Prognostic Factors of Cervical Adenocarcinoma With Positive Pelvic Lymph Node Metastases Without Preoperative Lymph Node Enlargement Treated With Radical Hysterectomy.

BACKGROUND/AIM: Pelvic lymph node (LN) metastases are found histopathologically after radical hysterectomy (RH) in some cases of cervical adenocarcinoma with no enlarged LNs on preoperatively. The aim was to clarify whether LN metastasis is a prognostic factor in these patients, and whether any postoperative therapy is advisable. PATIENTS AND METHODS: Sixty-one patients with stage I-II cervical adenocarcinoma [International Federation of Obstetrics and Gynecology (FIGO) 2008] with no enlarged pelvic LNs on preoperative imaging evaluation who underwent RH at our institution were retrospectively examined for clinicopathological, treatment, and prognosis-related factors. RESULTS: The median age was 47 years. FIGO stages were IB1 in 44 patients, IB2 in 10, IIA in 4, and IIB in 3. Seventeen patients (27.9%) had positive pelvic LNs. The multivariate analysis for both overall (OS) and disease-free (DFS) survival showed only pelvic LN metastasis was an independent prognostic factor. In a multivariate analysis of LN-positive cases, multiple LN metastases was an independent prognostic factor for poorer DFS. OS rates were 100%, 83.3%, and 30.0%, and DFS rates were 85.5%, 83.3%, and 12.5% for patients with no LN metastasis, single metastasis, and multiple metastases, respectively, showing a significant difference. Eight recurrences were observed in 10 patients with multiple node-positive disease, and six (75%) had an intrapelvic recurrence. CONCLUSION: Among patients who underwent RH for cervical adenocarcinoma with no preoperative enlarged LN and positive pelvic LNs confirmed postoperatively, multiple positive pelvic LNs are an independent poor prognostic factor. Because pelvic recurrence is common, concurrent chemoradiotherapy, possibly using paclitaxel and cisplatin, should be considered as adjuvant therapy.

Effects of Pegylated Liposomal Doxorubicin and CA125 Level Variability Analysis in Platinum-refractory/resistant Recurrent Ovarian Cancer.

BACKGROUND/AIM: Ovarian cancer is a disease with significant impact, because more than half of cases exhibit recurrence despite platinum therapy. The choice of drug for cases of recurrence remains controversial, but the current option is pegylated liposomal doxorubicin (PLD). PATIENTS AND METHODS: We retrospectively reviewed the use of PLD in patients with ovarian cancer refractory or resistant to platinum-based therapy at our Department. We also examined efficacy, predictive indices of efficacy, and adverse events as well. RESULTS: In this study of PLD monotherapy for 60 platinum-refractory/resistant recurrent ovarian cancers, there was a median progression-free survival (PFS) of 4 months, median overall survival (OS) of 11 months, and the disease control rate (DCR) was 71.7%. The treatment effect can be predicted by the reduction of CA125 level after 2 courses. Patients with an increase and decrease in CA125 after 2 cycles of PLD, respectively, had a median OS of 14.5 (2-60) and 8 (2-51) months and a median PFS of 6 (2-38) months and 3 (0-47) months. CONCLUSION: PLD is clinically effective and useful because it provides a high DCR and is tolerable to adverse events. These findings can help support the use of PLD and guide physicians in their choice of treatment when encountering such cases.

Comprehensive Genomic Profiling for Therapeutic Decision and Identification of Gene Mutation in Uterine Endometrial Dedifferentiated Carcinoma.

Endometrial dedifferentiated carcinoma is a new concept among endometrial malignancies, is rare, and has a poor prognosis as it is discovered in advanced stages and has no established treatment. It has higher rates of gene mutations, such as mismatch repair, than general endometrial cancer and has been associated with Lynch syndrome. However, due to its heterogeneity, case-by-case searches are needed. Comprehensive genomic profiling by Foundation One® CDx can comprehensively identify over 300 gene mutations via a next-generation sequencer and can evaluate biomarkers, such as the microsatellite status and tumor mutation burden. Therefore, it may be beneficial in identifying therapeutic targets and drugs for diseases whose treatment has not been established. In this case, 13 therapies, including immune checkpoint inhibitor therapy for microsatellite instability-High and 40 clinical trials for several gene mutations might be beneficial. We report a case of endometrial dedifferentiated carcinoma for which Foundation One® CDx gene profiling was used to propose treatment.

Hyperbaric Oxygen Therapy for Suburethral Vaginal Mucosal Necrosis after Interstitial Irradiation for Recurrent Cervical Cancer.

Patients with gynecological malignancies can develop radiation injuries, such as cystitis, proctitis, and soft tissue necrosis which have approved indications for hyperbaric oxygen therapy (HBOT). A 76-year-old Japanese woman with vaginal recurrence of cervical cancer was treated with the high-dose rate interstitial brachytherapy. Twenty-one months after the irradiation, she developed radiation necrosis on the external urethral opening. Two cycles of HBOT were performed. HBOT consisted of delivering 100% oxygen for 60 minutes at 2.4 atmospheres absolute. Pressure exposure was performed once daily, 5 days a week for 6 weeks. Eventually, the necrotic mucosa was completely replaced by the normal mucosa. No adverse effects were observed. We successfully treated a case of late adverse events of radiation therapy with HBOT. It was noninvasive and appears to be a useful treatment option which should be considered standard treatment practice.

A high-risk gestational trophoblastic neoplasia derived from a complete hydatidiform mole with coexisting fetus identified by short tandem repeats analysis: A case report.

A complete hydatidiform mole coexisting with a fetus (CHMCF) is a rare form of twin pregnancy. High-risk gestational trophoblastic neoplasia (GTN) can occur after a CHMCF pregnancy, although the frequency is low. In cases of GTN, the clinical diagnosis and that based on the International Federation of Gynecology and Obstetrics (FIGO) scoring system can differ. This case report concerns a patient with a choriocarcinoma that was initially diagnosed and treated as a low-risk stage III GTN following a live birth from a CHMCF pregnancy. We used short tandem repeat (STR) analysis to identify the causative pregnancy as the patient's earlier complete hydatidiform mole. Clinicians should anticipate a high-risk GTN when treating persistent trophoblastic disease (PTD) in patients with a non-typical course.

A case of nasal septal perforation caused by bevacizumab for advanced cervical cancer.

Nasal septal perforation caused by bevacizumab is rarely reported in other cancers such as ovarian cancer and breast cancer, but it has not been reported in cervical cancer. A 48-year-old woman with a medical history of chronic allergic rhinitis was diagnosed stage 4B (T2bN1M0) cervical cancer and paclitaxel and carboplatin along with bevacizumab (triweekly) were administered. After eight courses of chemotherapy, nasal septal perforation was noted. The possibility of nasal septal perforation by bevacizumab was considered by excluding other causes. We report the first case of nasal septal perforation caused by bevacizumab for advanced cervical cancer.

Long-term Outcomes of Cervical Adenocarcinoma Treated With Concurrent Chemoradiotherapy Using Paclitaxel and Cisplatin.

BACKGROUND/AIM: We retrospectively analyzed the locally advanced adenocarcinoma (AC)/adenosquamous carcinoma (ASC) of the uterine cervix treated with concurrent chemoradiotherapy using cisplatin plus paclitaxel (TP-CCRT). PATIENTS AND METHODS: Thirty patients with stage IB-IVA AC/ASC were treated with whole pelvis external beam radiotherapy. A high-dose-rate intracavitary brachytherapy was delivered once per week at a fractional dose of 6 Gy. For TP-CCRT, the patients received cisplatin and paclitaxel. RESULTS: A complete response was achieved in 17 patients (77.3%) in the TP-CCRT group and 4 patients (50.0%) in the P-CCRT group. The 5-year OS rate in the TP-CCRT and P-CCRT groups was 74.2% and 25.0% (p=0.0094), the central DFS rate was 58.0% and 12.5% (p=0.0267), and the distant DFS rate was 63.6% and 12.5% (p=0.0042), respectively. CONCLUSION: TP-CCRT achieves a considerably better disease control for AC of the cervix, leading to a better OS.

Hysterectomy for Recurrent/Residual Cervical Cancer Following Definitive Radiotherapy.

BACKGROUND/AIM: Radical hysterectomy has been used for local recurrent or persistent (LR) cervical cancer after radiotherapy (RT), but the rate of serious complications is high and tolerance is low. This study determined the efficacy, safety, and prognostic factors of adjuvant simple hysterectomy in LR cervical cancer post-RT. PATIENTS AND METHODS: A total of 21 patients who underwent hysterectomy for LR cervical cancer post-RT in our Department between May 2007 and September 2018 were included in the study. Primary, definitive RT was performed. Histological response by definitive RT in the extirpated uterus was classified on the basis of histological response criteria: effect (Ef) 0-3. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 51.9% and 50.1%, respectively. Ef 1 was significantly associated with poorer prognosis compared to Ef 2 or Ef 3. CONCLUSION: Adjuvant hysterectomy could be a treatment of choice for LR cervical cancer post-RT.

A Phase II Study of Neoadjuvant Chemotherapy Followed by Extended Field Concurrent Chemoradiotherapy for Para-aortic Lymph Node Positive Cervical Cancer.

BACKGROUND/AIM: We conducted a phase II study of neoadjuvant chemotherapy followed by extended field concurrent chemoradiotherapy in patients with cervical cancer with para-aortic node metastasis. PATIENTS AND METHODS: Thirty-seven women with stage IB1-IVA cervical cancer were enrolled. RESULTS: The median age was 52 years. Thirty-four patients other than 3 progressive disease, proceeded to extended field concurrent chemoradiotherapy. The 3-year overall survival and progression-free survival rates were 70.1% and 48.5%, respectively. The 3-year overall survival according to stages was significantly worse in stage IIIB. Twelve of the 17 patients with stage IIIB died of the disease. CONCLUSION: Neoadjuvant chemotherapy followed by extended field concurrent chemoradiotherapy may improve the prognosis of patients with stages IB and II cervical cancer with positive para-aortic node. However, new strategies should be investigated to improve a poor prognosis in stage IIIB disease with positive para-aortic node.

Direct evidence on the efficacy of GnRH agonist in recurrent steroid cell tumor-not otherwise specified.

BACKGROUND: Steroid cell tumor (SCT) not otherwise specified (NOS) is rare and recurrence and metastasis rarely occurs; therefore, reports regarding its treatment are limited. We report a case of recurrent SCT-NOS treated with gonadotropin releasing hormone agonist (GnRHa) and successful. CASE: A 50-year-old woman underwent a staging laparotomy and diagnosed as SCT-NOS. Multiple liver tumors and intraperitoneal dissemination were detected 5 years 10 months after the initial surgery. As the immunohistochemical analysis showed positive staining for GnRH receptor, GnRHa was attempted. After the first cycle the serum testosterone level was normalized and after six cycles CT scan confirmed reduction of the tumor size. CONCLUSION: Some ovarian SCT-NOS have GnRH receptors; thus, GnRHa may have a reducing effect for these tumors without major adverse event.

High-risk gestational choriocarcinoma with an unusual presentation and the treatment course of refractory or quiescent/minimally invasive disease.

•A patient with high-risk choriocarcinoma who had refractory or quiescent/minimally invasive disease.•She was treated with seven lines of chemotherapy and salvage surgeries.•The patient had persistently low hCG levels without evidence of disease for 4 years.•Then radiological evidence of pulmonary metastasis was finally achieved, and the patient was salvaged by surgery.•It is crucial to identify the site of active disease to facilitate surgical resection and cure.

Therapy-free interval has prognostic value in patients with recurrent cervical cancer treated with chemotherapy following definitive concurrent chemoradiotherapy.

PURPOSE: Patients with cervical cancer recurrence after concurrent chemoradiotherapy (CCRT) who are not candidates for surgical resection or salvage radiotherapy have a dismal prognosis. The predictive factors for the effects of chemotherapy and prognostic factors in these patients were analyzed. METHODS: We collected data for patients with recurrent cervical cancer who were primarily treated with CCRT between 2000 and 2013. Among them, 57 patients treated with only systemic chemotherapy were analyzed for the overall survival (OS), the overall response rate (ORR), and prognostic factors. RESULTS: The median age was 47 years. Inside the irradiated field recurrence occurred in 24, outside in 20 and both in 13 patients. Time to recurrence after the CCRT (i.e., therapy-free interval; TFI) were <6 months in 11, 6-12 months in 15, ≥12 months in 23 patients, and persistent disease in 8 patients. The median OS was 18 months and ORR was 15.7%. Those with a longer TFI showed a tendency for better ORR (p = 0.051) and those receiving a taxane-containing regimen showed significantly higher ORR (p = 0.0232). Multivariate analysis revealed a significant correlation between the median OS and TFI (HR = 4.688, 95% CI = 2.178-11.10, p < 0.0001) and chemotherapy response (HR = 20.08, 95% CI = 3.936-368.4, p < 0.0001). Furthermore, even in patients with stable disease, the median OS increased corresponding to the length of the TFI (p < 0.0001). CONCLUSIONS: TFI has predictive value for response to chemotherapy and prognosis of patients with recurrent cervical cancer after definitive CCRT.

Concurrent weekly cisplatin versus triweekly cisplatin with radiotherapy for locally advanced squamous-cell carcinoma of the cervix: a retrospective analysis from a single institution.

OBJECTIVE: To compare patients with cervical cancer who were primarily treated with concurrent chemoradiotherapy (CCRT) using 20 mg m-2 CDDP for 5 days every 3 weeks with weekly regimens of 40 mg m-2. METHODS: We retrospectively analyzed 185 patients with Stage IB-IVA squamous-cell carcinoma of the cervix who were treated with CCRT between 2005 and 2013 at our hospital. The CCRT regimen consisted of cisplatin (CDDP) at 20 mg m-2 for 5 days every 3 weeks or 40 mg m-2 weekly, administered concomitantly with RT. RESULTS: The median age was 50 years (range: 22-70 years) in the triweekly group and was 50.5 years (range: 28-70 years) in the weekly group. The 5-year overall survival rate in the triweekly and weekly groups were 82.0% and 83.3%, respectively (p = 0.851); their disease-free survival rate was 79.6% and 78.1%, respectively (p = 0.672). In the triweekly group, 56 patients (50.9%) had grade 3/4 leukopenia, which was significantly higher than that of 11 patients (15%) in the weekly group (p < 0.0001). CONCLUSION: The weekly CDDP regimen for CCRT seems better in patients with International Federation of Gynecology and Obstetrics Stages IB-IVA squamous-cell carcinoma of the cervix. Advances in knowledge: The weekly CDDP regimen for CCRT seems better in patients with International Federation of Gynecology and Obstetrics Stages IB-IVA squamous-cell carcinoma of the cervix.

Prognostic Factors and Treatment Outcome for Patients with Stage IVB Cervical Cancer.

AIM: We report a retrospective evaluation for patients with stage IVB cervical cancer in order to identify survival rates and to improve our current practice. PATIENTS AND METHODS: We analyzed 85 patients with stage IVB cervical cancer. For patients appropriate for radical treatment, a combination of external-beam radiotherapy and intracavitary brachytherapy was delivered with/without chemotherapy. Patients with distant metastasis were treated using systemic chemotherapy or palliative radiotherapy. RESULTS: Forty-two patients were treated using radiotherapy alone, 31 using chemotherapy followed by radiotherapy, eight using chemotherapy alone, and four using best supportive care. The 5-year overall survival rate was 9.9%. Multivariate analysis revealed leukocytosis and a poor performance status were independent prognostic factors. Of the 43 patients without these prognostic factors, patients with only lymph node metastasis had a 5-year overall survival rate of 40.5%. CONCLUSION: Radical treatment should be considered in patients who have only lymph rode metastasis and are without leukocytosis and a poor performance status.

Low-Grade Endometrial Stromal Sarcoma with Intravenous and Intracardiac Extension: A Multidisciplinary Approach.

Background. A rare case of low-grade endometrial stromal sarcoma (LG-ESS) extending to inferior vena cava (IVC) and cardiac chambers. Case Report. A 40-year-old woman had IVC tumor, which was incidentally detected by abdominal ultrasonography during a routine medical checkup. CT scan revealed a tumor in IVC, right iliac and ovarian veins, which was derived from the uterus and extended into the right atrium and ventricle. The operation was performed, the heart and IVC were exposed, and cardiopulmonary bypass was initiated. A right atriotomy was performed, and the intracardiac mass was removed. Then the tumor in IVC and the right internal iliac vein were removed after longitudinal venotomies in the suprarenal and infrarenal vena cava, the right common iliac vein. Next the pelvis was explored. Tumors were found originating from the posterior wall of the uterus and continuing into both the right uterine and ovarian vein. The patient underwent total hysterectomy with bilateral salpingooophorectomy. Complete tumor resection was achieved. Histopathological analysis confirmed a diagnosis of LG-ESS. She showed no evidence of disease for 2 years and 3 months. Conclusions. Our case highlights the importance of a multidisciplinary approach in treating this rare cardiovascular pathological condition through preoperative assessment to final operation.

Prognostic factors in patients with vulvar cancer treated with primary surgery: a single-center experience.

Vulvar cancer is a relatively rare disease. The aim of this study was to investigate prognostic factors in vulvar squamous cell carcinoma patients treated with primary surgery. Forty cases of vulvar squamous cell carcinoma treated with primary surgery were retrospectively analyzed. Overall survival (OS) and disease-specific survival (DSS) were calculated using the Kaplan-Meier method and prognostic factors were analyzed by multivariate analyses. The median age was 68 years. The FIGO stage distribution was as follows: 18 cases (45.0 %) in stage I, four cases (10.0 %) in stage II, 15 cases (37.5 %) in stage III, and three cases (7.5 %) in stage IV. A radical local excision was performed in 15 patients, and radical vulvectomy in 25 patients, and seven of these patients were treated with postoperative RT. The 5-year DSS rate was 72.6 %, and the 5-year OS rate was 70.3 %. Age and surgical margin ≤5 mm were independent prognostic factors for OS, and positive inguinal LN metastasis and surgical margin ≤5 mm were identified as independent prognostic factors for DSS. Complete radical excision is important regardless of operation mode. Adjuvant treatment should be considered for inguinal LN positive patients.

Matrices secreted during simultaneous osteogenesis and adipogenesis of mesenchymal stem cells affect stem cells differentiation.

The extracellular matrix (ECM) plays a pivotal role in regulating stem cell functions. The ECM dynamically changes during tissue development. It remains a great challenge to mimic the dynamically changing ECM. In this study, we prepared novel types of extracellular matrices that could mimic the dynamic variation of extracellular matrices, which were derived from simultaneous osteogenesis and adipogenesis of human bone marrow-derived mesenchymal stem cells (MSCs). Four ECMs simultaneously mimicking early osteogenesis and early adipogenesis (EOEA), early osteogenesis and late adipogenesis (EOLA), late osteogenesis and early adipogenesis (LOEA), late osteogenesis and late adipogenesis (LOLA) were prepared. The stepwise osteogenesis-co-adipogenesis-mimicking matrices had different compositions and different effects on the osteogenic and adipogenic differentiation of MSCs. The matrices could provide very useful tools to investigate the interaction between ECM and stem cells and the role of ECM on stem cell differentiation. STATEMENT OF SIGNIFICANCE: Extracellular matrices (ECMs) are dynamically remodeled to regulate stem cell functions during tissue development. Until now, mimicking the ECM variation during stem cell differentiation to single cell type has been reported. However, there is no report on simultaneous mimicking of stem cell differentiation to two types of cells. In this study, we prepared the mixture ECMs derived from simultaneous osteogenesis and adipogenesis of MSCs at different stages and found that they could regulate stem cell differentiation. The concept is new and the ECMs are novel. No such ECMs have been reported previously. The matrices will provide very useful tools to investigate the interaction between ECM and stem cells and the role of ECM on stem cell differentiation.

Gelatin Scaffolds with Controlled Pore Structure and Mechanical Property for Cartilage Tissue Engineering.

Engineering of cartilage tissue in vitro using porous scaffolds and chondrocytes provides a promising approach for cartilage repair. However, nonuniform cell distribution and heterogeneous tissue formation together with weak mechanical property of in vitro engineered cartilage limit their clinical application. In this study, gelatin porous scaffolds with homogeneous and open pores were prepared using ice particulates and freeze-drying. The scaffolds were used to culture bovine articular chondrocytes to engineer cartilage tissue in vitro. The pore structure and mechanical property of gelatin scaffolds could be well controlled by using different ratios of ice particulates to gelatin solution and different concentrations of gelatin. Gelatin scaffolds prepared from ≥70% ice particulates enabled homogeneous seeding of bovine articular chondrocytes throughout the scaffolds and formation of homogeneous cartilage extracellular matrix. While soft scaffolds underwent cellular contraction, stiff scaffolds resisted cellular contraction and had significantly higher cell proliferation and synthesis of sulfated glycosaminoglycan. Compared with the gelatin scaffolds prepared without ice particulates, the gelatin scaffolds prepared with ice particulates facilitated formation of homogeneous cartilage tissue with significantly higher compressive modulus. The gelatin scaffolds with highly open pore structure and good mechanical property can be used to improve in vitro tissue-engineered cartilage.

Cardiac parasympathetic outflow during dynamic exercise in humans estimated from power spectral analysis of P-P interval variability.

NEW FINDINGS: What is the central question of this study? Should we use the high-frequency (HF) component of P-P interval as an index of cardiac parasympathetic nerve activity during moderate exercise? What is the main finding and its importance? The HF component of P-P interval variability remained even at a heart rate of 120-140 beats min(-1) and was further reduced by atropine, indicating incomplete cardiac vagal withdrawal during moderate exercise. The HF component of R-R interval is invalid as an estimate of cardiac parasympathetic outflow during moderate exercise; instead, the HF component of P-P interval variability should be used. The high-frequency (HF) component of R-R interval variability has been widely used as an indirect estimate of cardiac parasympathetic (vagal) outflow to the sino-atrial node of the heart. However, we have recently found that the variability of the R-R interval becomes much smaller during dynamic exercise than that of the P-P interval above a heart rate (HR) of ∼100 beats min(-1). We hypothesized that cardiac parasympathetic outflow during dynamic exercise with a higher intensity may be better estimated using the HF component of P-P interval variability. To test this hypothesis, the HF components of both P-P and R-R interval variability were analysed using a Wavelet transform during dynamic exercise. Twelve subjects performed ergometer exercise to increase HR from the baseline of 69 ± 3 beats min(-1) to three different levels of 100, 120 and 140 beats min(-1). We also examined the effect of atropine sulfate on the HF components in eight of the 12 subjects during exercise at an HR of 140 beats min(-1) . The HF component of P-P interval variability was significantly greater than that of R-R interval variability during exercise, especially at the HRs of 120 and 140 beats min(-1). The HF component of P-P interval variability was more reduced by atropine than that of R-R interval variability. We conclude that cardiac parasympathetic outflow to the sino-atrial node can be estimated better by the HF component of P-P interval variability during exercise and that cardiac parasympathetic nerve activity exists during moderate dynamic exercise.