosuppression withdrawal and IL-2 therapy can lead to an efficient antitumor cellular mediated rejection possibly via 3 distinct mechanisms including (1) host-versus-graft, (2) host-versus-tumor, and (3) anti-BKPyV responses.

Genomic Instability Is an Early Event in Aluminium-Induced Tumorigenesis.

Genomic instability is generally considered as a hallmark of tumorigenesis and a prerequisite condition for malignant transformation. Aluminium salts are suspected environmental carcinogens that transform mammary epithelial cells in vitro through unknown mechanisms. We report here that long-term culture in the presence of aluminium chloride (AlCl3) enables HC11 normal mouse mammary epithelial cells to form tumours and metastases when injected into the syngeneic and immunocompetent BALB/cByJ strain. We demonstrate that AlCl3 rapidly increases chromosomal structural abnormalities in mammary epithelial cells, while we failed to detect direct modulation of specific mRNA pathways. Our observations provide evidence that clastogenic activity-a well-recognized inducer of genomic instability-might account in part for the transforming abilities of aluminium in mammary epithelial cells.

Publisher Correction: Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Concordance of tumour characteristics and survival clustering among pairs of first-degree relatives with breast cancer.

BACKGROUND: Family history is a known risk factor for breast cancer, but its prognostic value and the prognostic value of tumour characteristics in relation to family history has not been clearly established. In addition, studies of intra-familial tumour characteristics and prognosis in population-based settings are very rare. Two previous studies have suggested that breast cancer prognosis clusters within families. However, both studies lack information on HER2 expression status, which is a strong prognostic factor and could contribute to the observed results. METHODS: We conducted a population-based study on 145 mother-daughter and sister-sister affected pairs using data extracted from the Geneva Cancer Registry. Histopathological characteristics were determined in archived tumour blocks by immunochemistry techniques. Breast cancer survival among family members was studied according to patient and tumour characteristics. RESULTS: No significant intra-familial agreement of pathological characteristic features was observed. We found that relatives of breast cancer patients experienced a much higher risk of breast cancer death compared to the general population. However, we did not find significant concordance in good and poor breast cancer-specific survival between pairs. The small number of family pairs and deaths from breast cancer may partly explain our results. CONCLUSIONS: Large-scale studies with accurate data on strong prognosticators are still needed to confirm the possibility of familial inheritance of breast cancer prognosis.  .

Sustained response to pembrolizumab without prior chemotherapy in high-grade serous ovarian carcinoma with CSMD3 mutation.

•Metastatic CSMD3 mutated HGSOC showed objective and sustained response to pembrolizumab.•The tumor was massively infiltrated by CD8+ T cells while PD-L1 TPS was at 10%.•CSMD3 mutated HGSOC showed up-regulation of CCL5 and CXCL9.