ABSTRACT
BACKGROUND: Retrospective data suggest that the incidence of parametrial infiltration is low in patients with early-stage low-risk cervical cancer, which raises questions regarding the need for radical hysterectomy in these patients. However, data from large, randomized trials comparing outcomes of radical and simple hysterectomy are lacking. METHODS: We conducted a multicenter, randomized, noninferiority trial comparing radical hysterectomy with simple hysterectomy including lymph-node assessment in patients with low-risk cervical cancer (lesions of ≤2 cm with limited stromal invasion). The primary outcome was cancer recurrence in the pelvic area (pelvic recurrence) at 3 years. The prespecified noninferiority margin for the between-group difference in pelvic recurrence at 3 years was 4 percentage points. RESULTS: Among 700 patients who underwent randomization (350 in each group), the majority had tumors that were stage IB1 according to the 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria (91.7%), that had squamous-cell histologic features (61.7%), and that were grade 1 or 2 (59.3%). With a median follow-up time of 4.5 years, the incidence of pelvic recurrence at 3 years was 2.17% in the radical hysterectomy group and 2.52% in the simple hysterectomy group (an absolute difference of 0.35 percentage points; 90% confidence interval, -1.62 to 2.32). Results were similar in a per-protocol analysis. The incidence of urinary incontinence was lower in the simple hysterectomy group than in the radical hysterectomy group within 4 weeks after surgery (2.4% vs. 5.5%; P = 0.048) and beyond 4 weeks (4.7% vs. 11.0%; P = 0.003). The incidence of urinary retention in the simple hysterectomy group was also lower than that in the radical hysterectomy group within 4 weeks after surgery (0.6% vs. 11.0%; P<0.001) and beyond 4 weeks (0.6% vs. 9.9%; P<0.001). CONCLUSIONS: In patients with low-risk cervical cancer, simple hysterectomy was not inferior to radical hysterectomy with respect to the 3-year incidence of pelvic recurrence and was associated with a lower risk of urinary incontinence or retention. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov number, NCT01658930.).
Subject(s)
Carcinoma, Squamous Cell , Hysterectomy , Uterine Cervical Neoplasms , Female , Humans , Canada , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/surgery , Hysterectomy/adverse effects , Hysterectomy/methods , Lymph Nodes/pathology , Neoplasm Recurrence, Local/epidemiology , Neoplasm Staging , Prognosis , Retrospective Studies , Urinary Incontinence/etiology , Urinary Retention/etiology , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/surgeryABSTRACT
OBJECTIVES: To investigate whether HE4 and CA125 could identify endometrioid adenocarcinoma patients who might most benefit from full staging surgery with lymphadenectomy. METHODS: Sequential patients with a preoperative banked serum and histology of endometrioid adenocarcinoma of endometrium who had undergone surgical staging with lymph node dissection over a 5-year period between 2011 and 2016 were included from a tertiary Gynaecological Cancer Centre, Dublin, Ireland. Preoperative serum HE4 and CA125 were measured using ELISA, with the cut-offs HE4 81 pmol/L and CA125 35 U/ml. Predictive values were estimated using AUC, sensitivity, specificity and odds ratios. RESULTS: 9.5% of the cohort had lymph node metastases. A HE4 cut-off of 81 pmol/L yielded a sensitivity of 78.6% and specificity of 53.4% for predicting lymph node metastases. Sensitivity of CA125 at 35 U/ml was 57% and specificity 91.4%. The AUC was 0.66 (0.52-0.80) for HE4 and 0.74 (0.58-0.91) for CA125. Sensitivity was 92.8% and specificity 51.1% when an elevation of either HE4 or CA125 was included, AUC was 0.72 (0.61-0.83), this combination yielded the highest NPV of 98.6%. Sensitivity was 42.9% and specificity 93.8% if both markers were elevated simultaneously, AUC was 0.68 (0.51-0.86). Preoperative clinical predictors of high-grade preoperative histology and radiology had sensitivities of 21.4% and 41.7%, respectively. Patients with a HE4 above 81 pmol/L had an odds ratio of 4.2 (1.12-15.74), p < 0.05, of lymph node metastases and CA125 had an odds ratio of 14.2 (4.16-48.31), p < 0.001. CONCLUSIONS: Serum HE4 and CA125 improved on existing methods for risk stratification of endometrioid carcinomas and warrant further investigation.
Subject(s)
Biomarkers, Tumor/blood , CA-125 Antigen/blood , Carcinoma, Endometrioid/diagnosis , Endometrial Neoplasms/diagnosis , Lymphatic Metastasis/diagnosis , Membrane Proteins/blood , WAP Four-Disulfide Core Domain Protein 2/analysis , Adult , Aged , Aged, 80 and over , Carcinoma, Endometrioid/blood , Carcinoma, Endometrioid/pathology , Carcinoma, Endometrioid/surgery , Endometrial Neoplasms/blood , Endometrial Neoplasms/pathology , Endometrial Neoplasms/surgery , Endometrium/pathology , Endometrium/surgery , Female , Humans , Hysterectomy , Lymph Node Excision/statistics & numerical data , Lymph Nodes/pathology , Lymph Nodes/surgery , Lymphatic Metastasis/pathology , Middle Aged , Neoplasm Grading/statistics & numerical data , Neoplasm Staging/statistics & numerical data , Predictive Value of Tests , Preoperative Period , ROC Curve , Reference Values , Retrospective Studies , Risk Assessment/methods , Salpingo-oophorectomyABSTRACT
INTRODUCTION: CA 125, the biomarker in common clinical use for ovarian cancer, is limited by low sensitivity for early disease and high false positives. The aim of this study was to evaluate several candidate biomarkers, alone or in combination, compared with CA 125 in the prediction of malignant/borderline vs benign tumor status in premenopausal and postmenopausal women with pelvic masses. MATERIAL AND METHODS: This was a retrospective observational cohort study set in St James's Hospital, a tertiary referral center for gynecological malignancy in Dublin, Ireland. Women undergoing surgery for pelvic masses between 2012 and 2018 were included. Preoperative human epididymis protein 4 (HE4), the Risk of Ovarian Malignancy Algorithm, the Risk of Malignancy Index I and II, D-dimer, and fibrinogen were assessed. Logistic regression models were fitted for each biomarker alone and in combination. Receiver operating characteristics-area under the curve (ROC-AUC) and partial AUCs in the 90%-100% specificity range were determined. RESULTS: In all, 89 premenopausal and 185 postmenopausal women were included. In premenopausal women, no biomarker(s) outperformed CA 125 (AUC 0.73; 95% CI 0.63-0.84). In postmenopausal women, HE4 had a partial AUC (pAUC) of 0.71 (95% CI 0.64-0.79) compared with 0.57 (95% CI 0.51-0.69) for CA 125 (p = 0.009). HE4 + D-dimer had an improved pAUC of 0.74 (95% CI 0.68-0.81, p < 0.001) and HE4 + D-dimer + fibrinogen had a pAUC of 0.75 (95% CI 0.68-0.82). CONCLUSIONS: A novel biomarker panel of HE4 ± D-dimer ± fibrinogen outperformed CA 125 alone as a high-specificity biomarker in postmenopausal women and could aid in the preoperative triaging of pelvic masses. No biomarker(s) outperformed CA 125 in premenopausal women.
Subject(s)
Biomarkers, Tumor/blood , CA-125 Antigen/blood , Carcinoma, Ovarian Epithelial/blood , Fibrin Fibrinogen Degradation Products/analysis , WAP Four-Disulfide Core Domain Protein 2/analysis , Adult , Algorithms , Carcinoma, Ovarian Epithelial/diagnosis , Cohort Studies , Female , Humans , Ireland , Middle Aged , Retrospective Studies , Risk AssessmentABSTRACT
Background and Objectives: Women with gynecological cancers constitute a high-risk cohort for loss of bone density. International guidance stipulates women undergoing cancer treatments associated with bone loss should have a quantitative assessment of bone density. Access to Dual-energy X-ray Absorptiometry (DXA) is limited. This study aimed to assess the accuracy of opportunistic bone density measurement on staging computed tomography (CT) scans for gynaecological malignancies, in comparison to the gold standard DXA. Materials and Methods: Women with a staging CT scan of the abdomen and pelvis for a new diagnosis of gynecological cancer were recruited. DXA was performed within 6 weeks of treatment for gynaecological cancer. Lumbar bone density was measured by CT attenuation values, in Hounsfield units (HU), of the anterior trabecular region. Correlations between CT and DXA parameters were analysed. Receiver Operating Characteristic(ROC) curves for diagnosis of low bone density and osteoporosis were analysed. Results: Final cohort included 48 of 50 women recruited. There was good diagnostic accuracy for abnormal bone density and osteoporosis, with areas under the ROC curve at L1 of 0.77 (p = 0.002) and 0.80 (p = 0.020) respectively. CT-HU of 170-190 yielded sensitivities of 87-90%, positive predictive values of 75-84% and negative predictive values of 71-75% for the diagnosis of low bone mineral density. CT-HU of 90-110 yielded specificities of 85-93% for the diagnosis of osteoporosis. Moderate correlations were found between CT-HU and both DXA T-scores and diagnostic categories. Conclusions: This is the first study to assess the opportunistic application of CT in the assessment of bone health in women with gynaecological cancer, a cohort at high-risk of osteoporosis. The correlation between bone density assessment in CT-HU and DXA, and strong AUC values for the diagnosis of low bone density (0.77) and osteoporosis (0.80) support this pragmatic solution in resolving the care-gap in cancer treatment-induced bone loss, often associated with poor access to DXA.
Subject(s)
Bone Density , Genital Neoplasms, Female , Absorptiometry, Photon , Female , Genital Neoplasms, Female/diagnostic imaging , Humans , Lumbar Vertebrae , Retrospective Studies , Tomography, X-Ray ComputedABSTRACT
PURPOSE: Hydronephrosis due to ureteric obstruction (UO) is stage-defining at cervical cancer presentation but may occur after primary staging. We aimed to determine the incidence and review the presentation and management of UO in women with cervical cancer attending our center. Particular attention was paid to the evolving role of interventional radiology (IR) in management. METHODS: Women with a new diagnosis of cervical cancer between January 2012 and December 2016 formed the cohort that was retrospectively reviewed from the oncology database and patient records. RESULTS: There were 310 women diagnosed with cervical cancer; 240 were stages I/II and 70 were stages III/IV. Primary treatments were chemoradiotherapy (n = 168; 54.2%), surgery (n = 121; 39.0%), and palliative care alone (n = 21; 6.8%). UO occurred in 74 (23.9%); present at primary staging in 53 (71.6%) and arising after staging in 21 (28.4%). Primary interventions for hydronephrosis were IR (n = 50; 67.6%), cystoscopic stenting (n = 19; 25.7%), bowel urinary conduit construction (n = 2; 2.7%), and none (n = 3; 4.1%). For those who attended IR, the mean number of IR procedures was 2.2, range 1-7. Maximum serum creatinine was 303 µmol/L for women with UO at primary staging compared with 252 µmol/L for UO after staging (P = 0.267). Thirty-eight women experienced substantial morbidity related to UO. Stage-adjusted mortality risk was 2.3 times higher for UO cases compared with those without UO. CONCLUSIONS: UO is associated with substantial morbidity and survival disadvantage in cervical cancer and may present after primary cancer staging. We recommend renal biochemistry during routine follow-up. A majority of cervical cancer-associated UO cases are managed with IR in our center.
Subject(s)
Ureteral Obstruction , Uterine Cervical Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Chemoradiotherapy , Cohort Studies , Creatinine/blood , Female , Humans , Hydronephrosis/pathology , Incidence , Middle Aged , Neoplasm Staging , Retrospective Studies , Ureteral Obstruction/diagnosis , Ureteral Obstruction/pathology , Ureteral Obstruction/therapy , Uterine Cervical Neoplasms/therapy , Young AdultABSTRACT
OBJECTIVE: Gynaecological cancer patients have a high risk of developing venous thromboembolism (VTE). There is limited information on patient experience and compliance with an extended low molecular weight heparin prophylaxis in this setting. The aim of this study was to assess patient compliance, satisfaction and experience with the extended low molecular weight heparin prophylaxis after major surgery for gynaecological cancer. METHODS: This was a prospective observational study conducted in a large tertiary center for gynaecological cancer between July 2017-March 2018. Consecutive patients undergoing surgery for gynaecological cancer who received low molecular weight heparin prophylaxis for four weeks following surgery were recruited. All participants received a log book to record all injections, side effects, and questionnaire to be completed at the end of the study. RESULTS: A total of 106 patients completed and returned the VTE prophylaxis logbook and questionnaire. Sixty-six (62%) patients received low molecular weight heparin for 28 days, twenty-five (24%) for 26-27 days, and 15 (14%) for less than 26 days. The median number of days of therapy was 28 days (range; 12-28 days). Reasons for missed or stopped injections included: forgetfulness(n=12), medical procedures (n=6), pain (n=5), incorrect prescription (n=4), patient choice (n=3), cost (n=2), physician request (n=2), non-availability of person administering the injections (n=1) or unknown (n=5). Sixty-one (58%) patients self-administered the injections. Patients who had the injection performed by a third person were twice as likely to experience pain compared to patients who self-administered (OR 2.81, p=0.003). Eighty-nine (84%) patients self-reported side effects during low molecular weight heparin prophylaxis including: bruising (75%), pain after injections (49%), itchiness (9%), swelling (9%) or other (8%). Although 83 (78%) patients were satisfied with injections, 91 (86%) admitted they would much prefer a tablet form. CONCLUSIONS: Compliance with standard recommended regimen of 28-days prophylaxis was completed by 62% of patients. Majority of patients (86%) reported a preference for a tablet form, if one was available.
ABSTRACT
OBJECTIVE: The aim of this study was to examine the clearance of serum human epididymis protein 4 (HE4) in the immediate postoperative period in patients undergoing maximal effort cytoreductive surgery for ovarian carcinoma. METHODS: The study was performed at a tertiary gynecologic oncology center. The surgery was performed by accredited gynecological oncologists. RESULTS: Preoperative and serial postoperative venous blood samples at 4, 8, 24, 48, 72, 96, and 120 hours were taken from 10 sequential patients. Pretreatment HE4 is considered elevated at greater than 70 pmol/L. Human epididymis protein 4 was greater than 70 pmol/L in 7 patients, including all patients with high-grade serous carcinoma. Patients with preoperative elevation of serum HE4 and complete cytoreduction cleared more than 80% of serum HE4 in the first 4 hours and more than 88% within 5 days of surgery. One patient with incomplete cytoreduction of high-grade serous carcinoma had 66% clearance at 4 hours and a plateau thereafter. CONCLUSIONS: Human epididymis protein 4 derived from ovarian carcinoma had a short half-life of less than 4 hours in the circulation when cytoreductive surgery was complete. Sustained low HE4 following surgery could be a useful indicator of the completeness of cytoreduction. Plateau or rise in serum HE4 could suggest persistent disease. Comparison of values on day 1 and day 4 or 5 might have value in assessing the completeness of cytoreduction.
Subject(s)
Carcinoma, Ovarian Epithelial/blood , Carcinoma, Ovarian Epithelial/surgery , Proteins/metabolism , Adult , Aged , Biomarkers, Tumor/blood , Cytoreduction Surgical Procedures , Female , Gynecologic Surgical Procedures , Humans , Middle Aged , WAP Four-Disulfide Core Domain Protein 2 , Young AdultABSTRACT
This study describes a new technique for reconstructing the vagina and vestibule after radical extirpative surgery for urological and anorectal malignancy. The uterus is always excised when exenterative surgery is performed for gynecological cancer. The use of the uterus as a graft gives the gynecologic oncologist/reconstructive surgeon a role in the multidisciplinary team with urologists when the anterior vaginal wall and vestibule are excised and with the anorectal surgeons when the posterior vaginal wall and perineum are excised for nongynecological cancers. In some such cases, only the anterior or posterior wall of the vagina may be excised, leaving a healthy full-length, one-third, or half-circumference vaginal sleeve. A myoserosal flap is raised from the in situ uterus. The ectocervix is excised, and the adnexa are detached or excised. The uterus is opened to generate a hexagonal flap. The endometrium and endocervix are excised/ablated with electrocautery. The flap is advanced to the edge of the remaining anterior vestibule or reconstituted perineum. The serosal surface of the uterus forms the new wall of the vagina and undergoes metaplastic transformation to squamous epithelium within 3 months. The very satisfactory anatomical and functional outcome means that this technique merits further evaluation.
Subject(s)
Anus Neoplasms/surgery , Pelvis/surgery , Perineum/surgery , Plastic Surgery Procedures , Rectal Neoplasms/surgery , Surgical Flaps , Uterus/surgery , Vagina/surgery , Adenocarcinoma, Mucinous/pathology , Adenocarcinoma, Mucinous/surgery , Adult , Anus Neoplasms/pathology , Female , Gynecology , Humans , Quality of Life , Rectal Neoplasms/pathology , Treatment OutcomeABSTRACT
Groin node lymphadenectomy in vulva cancer carries a substantial risk of morbid sequelae. Sentinel lymph node (SLN) mapping is a valid alternative in patients with squamous cancer of diameter <4 cm and nonsuspicious lymph nodes. SLN are mapped according to the combined technique of radioscintigraphy using technetium-labelled colloid and blue dye. We describe early extranodal recurrence in 2 patients undergoing SLN mapping. They had lymph node metastases at their original dissection. We question whether rapid lymph flow promoted by injection of colloid and dye could cause retrograde flow of cancer cells along the lymphatics draining from the pubis to the groin and extravasation of cancer cells into the dermis since these metastases arose anterior to the pubis and medial to the groin. These recurrence sites were more medial and cephalad than would be expected for skin bridge metastasis. CT imaging shows the metastases are within the dermis. No lymphatic tissue was identified around these subcuticular cancer deposits at repeat resection. Body wall extension occurs in recurrent vulva cancer, but we never saw such an early recurrence when full inguinofemoral lymphadenectomy without SLN was the standard approach. These 2 cases raise a caveat in the application of SLN mapping in vulva cancer, especially when metastasis is detected on SLN as the afferent channels to the lymph nodes may be already blocked or flow impaired by the tumour.
Subject(s)
Carcinoma, Squamous Cell/pathology , Lymph Nodes/diagnostic imaging , Lymphatic Metastasis/diagnosis , Lymphoscintigraphy/adverse effects , Neoplasm Metastasis/pathology , Vulvar Neoplasms/pathology , Abdominal Wall/pathology , Adult , Female , Groin , Humans , Sentinel Lymph Node BiopsyABSTRACT
Platinum resistance is a major cause of treatment failure in ovarian cancer. We previously identified matrix metalloproteinase 9 (MMP-9) as a potential therapeutic target of chemoresistant disease. A2780cis (cisplatin-resistant) and A2780 (cisplatin-sensitive) ovarian carcinoma cell lines were used. The cytotoxic effect of MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) alone or in combination with cisplatin was determined using high content screening. Protein expression was examined using immunohistochemistry and ELISA. Co-incubation of cisplatin and an MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) resulted in significantly greater cytotoxicity as compared to either treatment alone in a cisplatin resistant MMP-9 overexpressing cell line; A2780cis. In addition, pre-incubating with MMP-9i prior to cisplatin further enhances the cytotoxic effect. No significant difference was observed in MMP-9 protein in tissue but a trend towards increased MMP-9 was observed in recurrent serum. We propose that MMP-9/MMP-2i may be utilized in the treatment of recurrent/chemoresistant ovarian cancers that overexpress MMP-9 mRNA but its role in vivo remains to be evaluated.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Neoplasm Proteins , Protease Inhibitors/pharmacology , Cell Line, Tumor , Humans , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolismABSTRACT
Circulating tumour cells (CTCs) are a critical intermediate step in the process of cancer metastasis. The reliability of CTC isolation/purification has limited both the potential to report on metastatic progression and the development of CTCs as targets for therapeutic intervention. Here we report a new methodology, which optimises the culture conditions for CTCs using primary cancer cells as a model system. We exploited the known biology that CTCs thrive in hypoxic conditions, with their survival and proliferation being reliant on the activation of hypoxia-inducible factor 1 alpha (HIF-1α). We isolated epithelial-like and quasi-mesenchymal CTC phenotypes from the blood of a cancer patient and successfully cultured these cells for more than 8 weeks. The presence of CTC clusters was required to establish and maintain long-term cultures. This novel methodology for the long-term culture of CTCs will aid in the development of downstream applications, including CTC theranostics.
Subject(s)
Neoplastic Cells, Circulating , Humans , Reproducibility of Results , Hypoxia , Models, Biological , PhenotypeABSTRACT
OBJECTIVE: Women with gynaecological cancers are at an increased risk of cancer treatment-induced bone loss, which impacts on their quality of life and overall survival. Clinical cancer follow-up reviews focus on cancer status and fail to attend to important health and quality-of-life issues. We questioned whether there was a care-gap between tertiary clinicians and primary care physicians in the management of bone health in this cohort. Significant care-gaps in relation to bone health have been demonstrated in other oncologic settings. The objective of this study was to determine the level of attention to bone health in the care of women living with and beyond gynaecological cancer at a tertiary referral centre for gynaecological oncology. METHODS: Retrospective, observational cohort study of attention to bone health in the management and follow-up of gynaecological cancers. RESULTS: This study shows that there has been suboptimal attention from the carers at a cancer centre to bone health during the oncological follow up of women undergoing treatment for gynaecological cancer. In those at particular risk of cancer treatment-induced bone loss (iatrogenic menopause and/or external beam pelvic radiotherapy), 52% of women had no reference to bone health in their notes, and 57% had no assessment of bone mineral density. CONCLUSION: Tertiary cancer carers may underestimate the importance of bone health or believe that it falls outside the remit of their gynaecologic oncology service. Further research is needed to explore whether these findings are indicative of a true care gap and to gain insight into possible corrective measures.
Subject(s)
Genital Neoplasms, Female , Quality of Life , Bone Density , Female , Follow-Up Studies , Genital Neoplasms, Female/epidemiology , Genital Neoplasms, Female/therapy , Humans , Retrospective Studies , Tertiary HealthcareABSTRACT
OBJECTIVE: Good survival rates from gynaecological cancers focus our attention on the quality of survivorship. Lymphoedema is a common complication that affects many aspects of quality of life (QOL). We undertook a prospective audit of QOL of patients with higher grade lymphoedema using home compression pneumatic devices. The aim of this study was to assess QOL in a mixed gynaecological cancer cohort before and after at least eight weeks of home compression treatment. METHODS: Thirteen patients with the most severely disabling lower limb lymphoedema based on routinely collected QOL scores or a history of hospital admissions with related infection were invited to participate. QOL was assessed using the EORTC QLQ-C30 Version 3.0 and a supplementary gynaecological cancer-specific lymphoedema questionnaire. Home compression therapy was introduced not sooner than 3 months after primary cancer treatment. All patients applied compression treatment for at least one hour per day. Descriptive statistics and Wilcoxon signed-rank test were applied. A p-value < 0.05 was considered statistically significant. RESULTS: All participants' functional and symptom scores improved with compression therapy with the exception of sexual function. CONCLUSIONS: Self-management with pneumatic compression devices at home is a useful adjunct in the management of severe lymphoedema. Our preliminary experience showed a substantial improvement in most QOL parameters. We cannot say if domiciliary treatment with this compression device would have broader application or a role in primary or secondary prevention of lymphoedema if introduced at an earlier stage.
ABSTRACT
INTRODUCTION: Ovarian cancer patients are at high risk of thrombosis particularly during chemotherapy treatment however the mechanism is not understood. The aim of this study is to investigate the role of the activated protein C (aPC) pathway in the procoagulant activity observed in ovarian cancer patients undergoing neoadjuvant chemotherapy. PATIENTS AND METHODS: Thrombin generation was determined before and after addition of thrombomodulin (TM) in high grade serous ovarian cancer (HGSOC) patients treated with neoadjuvant chemotherapy (n = 29) compared with HGSOC patients who were chemo naïve (n = 23) and patients with benign tumours (n = 29). Plasma expression of proteins from the aPC pathway was analysed. mRNA expression was determined in endothelial (EA.hy926) and ovarian (OAW42) cell lines following addition of carboplatin and paclitaxel. RESULTS: Lower levels of ETP (p < 0.007; p < 0.003) and peak thrombin (p < 0.0008; p < 0.0018) were found in the neoadjuvant group compared with both chemo naïve and benign groups. Following addition of TM, ETP (p < 0.0005) and peak thrombin (p < 0.0049) were higher in the neoadjuvant group compared with the benign controls indicating an increase in aPC resistance. Increased TM and lower levels of protein S were found in the neoadjuvant group compared with benign controls (p < 0.05; p < 0.003). Factor V levels were increased in the neoadjuvant group compared with the chemo naïve group (p < 0.05). Carboplatin and paclitaxel altered the expression of EPCR and thrombomodulin in OAW42 cells with a modest effect on EA.hy926 cells. CONCLUSION: Chemotherapy induced procoagulant activity in HGSOC is associated with an alteration in expression of key members of the aPC pathway. This acquired aPC resistance may explain the procoagulant phenotype associated with ovarian cancer patients undergoing chemotherapy.
Subject(s)
Ovarian Neoplasms , Protein C , Carboplatin/therapeutic use , Female , Humans , Neoadjuvant Therapy , Ovarian Neoplasms/drug therapyABSTRACT
BACKGROUND: Gynecologic cancers are associated with high rates of venous thromboembolism (VTE), which is exacerbated by pelvic surgery and chemotherapy. OBJECTIVES: The aim of this study was to develop and validate a risk score for VTE in patients with gynecologic cancer and to test the predictive ability of the score following addition of procoagulant biomarker data. PATIENTS AND METHODS: Clinical and laboratory variables were used to develop a risk score for the prediction of VTE in patients with gynecological cancer (n = 616), which was validated in a separate cohort of patients (n = 406). Endogenous thrombin potential and D-dimer levels were determined in a subset (n = 290) of patients and used to produce an extended score in the validation cohort. RESULTS: Multivariable regression analysis identified BMI >30, hemoglobin <11.5 g/dL and chemotherapy as independent predictors of VTE, which formed the Thrombogyn score. Following competing risk regression analysis, subdistribution hazard ratios (SHRs), adjusted for cancer stage, were 8.16 (95% confidence interval [CI], 1.69-43.77) in the high-risk group (score = 2-3) and 4.12 (95% CI, 0.85-20.15) in the intermediate-risk group (score = 1) compared with the low-risk group (score = 0). SHRs for the validation cohort were 6.26 (95% CI, 1.24-31.39) and 3.00 (95% CI, 0.67-13.32), respectively. Cumulative incidence of VTE in the validation cohort high-risk group was 10.34% (95% CI, 6.51-16.41) per women-years compared with 1.06% (95% CI, 0.26-4.26) in the low-risk group. Using the extended Thrombogyn score, adjusted SHRs were 16.83 (95% CI, 4.20-67.37) in the high-risk group with a cumulative incidence of 21.15% (95% CI, 10.32-45.24). External validation of the score is required. CONCLUSIONS: The Thrombogyn score identifies patients with gynecologic cancer at high and low risk of VTE. Addition of biomarker data improves the predictive power of the score.
ABSTRACT
Objective: The therapeutic benefits of poly(ADP-ribose) polymerase inhibitors highlight the need to evaluate BRCA1/2 defects in tubal/ovarian cancer (OC). We sought to determine the pattern and disease characteristics associated with tumor BRCA1/2 mutations and BRCA1 methylation in women with OC. Methods: We obtained 111 OC specimens from 2 university hospitals and assessed BRCA1/2 mutations and BRCA1 methylation in tumor DNA. The frequency and pattern of BRCA1/2 defects were examined. Associations between patient/disease characteristics and BRCA1/2 defects were ascertained (Fisher's exact test). Platinum-free interval (PFI), progression-free survival (PFS), and overall survival (OS) based on the underlying BRCA1/2 defect were determined (Kaplan-Meier analysis [log-rank test]). Results: We observed a BRCA1/2 dysfunction rate of 40% (28/70) in high-grade serous tubal/ovarian cancer (HGSC), including 14.3% BRCA1 methylation (n=10), 7.1% BRCA1 mutation (n=5), and 18.6% BRCA2 mutation (n=13). Defects in BRCA1/2 genes were associated with stage III/IV HGSC (BRCA1 methylation: P=0.005 [stage III/IV] and P=0.004 [HGSC]; BRCA1/2 mutation: P=0.03 [stage III/IV] and P<0.001 [HGSC]). Patients with BRCA1/2-mutated cancers showed improved OS (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.43-0.99; P=0.045) and a trend toward improved PFI (HR, 0.48; 95% CI, 0.22-1.06; P=0.07) and PFS (HR, 0.72; 95% CI, 0.51-1.03; P=0.07). No survival differences were observed between BRCA1-methylated and BRCA1/2 wild-type non-BRCA1-methylated cancers. Conclusion: We observed a high tumor BRCA1/2 dysfunction rate in HGSC with a unique predominance of BRCA2 over BRCA1 mutations. While BRCA1/2 mutations conferred survival benefits in OC, no such association was observed with BRCA1 methylation.
ABSTRACT
BACKGROUND: To present a diagnostic evaluation and treatment strategy for serous adenocarcinoma of the ovary discovered during an in vitro fertilisation (IVF) sequence, and report on reproductive outcome after tumour resection and embryo transfer. CASE PRESENTATION: Cycle monitoring in IVF identified an abnormal ovarian lesion which was subjected to ultrasound-guided needle aspiration. Cytology suggested malignancy, and unilateral oophorectomy was performed after formal staging. After surgery, the patient underwent an anonymous donor oocyte IVF cycle which established a viable twin intrauterine pregnancy. No recurrence of cancer has been detected in the >72 month follow-up interval; mother and twin daughters continue to do well. CONCLUSION: Suspicious adnexal structures noted during controlled ovarian hyperstimulation for IVF warrant assessment, and this report confirms the role of aspiration cytology in such cases. If uterine conservation is possible, successful livebirth can be achieved from IVF if donor oocyes are utilised, as described here.
Subject(s)
Cystadenocarcinoma, Serous/surgery , Fertilization in Vitro , Ovarian Neoplasms/surgery , Pregnancy Complications, Neoplastic/surgery , Adult , Cystadenocarcinoma, Serous/diagnosis , Female , Humans , Ovarian Neoplasms/diagnosis , Pregnancy , Pregnancy Complications, Neoplastic/diagnosisSubject(s)
Leiomyoma/complications , Muscle Weakness/etiology , Muscular Diseases/etiology , Neoplasms/complications , Uterine Neoplasms/complications , Aged , Atorvastatin , Female , Gynecologic Surgical Procedures , Heptanoic Acids/adverse effects , Heptanoic Acids/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipidemias/drug therapy , Leg , Leiomyoma/surgery , Muscle Weakness/physiopathology , Muscle, Skeletal/physiopathology , Muscular Diseases/physiopathology , Neoplasms/surgery , Pyrroles/adverse effects , Pyrroles/therapeutic use , Treatment Outcome , Uterine Neoplasms/surgeryABSTRACT
Uterine leiomyomas are the most common benign gynaecological tumours. However, 0.13 to 6% of them have malignant potential (Robboy et al. Environ Health Perspect 108(Suppl 5):779-784, 2000). Uterine smooth muscle tumours with unusual growth patterns include a spectrum of lesions such as intravenous leiomyomatosis, benign metastasizing leiomyoma and disseminated peritoneal leiomyomatosis (Vaquero et al. J Minim Invasive Gynecol 16:263-268, 2009). Benign metastasizing leiomyoma (BML) is a very rare condition with around 100 cases reported to date. BML is a cytologically bland, mitotically inactive smooth muscle tumour in extra uterine sites, occurring in conjunction with similarly appearing or previously removed uterine leiomyomas (Beck et al. Hong Kong Med J = Xianggang yi xue za zhi 18:153-155, 2012). Pulmonary metastases are the most common sites of metastases, but other sites include skin, bladder, liver, lymph nodes, oesophagus, skeletal muscles, heart, bones and central nervous system (Jo et al. Korean J Int Med 21:199-201, 2006; Arai et al. Chest 117:921-922, 2000; Kwon et al. Korean J Int Med 21:173-177, 2006; Rivera et al. J Clin Endocrinol Metab 89:3183-3188, 2004; Jautzke et al. Pathol Res Pract 192:215-223, 1996; Goyle et al. Am J Clin Oncol 26:473-476, 2003; Schneider et al. Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen 72:308-311, 2001; Andrade et al. Pathol Oncol Res: POR 4:44-47, 1998; Abramson et al. AJR Am J Roentgenol 176:1409-1413, 2001; Yoon et al. Cancer Res Treat 43:131-133, 2011; Egberts et al. Arch Gynecol Obstet 274:319-322, 2006). The condition is more common in late childbearing age, mean age of diagnosis is 43 years (Kwon et al. Korean J Int Med 21:173-177, 2006), suggesting that it is hormone related. Lung metastases in BML are usually an incidental finding during the preoperative assessment; however, on rare occasions, patients are symptomatic with cough, chest pain, haemoptysis or dyspnoea. The differential diagnosis includes pulmonary metastases from leiomyosarcoma, intravenous leiomyomatosis or metastasis from other malignancies. Lung biopsy is the only way to confirm the benign nature of these lesions. Recently, positron emission tomography (PET) scan showed promise in differentiating these benign lesions from malignant lung lesion (Sawai et al. Oncol Lett 14:3641-3646, 2017). We present three cases with pulmonary metastases from BML and discuss the pathogenesis and management of this rare condition.
Subject(s)
Fluorodeoxyglucose F18/adverse effects , Leiomyosarcoma/complications , Lung Neoplasms/secondary , Positron Emission Tomography Computed Tomography/adverse effects , Uterine Neoplasms/complications , Female , Fluorodeoxyglucose F18/pharmacology , Humans , Leiomyosarcoma/pathology , Lung Neoplasms/pathology , Middle Aged , Positron Emission Tomography Computed Tomography/methods , Uterine Neoplasms/pathologyABSTRACT
BACKGROUND: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. METHODS: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. FINDINGS: At a median follow up (FU) of 22â¯months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65â¢4% [CI95%: 60â¢2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. INTERPRETATION: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.