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

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

Chemopotentiating effects of low-dose fractionated radiation on cisplatin and paclitaxel in cervix cancer cell lines and normal fibroblasts from patients with cervix cancer.

The aim of the present study was to compare the effects (assessed by clonogenic survival and γH2AX foci assays) of low-dose fractionated radiation LDFR (4 × 0.125 Gy, 4 × 0.25 Gy and 4 × 0.5 Gy) versus single radiation doses (0.5 Gy, 1 Gy and 2 Gy) on cisplatin and paclitaxel in HRS-negative cervix cancer cell lines SiHa and CaSki to see if the effects of LDFR can emerge in cells that not present low-dose hyper-radiosensitivity (HRS) phenomenon. Additionally, we report the effects in normal fibroblasts (HRS-negative and HRS-positive) from two patients with cervix cancer to see if the chemopotentiating effects of LDFR also apply to normal cells. LDFR (4 × 0.125 Gy, 4 × 0.25 Gy and 4 × 0.5 Gy) as well as single doses (0.5 Gy, 1 Gy and 2 Gy) enhanced cytotoxicity of cisplatin and paclitaxel in all the cell lines. Cisplatin-potentiating effects were maximum with LDFR 4 × 0.5 Gy, and were two-fold greater than those with a single dose of 2 Gy in SiHa, CaSki and HFIB2 cells. Paclitaxel-enhancing effects were also maximum with LDFR 4 × 0.5 Gy, however only in HRS-positive HFIB2 fibroblasts were significantly greater than those with a single dose of 2 Gy. The results demonstrate that LDFR may enhance the effects of cisplatin and paclitaxel in SiHa and CaSki cells, although they lack HRS phenomenon, and show that the magnitude of the potentiating effects of LDFR depends on cytostatic type and the size of low doses. In normal fibroblasts the chemopotentiating effects of LDFR seem to depend on HRS status. In conclusion, the unique enhancing effects of LDFR on cisplatin in cervical cancer cell lines, even when HRS negative, suggest that all patients with cervical cancer may benefit from the addition of LDFR to adjuvant cisplatin-based chemotherapy.

Central Pathology Review in SENTIX, A Prospective Observational International Study on Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer (ENGOT-CX2).

The quality of pathological assessment is crucial for the safety of patients with cervical cancer if pelvic lymph node dissection is to be replaced by sentinel lymph node (SLN) biopsy. Central pathology review of SLN pathological ultrastaging was conducted in the prospective SENTIX/European Network of Gynaecological Oncological Trial (ENGOT)-CX2 study. All specimens from at least two patients per site were submitted for the central review. For cases with major or critical deviations, the sites were requested to submit all samples from all additional patients for second-round assessment. From the group of 300 patients, samples from 83 cases from 37 sites were reviewed in the first round. Minor, major, critical, and no deviations were identified in 28%, 19%, 14%, and 39% of cases, respectively. Samples from 26 patients were submitted for the second-round review, with only two major deviations found. In conclusion, a high rate of major or critical deviations was identified in the first round of the central pathology review (28% of samples). This reflects a substantial heterogeneity in current practice, despite trial protocol requirements. The importance of the central review conducted prospectively at the early phase of the trial is demonstrated by a substantial improvement of SLN ultrastaging quality in the second-round review.

Molecular prognostic factors in early-stage cervical adenocarcinoma.

Within the past years the proportion of cervical adenocarcinomas has increased, however, there is a shortage of data regarding immunohistochemical and molecular features and their prognostic relevance in early-stage cervical adenocarcinoma (esCAC). Aim of the present study was to evaluate molecular prognostic factors in esCAC patients treated with primary surgery. Analyses of surgical specimens in 59 patients with esCAC were performed on fixed paraffin-embedded sections of tumour tissue. Tumour tissue sections were routinely stained with hematoxylin and eosin followed by microscopic examination. Immunohistochemical analyses (IHC) were performed on paraffin-embedded section. Flow cytometry (FCM) analysis of paraffin-embedded tumor tissue was performed using flow cytometer FACSCalibur equipped with argon laser. DNA histogram analysis was performed with ModFit application. Treatment effectiveness was evaluated using overall 5-year survival. Survival probability was estimated using the Kaplan-Meier method. Overall survival rate estimated using Kaplan-Meier method was 74.6%. Among the IHC and FCM features univariate analysis showed statistical significance of nm23-H1 gene expression and total S-phase fraction ≤ 11.9% (S-TOT). In multi- variate analysis LVSI and parametrial involvement had significant, negative impact on survival (HR = 8.04, p < 0.003 and HR = 4.03, p < 0.017, respectively). However, none of the tested IHC and FCM features had any influence on overall 5-year survival.

Low-Dose Hypersensitive Response for Residual pATM and γH2AX Foci in Normal Fibroblasts of Cancer Patients.

PURPOSE: To define the dose-response relationship for initial and residual pATM and γH2AX foci and temporal response of pATM foci in fibroblasts of 4 hyper-radiosensitivity (HRS)-positive cancer patients and 8 HRS-negative cancer patients and answer the question regarding the role of DNA double-strand break (DSB) recognition and repair in the mechanism of HRS. METHODS AND MATERIALS: The cells were irradiated with single doses (0.1-4 Gy) of 6-MV X rays. The number of initial and residual pATM and γH2AX foci was assessed 1 hour and 24 hours after irradiation, respectively. Kinetics of DSB recognition and repair was estimated by pATM foci assay after irradiation with 0.2 and 2 Gy. RESULTS: Hyper-radiosensitivity response (confirmed by the induced-repair model) was clearly evident for residual pATM and γH2AX foci in fibroblasts of HRS-positive patients but not in fibroblasts of HRS-negative patients. Significantly less DSB was recognized by pATM early (10-30 minutes) after irradiation with 0.2 Gy in HRS-positive compared with HRS-negative fibroblasts. CONCLUSIONS: The present results provide evidence for the role of DSB recognition by pATM and repair in the mechanism of HRS and seem to support the idea of nucleo-shuttling of the pATM protein to be involved in HRS response.

Asymptomatic uterus-like mass (ULM) of the extraperitoneal space - a case report of a rare finding with unusual clinical presentation and review of the literature.

The paper presents a case of a uterus-like mass (ULM), a rare type of tumour of the female reproductive system, which did not present any clinical symptoms described in other cases of ULMs. There are 35 reported cases of this type of tumour. It is defined as a lesion composed of smooth muscle-like stromal cells with a central cavity lined with endometrial type epithelium. There are three theories on the pathogenesis of ULMs which we discuss along with clinical presentation, diagnostic features, treatment options and potential oncological implications of this type of tumour, based on our case, and the review of the literature.

Comparison of effectiveness of treatment of patients with sporadic and germline BRCA1-related ovarian cancer.

OBJECTIVES: Numerous reports suggest that the clinical course of ovarian cancer (OC) in BRCA, including BRCA1, mutation carriers (BRCA1-OC) is different than in patients with sporadic ovarian cancer (SOC). Most of the authors indicate more fa-vourable treatment results in patients with BRCA1-OC. The aim of the study was to compare the effectiveness of treatment of patients with advanced-stage (FIGO III/IV) SOC and BRCA1-OC. MATERIAL AND METHODS: Between 2004 and 2009, 957 OC patients were treated in Cracow Branch of Cancer Center, M. Sklodowska-Curie Memorial Institute, Poland. Germline BRCA1 mutation was found in 66 patients. To compare the effective-ness of treatment, the group of 47 advanced-stage BRCA1-OC patients was matched with the group of 47 advanced-stage SOC patients. Pairs of patients were matched in terms of the most important prognostic factors, i.e. stages according to FIGO, primary cytoreduction extent, tumour histologic subtype and grade, as well as year of diagnosis and treatment. RESULTS: The 5-year overall survival rate was 42.9% for BRCA1-OC patients and 34.3% for SOC patients (p = 0.354). Mean time to progression was 22.7 and 14.5 months for BRCA1-OC and SOC group, respectively (p = 0.05). Complete response to pri-mary surgery and first line chemotherapy was obtained in 42.5% and 37.9% of cases, respectively; the difference, however, did not reach the statistical significance. CONCLUSIONS: Results of combined treatment in the group of BRCA1-related OC patients seem to be better than in the group of sporadic ovarian cancer patients.

Prognostic factors in Polish patients with BRCA1-dependent ovarian cancer.

BACKGROUND: Treatment outcomes appear to be better for ovarian cancer (OC) patients carrying the BRCA1/2 germline mutation than for patients with sporadic OC. However, most published data are for North American, British and Jewish populations. There have been very few studies on treatment outcomes in Central and Eastern European patients with OC. The aim of this study was to analyse prognostic factors in Polish patients with BRCA1-dependent OC (BRCA1-OC). METHODS: The records of patients with OC treated with surgery and chemotherapy at the Centre of Oncology in Kraków, Poland, between 2004 and 2009 were reviewed. Based on family history, a group of 249 consecutive patients fulfilling the criteria for risk of hereditary OC were selected and tested for the germline BRCA1 mutation. Response to combination therapy (surgery and chemotherapy) in the BRCA1-OC group was assessed based on clinical examination, imaging and serum CA125. RESULTS: Germline BRCA1 mutations were detected in 69 of the 249 patients, but three of these patients failed to complete the study. Finally, 66 patients with BRCA1-OC were included in the study group. The median age of the study patients was 49.5 years. All had undergone primary or interval cytoreductive surgery and chemotherapy. Progression occurred in 48 (72.7 %) of the 66 patients and median time to progression was 20 months. The 5-year overall survival rate in was 43.9 % and median survival time was 32.3 months. On multivariate analysis, the endometrial subtype of OC and serum CA125 < 12.5 U/ml at the end of treatment were independent, positive prognostic factors for 5-year overall survival. CONCLUSION: Prognostic factors for favourable treatment outcomes in Polish patients with BRCA1-OC do not appear to differ from those in patients with sporadic OC. The incidence of the endometrial subtype of OC was relatively high (34.9 %) among women in the study. This was unexpected and has not been reported previously. This subtype of OC was an independent prognostic factor for favourable treatment outcomes.

[Clinical features and disease course in patients with BRCA1-dependent ovarian cancer]. / Cechy kliniczne i przebieg choroby u chorych na BRCA1-zaleznego raka jajnika.

INTRODUCTION: Ovarian cancer (OC) remains a challenge for gynecologic oncologists due to poor prognosis and increasing morbidity. About 10% of cases is hereditary and BRCA1 gene mutation-dependant. Some authors claim that clinical features, the course of the disease and prognosis of BRCA1-dependent OC vary between sporadic cases. AIM OF THE STUDY: To analyze clinical features and disease courses of BRCA1-dependent OC in the material from Center of Oncology Cracow Branch. MATERIAL AND METHODS: Between 2004 and 2008, 66 mutations of BRCA1 gene were found in patients with OC. All patients were treated with primary surgery followed by platinum-based chemotherapy Outcomes were assessed by means of clinical examination and imaging tests. Patients with complete response were followed up in the outpatient office. Secondary chemotherapy was administered if persistent or progressive disease was diagnosed. RESULTS: In the analyzed group of 66 (100%) patients, the following mutations of BRCA1 gene were found: in 31 (47%) - C61G (exon 5), in 21 (31,8%) - 5382insC (exon 20), in 6 (9.1%) - 185delAG and in 8 (12.1%) - other (exon 11). Mean patient age was 48. FIGO stage I and stage II were diagnosed in 7 (10,6%), stage III in 58 (89,9%) and stage IV in 1 patient (1,5%). Twenty five (37.9%) patients underwent complete macroscopic primary cytoreduction. Platinum-based chemotherapy was administered to all 66 patients after surgery Complete response (CR), partial response (PR) and progressive disease (PD) was achieved in 31 (46.9%), 30 (45,5%) and 5 (7.6%) patients, respectively Secondary surgery was performed in 29 (43.9%) of patients after completion of adjuvant therapy Second-line chemotherapy was administered in 40 (60.6%) patients due to residual or progressive disease. Mean time of follow-up was 65 months. Forty one (62. 1%) patients died due to OC progression. CONCLUSIONS: Clinical features and disease courses in BRCA1-dependent OC patients in the analyzed group were similar to other results reported in the literature.

[The prevalence of BRCA1 mutations among families at high-risk of breast and ovarian cancer in province of Malopolska between 2004-2009]. / Wystepowanie mutacji genu BRCA1 w populacji rodzin wysokiego ryzyka zachorowania na raka piersi i jajnika w Malopolsce w latach 2004-2009.

INTRODUCTION: Germinal mutations of BRCA1/BRCA2 genes are one of the important reasons of breast and ovarian cancer development. The prevalence of BRCA1 mutations in Polish population is relatively frequent, particularly among families at high-risk of breast and/or ovarian cancer. Moreover, the presence of "founder effect" is characteristic for those families. The aim of this paper was analysis of the incidence of BRCA1 mutation among such families in province of Malopolska, Poland. MATERIAL AND METHODS: In the Genetic Outpatient Clinic of Center of Oncology, Cracow Department 630 families with positive and characteristic for hereditary breast and/or ovarian cancer familial history were registered since 2004. The main criterion were recommendations for genetic testing of families at high-risk, expressed in National Program for Cancer Control in Poland. The BRCA1 test was done in 710 representatives of families at high-risk of breast and/or ovarian cancer. RESULTS: The BRCA1 mutations were found in 101 (16%) families. The domination of 3 types of mutation--5382insC, C61G and 4153delA--typical for Polish population, was described. They have been found in 94.6% of all mutation carriers. CONCLUSIONS: The prevalence of BRCA1 mutations in families at high-risk of breast and/or ovarian cancer is relatively frequent. Among the carriers, the founder mutations were found in the most of cases.