Potential competing risk of death in older high-risk endometrial carcinoma patients: Results from a multicentric retrospective cohort.

INTRODUCTION: Adjuvant therapeutic decisions in older endometrial carcinoma (EC) patients are challenged by a balance between more frequent aggressive EC and comorbidities. We assessed whether EC and comorbidities are competing or cumulative risks in older EC patients. METHODS: All consecutive patients treated for FIGO stage I-IV EC in two University Hospitals in Paris between 2010 and 2017 were retrospectively included. Patients were categorized as: <70 years (y), >70y without comorbidity (fit), and > 70y with a Charlson comorbidity index>3 (comorbid). Association between high-risk EC (2021-ESGO-ETRO-ESP) or comorbidity, and disease-specific-survival (DSS), was evaluated using Cox model (estimation of cause-specific hazard ratio (CSHR), and Fine-Gray model (subdistribution HR) to account for competing events (death unrelated with EC). RESULTS: Overall, 253 patients were included (median age = 67y, IQR[59-77], median follow-up = 61.5 months, [44.4-76.8]). Among them, 109 (43%) were categorized at high-risk (proportion independent of age), including 67 (26%) who had TP53-mutated tumors. Comorbidity and high-risk group were both associated with all-cause mortality (HR = 4.09, 95%CI[2.29; 7.32] and HR = 3.21, 95%CI [1.69; 6.09], respectively). By multivariate analysis, patients with high-risk EC exhibited poorer DSS, regardless of age/comorbidity (Adjusted-CSHR = 6.62, 95%CI[2.53;17.3]; adjusted-SHR = 6.62 95%CI[2.50;17.5]). Patients>70y-comorbid with high-risk EC had 5-years cumulative incidences of EC-related and EC-unrelated death of 29% and 19%, respectively. In patients <70y, 5-years cumulative incidence of EC-related and EC-unrelated death were 25% and < 1% (one event), respectively. CONCLUSION: High-risk EC patients are exposed to poorer DSS regardless of age/comorbidities, comorbidities and cancer being two cumulative rather than competing risks. Our results suggest that age/comorbidity alone should not lead to underestimate EC-specific survival.

Diagnostic Algorithm to Differentiate Benign Atypical Leiomyomas from Malignant Uterine Sarcomas with Diffusion-weighted MRI.

Background Improving the differentiation of uterine sarcomas from atypical leiomyomas remains a clinical challenge and is needed to avoid inappropriate surgery. Purpose To develop a diagnostic algorithm including diffusion-weighted MRI criteria to differentiate malignant uterine sarcomas from benign atypical leiomyomas. Materials and Methods This case-control retrospective study identified women with an atypical uterine mass at MRI between January 2000 and April 2017, with surgery or MRI follow-up after 1 year or longer. A diagnostic algorithm including T2-weighted MRI and diffusion-weighted imaging (DWI) signal and apparent diffusion coefficient (ADC) values was developed to predict for sarcoma. The training set consisted of 51 sarcomas and 105 leiomyomas. Two external validation sets were used to evaluate interreader reproducibility (16 sarcomas; 26 leiomyomas) and impact of reader experience (29 sarcomas; 30 leiomyomas). Wilson confidence intervals (CIs) were calculated for sensitivity and specificity. Results Evaluated were 156 women (median age, 50 years; interquartile range, 44-63 years). Predictive MRI criteria for malignancy were enlarged lymph nodes or peritoneal implants, high DWI signal greater than that in endometrium, and ADC less than or equal to 0.905 × 10-3 mm2/sec. Conversely, a global or focal area of low T2 signal intensity and a low or an intermediate DWI signal less than that in endometrium or lymph nodes allowed readers to confidently diagnose as benign a uterine mass demonstrating one or more of these signs (P < .001) in 100% cases in all three data sets. The sensitivities and specificities of the algorithm for diagnosis of malignancy were 98% (50 of 51 masses; 95% CI: 90%, 100%) and 94% (99 of 105 masses; 95% CI: 88%, 98%) in the training set; 88% (14 of 16 masses; 95% CI: 64%, 97%) and 100% (26 of 26 masses; 95% CI: 87%, 100%) in the validation set; and 83% (24 of 29 masses; 95% CI: 65%, 92%) and 97% (29 of 30 masses; 95% CI: 83%, 99%) for the less experienced reader, respectively. Conclusion A diagnostic algorithm with predictive features including lymphadenopathy, high diffusion-weighted imaging signal with reference to endometrium, and low apparent diffusion coefficient enabled differentiation of malignant sarcomas from atypical leiomyomas, and it may assist inexperienced readers. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Méndez in this issue.

Sustained response to vemurafenib in a low grade serous ovarian cancer with a BRAF V600E mutation.

Low-grade serous ovarian adenocarcinomas (LGSOC) make up approximately 10 % of serous ovarian carcinomas. While rarely aggressive, this slow-growing tumor is well known to respond poorly to chemotherapy. Specific treatments for this ovarian subtype are lacking, with the same global approaches used for high grade cases being applied for LGSOC patients. LGSOCs have been reported to have a specific genetic profile, with notable implication of the MAPK pathway. This has opened up opportunities for novel therapeutic strategies, with in particular the use of targeted therapies. We report here the case of a heavily pretreated unresectable BRAF p.V600E-mutated LGSOC, which we treated vemurafenib, a BRAF inhibitor specific for V600E mutations. We saw impressive efficacy, with a long-term partial response along with CA125 reductions and symptom relief. Although this mutation is present in LGSOC at very a low incidence, we recommend routine testing for BRAF and other targetable mutations in this patient population, along with further evaluation in the increasingly popular basket trial approach.

Value of three-dimensional contrast-enhanced power Doppler ultrasound for characterizing adnexal masses.

AIMS: The aim of this study was to assess the diagnostic performance of 3-D contrast-enhanced power Doppler ultrasonography (3-D CEPDUS) for differentiating benign and malignant adnexal masses. MATERIAL AND METHODS: Consecutive patients with adnexal masses were included prospectively and underwent 2-D ultrasonography and 3-D CEPDUS in a tertiary centre in Paris, France. The main outcome measure was the diagnostic accuracy of 3-D CEPDUS to diagnose malignant and borderline adnexal masses. The reference standard was the final histological examination. Two-dimensional ultrasonography and 3-D CEPDUS were compared using semiquantitative scores. Three-dimensional CEPDUS assessed vessel density, vessel pattern, and three vascular indexes in a 5-mL region of interest (vascularization index [VI], flow index [FI], and vascularization flow index [VFI]). The 2-D and 3-D examinations were done by different sonographers who were blinded to the other test. The pathologist was blinded to ultrasonography findings. RESULTS: Of 99 patients, 88 had benign tumors and were compared to the 11 patients with borderline (n = 5) or malignant (n = 6) tumors. The sensitivity of the subjective 2-D score was 55% (95% confidence interval [CI], 25-84) and specificity 94% (95%CI, 89-99). The sensitivity of the subjective 3-D score was 82% (95%CI, 58-100) and specificity 90% (95%CI, 83-96). Improvement of detection of malignant or borderline tumors by subjective 3-D score was 150%. Vessel density and patterns were not more efficient than the subjective 3-D score. The mean vascular index values were significantly different between benign and borderline/malignant groups: VI, 7.2 versus 35.5 (P < 0.0001); FI, 37.0 versus 48.2 (P = 0.003); and VFI, 2.9 versus 17.6 (P < 0.0001), respectively. CONCLUSIONS: 3-D CEPDUS improves detection of malignant and borderline adnexal masses.

A phase II study of the cancer vaccine TG4010 alone and in combination with cytokines in patients with metastatic renal clear-cell carcinoma: clinical and immunological findings.

MUC1 over-expression in renal clear-cell carcinoma (RCC) is associated with poor prognosis. This phase II study determined the efficacy and tolerability of TG4010, a cancer vaccine based on a modified vaccinia virus expressing MUC1 and interleukin-2, in combination with cytokines, as first-line therapy in metastatic RCC. Thirty-seven patients with progressive, MUC1-positive RCC received TG4010 10(8) pfu/inj weekly for 6 weeks, then every 3 weeks until progression, when TG4010 was continued in combination with interferon-α2a and interleukin-2. Assessments included clinical response (primary endpoint), safety, time to treatment failure (TTF), overall survival (OS), and immune response. No objective clinical responses occurred. Five of the 27 evaluable patients (18%) had stable disease for >6 months with TG4010 alone and six of 20 patients (30%) had stable disease for >6 months with TG4010 plus cytokines. Median TTF was 4.1, 3.6, and 9.3 months for monotherapy, combination therapy, and overall, respectively. Median OS was 19.3 months for all patients and 22.4 months combination therapy recipients. The most frequent TG4010-related adverse events were minor-to-moderate injection-site reactions, fatigue, and flu-like symptoms. Six of 28 patients showed a MUC1 CD4+ T cell proliferative response during therapy. Anti-MUC1 CD8+ T cells were detected before and after therapy in 3 and 4 patients, respectively. MUC1-specific CD8+ T cell responses were associated with longer survival. Therapy with TG4010 plus cytokines appears to be feasible and well tolerated in patients with metastatic RCC. However, these data should be interpreted with caution, as additional prospective studies are necessary to clarify the clinical efficacy of this therapy.

Discovery of an endometrioid cancer lymph node metastasis without primary tumor in a context of Lynch syndrome.

INTRODUCTION: Lynch syndrome is a hereditary predisposition to cancers, including colo-rectal and endometrial cancers in women. Prophylactic surgery including hysterectomy and bilateral salpingo-oophorectomy is recommended once the parental project is completed in case of identified mutation. CASE PRESENTATION: We describe the case of a 50-year-old patient with Lynch syndrome and identified MSH6 mutation who underwent a prophylactic hysterectomy with bilateral salpingo-oophorectomy. A left large broad ligament lesion suggestive of a fibroma was intraoperatively discovered and removed. Pathological examination and immunohistochemical study showed a lymph node macro-metastasis of an endometrioid adenocarcinoma, without primary tumor. DISCUSSION/CONCLUSION: Lymph node metastasis can occur before endometrial cancer but the link with Lynch syndrome remains to be proved. Lymph node assessment by imaging before prophylactic surgery in Lynch syndrome could be considered.

[Management of epithelial ovarian cancer. Short text drafted from the French joint recommendations of FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY and endorsed by INCa]. / Texte court rédigé à partir de la recommandation nationale de bonnes pratiques cliniques « Conduites à tenir initiales devant des patientes atteintes d'un cancer épithélial de l'ovaire ¼ élaborée par FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY et labélisée par l'INCa ¼.

Faced to an undetermined ovarian mass on ultrasound, an MRI is recommended and the ROMA score (combining CA125 and HE4) can be proposed (grade A). In case of suspected early stage ovarian or fallopian tube cancer, omentectomy (at least infracolonic), appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C) and pelvic and para-aortic lymphadenectomy are recommended (grade B) for all histological types, except for the expansive mucinous subtype where lymphadenectomy may be omitted (grade C). Minimally invasive surgery is recommended for early stage ovarian cancer, if there is no risk of tumor rupture (grade B). Adjuvant chemotherapy with carboplatin and paclitaxel is recommended for all high-grade ovarian or Fallopian tube cancers, stage FIGO I-IIA (grade A). In case of ovarian, Fallopian tube or primitive peritoneal cancer of FIGO III-IV stages, thoraco-abdomino-pelvic CT scan with injection (grade B) is recommended. Laparoscopic exploration for multiple biopsies (grade A) and to evaluate carcinomatosis score (at least using the Fagotti score) (grade C) are recommended to estimate the possibility of a complete surgery (i.e. no macroscopic residue). Complete medial laparotomy surgery is recommended for advanced cancers (grade B). It is recommended in advanced cancers to perform para-aortic and pelvic lymphadenectomy in case of clinical or radiological suspicion of metastatic lymph node (grade B). In the absence of clinical or radiological lymphadenopathy and in case of complete peritoneal surgery during an initial surgery for advanced cancer, it is possible not to perform a lymphadenectomy because it does not modify the medical treatment and the overall survival (grade B). Primary surgery is recommended when no tumor residue is possible (grade B). After a complete first surgery, it is recommended to deliver 6 cycles of intravenous (grade A) or to propose intraperitoneal (grade B) chemotherapy, to be discussed with patient, according to the benefit/risk ratio. After a complete interval surgery for a FIGO III stage, the hyperthermic intra peritoneal chemotherapy (HIPEC) can be proposed in the same conditions of the OV-HIPEC trial (grade B). In case of tumor residue after surgery or FIGO stage IV, chemotherapy associated with bevacizumab is recommended (grade A).

Simplified technique of radioguided occult lesion localization (ROLL) plus sentinel lymph node biopsy (SNOLL) in breast carcinoma.

BACKGROUND: Radioguided occult lesion localization (ROLL) is a new technique to detect nonpalpable breast tumors. We report our experience using injection of a single radiotracer to localize occult lesions together with sentinel lymph node (SLN) biopsy (SNOLL). The aim of this series was to evaluate the feasibility of the technique, its efficacy, and the rate of reoperation. METHODS: Under sonographic guidance, a nanocolloidal tracer was injected peritumorally above and below the lesion. A handheld gamma probe detector was used to locate and to guide its surgical removal. An intraoperative (IO) macroscopic examination of the specimen with margins evaluation and IO imprint cytology of SLN was always performed. RESULTS: The targeted lesion was localized and removed in all cases. Final pathological diagnosis identified invasive in 70 patients and ductal carcinoma in situ (DCIS) in 2 patients. The average size of the resected lesion was 11 mm (4-50 mm). In 61 out of the 72 patients (85%), the breast specimen had clear and large margins. Sentinel lymph node (SLN) biopsy was performed in 70 patients with an identification rate of 90%. Final pathological SLN metastasis rate approached 25% (pN1 14%, pN1(mi) 11%). Despite intraoperative examination of the specimen, a total of 29% (21 out of 72) patients had to be reoperated (8 patients for involved margins, 10 patients for an involved SLN, and 3 for both). CONCLUSION: This technique with a single nanocolloid tracer used both for ROLL and SLN detection is reliable for removing nonpalpable lesions. The use of this technique may have implications for further reducing reoperation rates.

Prognostic value of EGF receptor and tumor cell proliferation in bladder cancer: therapeutic implications.

Changes in growth factor receptor expression may confer a growth advantage on tumour cells. Epidermal growth factor-receptor (EGF-R) has been associated with the genesis of bladder tumours. We sought a link between EGF-R expression and MIB-1 cell proliferation and examined their prognostic value in the progression of bladder cancer. Fresh frozen samples from 113 transitional cell carcinomas (TCC) of the bladder and 10 healthy bladders were studied by immunohistochemistry, using monoclonal antibodies for EGF-R expression and MIB-1 for cell proliferation. Qualitative and quantitative immunostaining were analyzed in relation to time to progression and compared with clinical and pathologic parameters for prognostic significance in univariate and multivariate analysis (stepwise logistic regression). EGF-R stained more intensively in invasive tumours. Median nuclear over-expression of MIB-1 was 28%. Progression free survival rate estimates (log rank test) were significantly lower in patients EGF-R positive and with MIB-1 score above 28% (P < 0.0001, P < 0.0001, respectively). Multivariate analysis indicated that MIB-1 immunostaining was the most significant independent variable and EGF-R expression had no additional prognostic value over clinical stage and grade and cell proliferation. The MIB-1 proliferation index is a stronger predictor of bladder tumour progression than is EGF-R over-expression. This marker yield significant prognostic information in addition to stage and grade and may be of value for the clinical management of superficial and invasive bladder carcinomas. The pattern of EGF-R immunostaining and its association with tumour progression makes it a candidate for antigrowth factor therapy.

[Ovarian cancer: diagnosis of early stages, referral of patients and management]. / Cancer de l'ovaire: diagnostic des formes précoces, orientation des malades et prise en charge.

Early ovarian cancers account for 25 to 30% of cases. They constitute the only curable cases. There is no specific clinical symptom of early ovarian cancer. Paraneoplasic syndroms, especially phlebitis, are of major importance when they occur in young women. In most of cases, the diagnosis is performed during the management of a complex ovarian cysts. Quality of the preoperative work-up, especially sonography, and management by a specialised team are the best factors to provide an early diagnosis and a comprehensive staging. These two factors are known as predictive of good prognosis. Chemotherapy is frequently indicated post-operatively. In young women, a conservative management can be proposed to preserve their fertility.

A case report on radiation-induced angiosarcoma of breast post skin-sparing mastectomy and reconstruction with transverse rectus abdominal muscle.

Radiation-induced angiosarcomas (RIA) are rare tumours that can affect breast cancer patients following treatment with breast conservative surgery and radiotherapy. Their diagnosis is often delayed because of their benign appearance and the difficulty in differentiation from radiation-induced skin changes. We report here a case of RIA which occurred seven years after radiotherapy to highlight awareness of the disease and the role of careful histological evaluation of these tumours.

Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure.

OBJECTIVE: Premature ovarian failure (POF) encompasses a heterogeneous spectrum of conditions, with phenotypic variability among patients. The etiology of POF remains unknown in most cases. We performed a global phenotyping of POF women with the aim of better orienting attempts at an etiological diagnosis. DESIGN AND METHODS: We performed a mixed retrospective and prospective study of clinical, biological, histological, morphological, and genetic data relating to 357 consecutive POF patients between 1997 and 2008. The study was conducted at a reproductive endocrinology referral center. RESULTS: Seventy-six percent of the patients presented with normal puberty and secondary amenorrhea. Family history was present in 14% of the patients, clinical and/or biological autoimmunity in 14.3%. Fifty-six women had a fluctuating form of POF. The presence of follicles was suggested at ultrasonography in 50% of the patients, and observed in 29% at histology; the negative predictive value of the presence of follicles at ultrasonography was 77%. Bone mineral density alterations were found in 58% of the women. Eight patients had X chromosomal abnormalities other than Turner's syndrome, eight other patients evidenced FMR1 pre-mutation. Two other patients had autoimmune polyendocrine syndrome type 2 and 1. CONCLUSION: A genetic cause of POF was identified in 25 patients, i.e. 7% of the whole cohort. POF etiology remains most often undiscovered. Novel strategies of POF phenotyping are in such content mandatory to improve the rate of POF patients for whom etiology is identified.

Sentinel lymph node biopsy improves staging in early cervical cancer.

OBJECTIVES: The main study objective was to describe the distribution of sentinel lymph nodes (SLNs) and the prevalence of SLN micrometastases in patients with early cervical cancer. The secondary objective was to confirm the SLN detection rate and negative predictive value found in our preliminary study. PATIENTS AND METHODS: We prospectively included 25 patients with early cervical cancer, each of whom received an injection of 120 MBq of technetium-99m for preoperative lymphoscintigraphy and intraoperative node detection using an endoscopic gamma probe. Patent blue dye was injected intraoperatively. SLNs were sought in the pelvic and para-aortic drainage areas. Radical iliac dissection was performed routinely at the end of the procedure. SLNs were examined after hematoxylin-eosin-saffron staining; negative specimens were assessed using immunohistochemistry. RESULTS: Most (85%) of the SLNs were in the inter-iliac territory. Para-aortic or parametrial SLNs were found respectively in 2 patients and common iliac SLNs in 5 patients. Thus 9/25 patients had additional information due to SLN detection. One metastasis and one micrometastasis were detected in SLNs. No patients had positive non-sentinel nodes with negative SLNs. CONCLUSION: SLN detection ensures the identification of SLNs in unusual locations in 36% of patients. SLN disease was found in 8% of our patients. Thus, SLN biopsy improves staging in patients with early cervical cancer. Studies in larger patient populations are needed to evaluate the clinical impact of SLN biopsy.

[Comparison of different approaches in surgical management of early endometrial cancer]. / Comparaison de la coelioscopie à la laparotomie dans la prise en charge du cancer de l'endomètre précoce.

The objective is to assess the feasibility of laparoscopy in the treatment of endometrial carcinoma and to compare operating data and morbidity to laparotomy. Retrospective review of 70 consecutive patients with supposed early endometrial cancer managed between December 2000 and December 2005. Two groups were defined, whether they had been operated by laparoscopy (N = 44 ; LPS group) or by laparotomy (N = 21 ; LPM group). Both groups were comparable in mean age and body mass index. There was no significant difference in median operating time for LPS group (240 minutes [90-390]) and LPM group (195 minutes [120-600]), (p = 0.234). Intraoperative complications occurred in 2 LPS patients (4.7 %) and in 2 LPM cases (9.5 %). Women who underwent laparoscopy had more pelvic lymph nodes removed (11.5 [2-33] versus 7.5 [3-37], p < 0.05). There were comparable early and late postoperative complications in patients managed by laparoscopy (5 and 0 cases ; 27.8 and 0 %) and by laparotomy (5 and 2 cases ; 11.6 and 4.5 %), (p = 0.143 and p > 0.999). Hospital stay was longer in LPM group (9.5 days [6-39] versus 5.0 (4-27), p < 0.05). Patients who undergo laparoscopy have more pelvic lymph nodes removed, with comparable operating time, shorter hospital stay, and similar morbidity. Laparoscopic staging combined with vaginal hysterectomy appears to be a feasible alternative to conventional surgical approach in patients with endometrial carcinoma.

Sono-guided endometrial biopsy: comparison with hysteroscopy biopsy. Sono-guided endometrial biopsy using the Bernard catheter had no impact on endometrial assessment by sonohysterography.

OBJECTIVE: To assess the feasibility, tolerance and diagnostic accuracy of endometrial biopsy (EB) during sonohysterography (SH) compared to EB after hysteroscopy (HSC) in endometrial disorders. METHODS: 105 consecutive patients with irregular uterine bleeding were included prospectively in the calendar year 2001. SH and flexible HSC were performed in an office setting, subsequently and in a random order, by two different practitioners blind to the former experiment. SH-EB was performed using a 3.1-mm ultrasound-guided Bernard catheter in the uterine cavity still partly distended and with a gentle 20-ml syringe vacuum aspiration. The biopsy was directed on focal lesions or else randomly when no targets had previously been found. A Cornier Pipelle was used to perform EB after HSC. We investigated all patients by biopsy, independent of the endometrial thickness. HSC-EB was the gold standard. RESULTS: For both methods, cervical catheterism was impossible in 20 patients, 75 of them successfully underwent both exams. Duration and tolerance were similar. SH was effective in the distinction between normal and pathologic cavities, as well as in the diagnosis of polyps. Endometrium appeared significantly thinner with HSC (1.8 mm) when compared to SH (2.9 mm, p < 0.05). Histological endometrial assessment failed in 30 cases of SH-EB and in 22 cases in HSC-EB (NS). There was a poor correlation of the histological results of both techniques. Hyperplasia has never been diagnosed by SH-EB, whereas 3 EB issued from HSC-EB brought up this diagnosis. CONCLUSION: SH-EB with our technique did not improve the diagnostic potential of SH and severe diagnosis was missed. Histological assessment should fail less when we exclude endometrial atrophy. The diameter of the catheter and the aspiration technique must be revised and the learning curve must be considered. Our technique cannot replace EB by HSC.