New staging of endometrial carcinoma - FIGO 2023.

AIM: To review the changes in the new version of the FIGO 2023 staging system for endometrial cancer. METHODS AND RESULTS: The new FIGO 2023 endometrial cancer staging system provides key updates for the diagnosis and treatment of endometrial cancer. An important step in diagnosis is molecular classification, which allows more accurate risk stratification for recurrence and the identification of targeted therapies. The new staging system, based on the recommendations of the international societies ESGO, ESTRO and ESP, incorporates not only the description of the pathological and anatomical extent of the disease, but also the histopathological characteristics of the tumour, including the histological type and the presence of lymphovascular space invasion. In addition, the staging system uses molecular testing to classify endometrial cancers into four prognostic groups: POLEmut, MMRd, NSMP and p53abn. Each group has its own specific characteristics and prognosis. The most significant changes have occurred in stages I and II, in which the sub-staging better reflects the biological behaviour of the tumour. This update increases the accuracy of prognosis and improves individualized treatment options for patients with endometrial cancer. CONCLUSION: The updated FIGO staging of endometrial cancer for 2023 incorporates different histologic types, tumour features, and molecular classifications to better reflect the current improved understanding of the complex nature of several endometrial cancer types and their underlying bio logic behaviour. The aim of the new endometrial cancer staging system is to better define stages with similar prognosis, allowing for more precise indication of individualised adjuvant radiation or systemic treatment, including the use of immunotherapy.

Human papillomavirus infection (HPV) and pregnancy.

Human papillomavirus (HPV) is the most common sexually transmitted viral infection worldwide, which may result in the development in benign lesions or malignant tumors. The prevalence of HPV infection is twice as high in pregnancy as in non-pregnant women. Additionally, there is a risk of vertical transmission of HPV from mother to fetus during pregnancy or childbirth. Various studies have reported an increased risk of adverse pregnancy outcomes in HPV-positive women, including miscarriage, preterm birth, premature rupture of membranes, preeclampsia, fetal growth restriction, and fetal death. HPV vaccination is not currently recommended during pregnancy. On the other hand, there is no evidence linking HPV vaccination during pregnancy with adverse pregnancy outcomes and termination of pregnancy is not justified in this case.

Preoperative and postoperative staging in endometrial cancer - a prospective study.

OBJECTIVE: The aim of this study was to determine how often changes the stage of the tumour in definitive histology against preoperative clinical stage in patient cohort with diagnosed endometrial cancer. METHODS: We evaluated prospectively a cohort of 166 patients with endometrial cancer. They all underwent abdominal hysterectomy, bilateral salpingo-oophorectomy, sentinel lymph node biopsy. Patients with high-risk tumours also pelvic lymfadenectomy. We collected data of preoperative diagnostic biopsy and postoperative definitive histology. The data were statistically processed. RESULTS: Detection of sentinel lymph node was successful in 71.1%, bilateral successful detection was in 40.6%. Discrepancy of tumour grade between preoperative biopsy and definitive histology was generally 31.4%. Upgrading of the tumour was in 22 (14.4%) cases, downgrading in 26 (17%) cases. Upgrade from low-risk to high-risk group of tumours was noticed in eight cases. Histopathological tumour type changed in 6.6%, 4.6% moved to histopathologic high-risk group. The tumour stage changed in definite histology in 57.3%, in 19.2% of cases moved from stage low/intermediate-risk group to intermediate-high/high-risk disease group. CONCLUSION: Correct assessment of preoperative clinical stage and histological grade of endometrial cancer is burdened with a high inaccuracy rate. A lot of cases is up-staged after surgical staging and moved to intermediate-high/high-risk disease group. Results confirm the importance of oncogynaecologic centre II. evaluation of histopathology findings from diagnostic biopsies made in referring hospitals. Sentinel lymph node biopsy should be performed even in clinically low/intermediate-risk disease group.

Individualization of surgical management of cervical cancer stages IA1, IA2.

OBJECTIVE: To evaluate the risk of involvement of sentinel lymph nodes in cervical cancer stage IA1 with lymphovascular space invasion and IA2 using the detection of sentinel lymph nodes. DESIGN: Original article. SETTINGS: Department of Gynecology and Obstetrics 3rd Faculty of Medicine, Charles University, Faculty Hospital Královské Vinohrady, Prague; Oncogynecological centrum; Department of Pathology 3rd Faculty of Medicine, Charles University, Faculty Hospital Kralovské Vinohrady, Prague. METHODS: The study included women from prospective protocols LAP I and LAP II with cervical cancer stage IA1 with lymphovascular space invasion and stage IA2 from 2002 to 2018 classified according to FIGO 2014 staging, TNM 8. Detection of sentinel lymph nodes throughout this period was performed using ultra-short protocol with Tc and patent blau and also by histopathological examination. RESULTS: In the first group (28 women) with stage IA1 and lymphovascular space invasion diagnosed from cone biopsy there were two women with positive lymph nodes (7.1%). In the group stage IA2 (34 women) there were 13 women (38.2%) with positive lymphovascular space invasion and two women had positive lymph nodes (5.9%). The risk of positive lymph nodes for stage IA1 with lymphovascular space invasion and for stage IA2 is not statistically significant OR = 0.8125 (95% CI 0.1070-6.172). CONCLUSION: The detection of sentinel lymph nodes aids to individualize the therapy of early stage cervical cancer and helps to reduce the radicalization of surgery. The risk of positive lymph nodes in stage IA1 with lymphovascular space invasion and stage IA2 with/without lymphovascular space invasion is the same. The results confirm, that the detection of sentinel lymph nodes in stage IA1 with lymphovascular space invasion is fully indicated.

Histopathological and clinical features of molar pregnancy.

OBJECTIVE: To analyse own set of molar pregnancies and to develop clinically relevant procedures. TYPE OF STUDY: Review article with analysis of own data. SETTINGS: Department of Pathology 3rd Faculty of Medicine, Charles University, Faculty Hospital Královské Vinohrady, Prague; Department of Obstetrics and Gynecology 3rd Faculty of Medicine, Charles University, Faculty Hospital Královské Vinohrady, Prague. INTRODUCTION: The study monitors the decrease of laboratory values of beta-subunit of hCG gonadotropin (beta-hCG) after evacuation of partial and complete hydatidiform moles in a set of 45 partial and 46 complete moles. Two case reports of invasive moles. RESULTS: In cases of partial hydatidiform moles there was complete regression of beta-hCG in all cases, 89% regressed in six weeks, none of the women showed no subsequent elevation after reaching negativity. In cases of complete hydatidiform moles the decrease was less gradual, the negativity after six weeks was confirmed in 78%, three complete moles became malignant. CONCLUSION: The decrease of beta-hCG after molar pregnancy termination is variable. Even if in cases of complete hydatidiform moles the risk of malignization after reaching negativity is low, beta-hCG checks are recommended at monthly intervals for 6 months. Correct diagnosis of complete mole and its differentiation from partial mole can be achieved using immunohistochemistry - p57 antibody.

[Ovaria borderline tumor - fertility-sparing surgery; case report]. / Fertilitu zachovávající lécba borderline tumoru ovaria - kazuistika.

The borderline tumors are known as low malignant potential tumors. Usually younger women suffer for them, than by the invasive ovarian carcinoma. They often which to be pregnant. The fertility-sparing surgery is posile but contain higher risk of the new disease on contralateral ovary.

The role of trachelectomy in cervical cancer.

Cervical cancer is one of the most common cancers in women worldwide. Because it often affects women of childbearing age (19-45 years), fertility-sparing surgery is an important issue. The article reviews current viable fertility-sparing options with a special focus on trachelectomy, including vaginal radical trachelectomy, abdominal radical trachelectomy and simple trachelectomy. Neoadjuvant chemotherapy is also discussed. Finally, the decision to proceed with fertility-sparing treatment should be a patient-driven process.

A pilot study on peak systolic velocity monitoring of fetal anemia after administration of chemotherapy during pregnancy.

OBJECTIVES: To monitor fetal anemia during administration of chemotherapy to the fetus's mother. STUDY DESIGN: Between 2007 and 2012 six patients with malignancy diagnosed during pregnancy were included in our prospective study. For evaluation of fetal anemia, peak systolic velocimetry (PSV) of the middle cerebral artery is considered the best method. The patients were repeatedly examined one day before and on the third day after the administration of chemotherapy. At least three measurements were performed and the highest value was used as appropriate. Multiples of the median (MoM) were calculated using the website http://www.perinatology.com/calculators/MCA.htm. When the MoM reached 1.29, moderate anemia was diagnosed. RESULTS: The women's average age was 30 years. The average gestational age at diagnosis was 20.7 weeks of pregnancy. Borderline fetal anemia was detected in only in one patient. After delivery newborns were examined by standard pediatric evaluation and blood count was provided. There was no evidence of any newborn anemia. CONCLUSIONS: Chemotherapy administered during pregnancy is becoming more frequent due to increasing knowledge and data on such cases. Close monitoring of the fetus should be performed in specialized centers. For detection of chemotherapy-induced anemia, PSV measurement should be employed.

[Lymphedema after vulvar cancer surgery. A prospective study]. / Lymfedémy po operacích karcinomu vulvy. Prospektivní studie.

INTRODUCTION: Prospective detection of postoperative lymphedema of the lower limbs (LLL) in patients after surgery for vulvar cancer using different examination methods and their comparison. DESIGN: Prospective clinical study. SETTING: Department of Obstetrics and Gynecology, 2nd Medical Faculty of the Charles University and University Hospital Motol, Prague. METHODS: Totally 36 women were followed after surgery for vulvar cancer. Due to the radicality of surgery the patients were divided into conservative (sentinel lymph node biopsy) and radical (inguinofemoral lymphadenectomy) group. Lower limbs were preoperatively and 3, 6 and 12 months after surgery assessed for the presence of lymphedema by measuring of circumferences, multifrequency bioelectrical impedance analysis (MFBIA) and subjective evaluation of patients. RESULTS: The prevalence of lower limb lymphedema 12 months after surgery diagnosed by subjective evaluation reached 19,44%, by circumference measurement 38,89% and with MFBIA 66,67%. The prevalence of lymphedema after inguinofemoral lymphadenectomy diagnosed by circumference measurement was in 12 months after surgery higher (45.83%) than after the conservative surgery (25%). Risk factors were evaluated 12 months after surgery (age, BMI, adjuvant radiotherapy, type of surgery) and none of them were found to be statistically significant for the development of the lower limbs lymphedema. CONCLUSION: The prevalence of lymphedema significantly depends on the diagnostic method, because they capture lymphedema in its various stages. Due to the high sensitivity MFBIA can be used for the detection of early stages of lymphedema. Preoperative measurement of the lower limbs is important for early detection of postoperative lymphedema.

[Gynaecological precanceroses from the clinical perspective - today and tomorrow]. / Gynekologické prekancerózy z pohledu klinika dnes a zítra.

During the last twenty-five years an enormous shift in our knowledge of cancerogenesis in all gynaecological precancerous and cancerous diseases can be seen. Early diagnosis of these lesions of the lower genital tract (vulva, vagina and cervix) is enabled mainly due to easy access. The major role in the pathogenesis of most precancerous lesions can be accounted to high risk human papillomavirus. Recently, new information about HPV genotypisation of single precancerous lesions and single histological cancer types were revealed. Thus we can better estimate the effect of vaccines on different age groups of women in relation to different types of cancer. The development and introduction of prophylactic vaccines into clinical practice was one of the major improvements of current medicine. Precancerous and cancer lesions of endometrium make themselves known by early symptoms such as perimenopausal and postmenopausal bleeding. Optimal diagnostic and therapeutic procedures have to be based on close cooperation between the clinician and pathologist.

[Review of precancerous vulvar lesions]. / Prekancerózní léze vulvy.

Classification of squamous vulvar precancerous lesions is based on the concept of vulvar intraepithelial neoplasia (VIN) and incorporates a three grade evaluation of the intensity of dysplastic changes (VIN I, II and III). On the basis of histological features, VIN has been subdivided into the usual VIN (u-VIN) and differentiated VIN (d-VIN), which represent the two basic pathways of the pathogenesis of vulvar squamous cell carcinoma. Although u-VIN is etiologically associated with the human papillomavirus (HPV) infection and histologically corresponds to cervical intraepithelial neoplasia, d-VIN represents the HPV-negative sequence of vulvar carcinogenesis, which is linked to lichen sclerosus (LS) and lichen simplex chronicus (LSC). u-VIN preferentially occurs in relatively young women with a history of cervical, vaginal or vulvar premalignant lesions. On the other hand, d-VIN usually affects postmenopausal women without anamnestic data of other dysplastic lesions of the lower female genital tract. d-VIN is characterized by a higher tendency of stromal invasion than u-VIN and its malignant potential is analogous to carcinoma in situ (VIN III). The histological appearance of d-VIN is subtle with basal atypia and a well-preserved differentiation of the superficial parts of the squamous epithelium, therefore it is frequently misdiagnosed for u-VIN I, LS or LSC in vulvar biopsies. Primarily because of the low diagnostic reproducibility of the u-VIN I category and the doubts about its precancerous potential as well as due to the questionable differentiation between u-VIN II and III, a revised VIN classification was proposed in 2004. The grading of vulvar precancerous lesions was abandoned, the u-VIN I category was discontinued and u-VIN II and III were merged. In the revised terminology, the term u-VIN represents HPV-associated high grade precancerous vulvar lesions (formerly u-VIN II and III) and d-VIN encompasses HPV-negative high grade dysplasias.

[Czech version of EORTC QLQ-CX24 questionnaire for patients with cervical cancer]. / Ceská verze dotazníku EORTC QLQ-CX24 pro pacientky s karcinomem delozního hrdla.

OBJECTIVE: Translation and validation of the EORTC QLQ-CX24 questionnaire on quality of life into the Czech language and literature. TYPE OF STUDY: Prospective study. SETTING: Dept. of Obstetrics and Gynaecology, 2nd Medical Faculty, Charles University and Faculty Hospital Motol, Prague. METHODS: In concordance with the EORTC guidelines a questionaire for patients with cervical cancer was translated and validated. A group of 14 women who underwent the treatment for cervical cancer filled in the questionaire. T-test was used for the evaluation of the patient's characteristics and the differences in quality of life. RESULTS: We present a Czech version of the questionaire EORTC QLQ-CX24 and the description how to evaulate it. In comparison of the two treatment groups no statistically significant differences have been found. CONCLUSION: EORTC QLQ-CX24 is an internationally accepted questionnaire focused on patients with cervical cancer which should be incorporated into the projects dealing with women undergoing treatment for this disease.

[Chemotherapy during pregnancy]. / Chemoterapie behem tehotenství.

OBJECTIVE: The aim of the study is to summarize current data on chemotherapy administered during pregnancy. TYPE OF STUDY: Review article. SETTING: Dept. of Obstetrics and Gynaecology of the Charles University in Prague, 2nd Medical Faculty, University Hospital. SUBJECT AND METHOD: Pubmed database was searched between the years 1980 and 2009 with the combinations of key words concerning cytostatics, therapy and pregnancy. Cisplatin administration was identified in 38 cases. Eight cases of administration of carboplatin during pregnancy were found with normal neonatal outcome Twenty-one case reports were found on the use of taxanes during pregnancy: 14 on paclitaxel and 7 on docetaxel. CONCLUSION: Based on the literature the administration of cytostatics during pregnancy can be considered under a close supervision and long-term follow-up in dedicated teams.

[Treatment of recurrent ovarian cancer]. / Lécba recidivujícího ovariálního karcinomu.

OBJECTIVE: The description of current treatment possibilities in recurrent ovarian cancer. DESIGN: Review article. SETTING: Obstetrics and Gynecology Department, Charles University 2nd Medical Faculty and University Hospital Motol, Prague. METHODS: The review of literature on treatment of recurrent ovarian cancer. Current data on chemotherapy, surgery and targeted biological therapy in recurrent ovarian cancer. CONCLUSIONS: Chemotherapy is indicated in most cases of recurrent ovarian cancer, surgery does not play an important role. Standard treatment of platinum-sensitive recurrent ovarian cancer is based on platinum combination chemotherapy. Standard treatment of platinum-refractory ovarian cancer represents non-platinum monotherapy. Targeted biological therapy should be still used only in the studies.

High-dose density chemotherapy followed by simple trachelectomy: full-term pregnancy.

We report five patients with early-stage cervical cancer who do not fulfill criteria of fertility-sparing surgery (tumor more than 2 cm in the biggest diameter or infiltrating more than half of stroma). Five patients received three cycles of dose density neoadjuvant chemotherapy (NAC) at a 10-day interval: cisplatin plus ifosfamide in squamous cell cancer or plus doxorubicin in adenocarcinoma with good tolerance. After NAC, they underwent laparoscopic pelvic lymphadenectomy and vaginal simple trachelectomy. Two patients had no residual tumor, two had only microscopic residual disease, and one had macroscopic residual disease. Two women became pregnant 5 and 8 months after surgery, one delivered in term healthy baby and one is now in the second trimester of pregnancy without any complications. NAC followed by fertility-sparing surgery seems to be feasible treatment for women with tumor bigger than 2 cm or infiltrated more than half of the stroma.

Endodermal sinus tumor diagnosed in pregnancy: a case report.

Pure endodermal sinus tumor (EST) of the ovary is an uncommon germ cell tumor characterized by rapid growth. Its occurrence during pregnancy is extremely rare. The case of a 34-year-old woman with EST stage IC diagnosed in the 22nd week of gestation is presented. She received four cycles of cisplatin monotherapy during pregnancy. Further, three cycles of combination chemotherapy (cisplatin, bleomycin, and etoposide) were administered. Twenty-eight months posttreatment the patient was in complete remission with good health. A healthy female infant was delivered by cesarean section in the 35th week of pregnancy. The child showed normal laboratory, pediatric, and neurologic examination at the time of discharge from hospital and during the first and second years of her life. We conclude that the prognosis of EST is very good if patient receives adjuvant therapy. Cisplatin monotherapy seems to be effective and safe during pregnancy.

Less radical fertility-sparing surgery than radical trachelectomy in early cervical cancer.

The purpose of this pilot study was to determine feasibility and safety of a novel and less radical fertility-preserving surgery; laparoscopic lymphadenectomy with sentinel lymph node identification (SLNI) followed by large cone or simple trachelectomy. Obstetrical and oncologic outcomes were evaluated. Twenty-six patients (6-IA2, 20-IB1) selected on basis of favorable cervical tumor characteristics and the desire to maintain fertility underwent laparoscopic SLNI, frozen section (FS), and a complete pelvic lymphadenectomy as first step of treatment. All of nodes were submitted for microscopic evaluation (sentinel nodes for ultramicrostaging). After a 7-day interval, large cone or simple vaginal trachelectomy was performed in patients with negative nodes. The average of sentinel nodes per side was 1.50 and the average of total nodes was 28.0. Four FS were positive (15.4%). In these cases, Wertheim radical hysterectomy type III was immediately performed. We had no false-negative SLN neither on FS nor on final pathology assessment. Median follow-up was 49 months (18-84). One central recurrence (isthmic part of uterus) was observed 14 months after surgery. This patient was treated with radical chemoradiotherapy, and there was no evidence of the disease 36 months after treatment. Fifteen women planned pregnancy, 11 women became pregnant (15 pregnancies), and 7 women delivered eight children (one in 24 weeks, one in 34 weeks, one in 36 weeks, and five between 37 and 39 weeks). We conclude that lymphatic mapping and SLNI improves safety in this fertility sparing surgery. Large cone or simple trachelectomy combined with laparoscopic pelvic lymphadenectomy can be a feasible method with a high successful pregnancy rate.

[Progression and regression low grade intraepitelial squamous lesions in context of positivity of high risk human papillomavirus]. / Progrese a regrese low grade intraepiteliálních skvamózních neoplazií v závislosti na prítomnosti HPV HR viru.

OBJECTIVE: Evaluation of regression and progression of histologically confirmed low grade squamous intraepithelial lesions (LG SIL) in women under the age of 35 in context of positivity of high risk human papillomavirus (HPV HR). Evaluation of sensitivity of PAP smear and HPV HR test in women with LG SIL. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology, Charles University Prague, 2nd Medical Faculty, University Hospital Motol. PATIENTS AND METHODS: 166 women with SIL low or repeated ASC-US PAP smear were included to the study. 1 to 3 punch biopsy under the expert colposcopy and HPV HR test were performed in all women. Follow up were done every 6 month in all women with histologically confirmed LG SIL. RESULTS: LG SIL was detected in 120 women. Sensitivity of PAP smear was 72.3% and sensitivity of HPV HR test 60.2 % in women with LG SIL. 84 women (70 %) were HPV HR positive. Regression of LG SIL was detected in 20 (23 %) HPV HR positive women and in 18 (50%) HPV HR negative women. This difference is statistically significant (p = 0.0094). Progression of LG SIL was detected in 24 (29 %) HPV HR positive women and in 4 (11%) women HPV HR negative women. This difference is borderline statistically significant (p = 0.058). Progression of LG SIL to the carcinoma in situ or invasive cancer had not been detected during follow up period. CONCLUSION: PAP smear is a standard for LG SIL detection in women under the age of 35 and HPV HR test is not so important for LG SIL detection in this group of women. HPV HR test could be useful for prediction of the risk of progression, but positivity of HPV HR in LG SIL cannot indicate surgical treatment (conisation) in this cohort of women under the age of 35.

[Sentinel lymph nodes identification in vulvar cancer--methods and technique]. / Detekce sentinelových uzlin u karcinomu vulvy--metody a technika.

OBJECTIVE: To evaluate detection of sentinel lymph nodes (SLN) in squamous vulvar cancer with blue dye and 99mTc. The study describes technique of application, timing, management, detection rate (DR), specific side detection rate (SSDR) and false negative rate. DESIGN: Prospective clinical study. SETTING: Department of Obstetrics and Gynecology, Charles University Prague, 2nd Medical Faculty, Teaching Hospital Motol. PATIENTS AND METHODS: 46 women with squamous cell carcinoma tumors stage I or II, <4 cm with no clinical suspect lymph nodes were included. Blue dye alone was used in 16 women and the combination of 99mTc and blue dye was used in 30 women. Radiocoloid 99mTc was applied 3-5 hours and blue dye 3-5 minutes prior to ingvinal incision. RESULTS: We detected 88 SLN in 61 inguinal spaces. The detection rate in the blue dye group was 68.8 % (11 cases). One false negative SLN (6.3 %) appeared in this group. In blue dye+ 99mTc group detection rate was 100 % with no false negative SLN. CONCLUSION: Detection of SLN in squamous vulvar cancer with the combination of 99mTc and blue dye was statistically significantly more effective than using the blue dye alone.

[Fertility sparing surgery in early cervical cancer today and tomorrow]. / Fertilitu zachovávající operace u casného stadia karcinomu delozního hrdla dnes a zítra.

OBJECTIVE: Describtion and evaluation of proposed protocol for conservative, fertility sparing surgeries in the treatment of early stages of cervical cancer and its comparison to most frequently used protocols regarding its reproductive and oncological outcomes. DESIGN: Prospective clinical study. SETTING: Department of Obstetrics and Gynecology, Charles University Prague, 2nd Medical Faculty, University Hospital Motol. PATIENTS AND METHODS: 24 patients that fitted into the inclusion criteria were recruited in the study (6 in stage T1A2 and 18 T1B1). Inclusion criteria were: tumor less than 20 mm in largest diameter, less than 1/2 of the stromal invasion, SCC serum levels within normal range, signed informed consent. Minimum follow up was 24 months. Described therapeutic protocol, evaluation of oncological and reproductive outcomes and comparison with different fertility sparing regimens were performed. RESULTS: In four cases (16.7%) peroperative histopatghological evaluation (frozen section: FS) detected metastatic involvement of lymphatic nodes. In one case (4.1%) following 14 months since initial surgery, reccurent disease in uterine isthmus was detected. The patient underwent chmotherapy and she is 36 months in complete remission. In the series of 15 women planning pregnancy 11 subjects become pregnant so far. Eight deliveries occurred (one in 24th week of gestation--650g, one in 34w--2240g, one in 36w--2700g and five between 37-39w). Only one newborn was delivered in the cathegory of extreme prematurity. CONCLUSION: Sentinel node detection involving peroperative histopathological evaluation followed by subsequent serial processing and together with 2-step therapeutic management increases efectivity of fertility sparing surgeries. Less radical surgery on uterine cervix: reconisaton (in stage IA2) or simple trachelectomy (in early stage T1B1) with negative finding after laparoscopic lymph node dissection has comparative results with radical trachelectomy and abdominal radical trachelectomy. Pregnancy rates and pregnancy outcomes particularly regarding in term delivery is the best after treatment of early stages of cervical cancer using proposed protocol, while very promising results are published in studies with radical vaginal trachelectomy as well. Results published for the patients treated with abdominal radical trachelectomy are unsatisfactory.