Treatment-related leukemia after taxane and platinum therapy in gynecological cancer patients (Gynecologic Oncology Trial and Investigation Consortium 011).

AIM: To clarify incidence and clinical features of treatment-related leukemia (TRL) due to taxane/platinum therapy in gynecological cancer patients. METHODS: We conducted a retrospective study of gynecological cancer patients who were diagnosed at facilities participating in the Gynecologic Oncology Trial and Investigation Consortium and started only taxane/platinum therapy as chemotherapy between 2002 and 2006. RESULTS: The site of the primary lesion was the ovary in 124, endometrium in 37, and uterine cervix in 4. The regimen of chemotherapy was paclitaxel (T) + carboplatin (C) therapy in 134 and others in 31 patients. The cumulative incidence was 2.4% (4/165), and the incidence was 2.9/1,000 person-years. All four cases were acute myeloid leukemia. The average total doses of T and C in patients without TRL were 1,693 (SD 1,050) and 4,170 (SD 2,423) mg. For TRL patients, the total T and C doses were, respectively, 1,555 and 3,540 mg, 1,620 and 4,200 mg, 2,130 and 4,700 mg, 3,220 mg and 8,310 mg. The fourth patient received additional 2,415 mg of docetaxel and 2,155 mg of nedaplatin. The intervals from the primary chemotherapy to the onset of TRL were 27, 34, 67, and 114 months. Three patients had no evidence of ovarian cancer. Three patients died of TRL at 4 days, 5 months, and 11 months, one patient remained in remission at 25 months after diagnosis of TRL. CONCLUSION: Patients receiving taxane/platinum therapy should undergo long-term follow-up with attention to the development of TRL, even if the gynecologic malignant cancer is in remission.

PD-L1 and CD4 are independent prognostic factors for overall survival in endometrial carcinomas.

BACKGROUND: Tumor microenvironment (TME) including the immune checkpoint system impacts prognosis in some types of malignancy. The aim of our study was to investigate the precise prognostic significance of the TME profile in endometrial carcinoma. METHODS: We performed immunohistochemistry of the TME proteins, PD-L1, PD-1, CD4, CD8, CD68, and VEGF in endometrial carcinomas from 221 patients. RESULTS: High PD-L1 in tumor cells (TCs) was associated with better OS (p = 0.004), whereas high PD-L1 in tumor-infiltrating immune cells (TICs) was associated with worse OS (p = 0.02). High PD-L1 in TICs correlated with high densities of CD8+ TICs and CD68+ TICs, as well as microsatellite instability (p = 0.00000064, 0.00078, and 0.0056), while high PD-L1 in TCs correlated with longer treatment-free interval (TFI) after primary chemotherapy in recurrent cases (p = 0.000043). High density of CD4+ TICs correlated with better OS and longer TFI (p = 0.0008 and 0.014). Univariate and multivariate analyses of prognostic factors revealed that high PD-L1 in TCs and high density of CD4+ TICs were significant and independent for favorable OS (p = 0.014 and 0.0025). CONCLUSION: The current findings indicate that PD-L1 and CD4+ helper T cells may be reasonable targets for improving survival through manipulating chemosensitivity, providing significant implications for combining immunotherapies into the therapeutic strategy for endometrial carcinoma.

Impact of tricuspid annuloplasty on postoperative changes in the right ventricular systolic and diastolic function: A retrospective cohort study.

OBJECTIVES: To elucidate the impact of regulation of tricuspid regurgitation (TR) using tricuspid annuloplasty on postoperative changes in right ventricular (RV) systolic and diastolic functions. METHODS: We enrolled 69 patients who underwent aortic or mitral valve surgery between July 2016 to March 2018 without recurrence. Patients with concomitant coronary artery bypass grafting or a history of previous cardiovascular surgery were excluded, remaining 45 patients enrolled. Patients were divided into two groups according to concomitant tricuspid annuloplasty (T: n = 12 vs non-T: n = 33). RV global longitudinal strain (RVGLS), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and early tricuspid inflow velocity/early diastolic tricuspid annular velocity ratio (tricuspid E/e') were assessed as functional indices at preoperative, postoperative and 1-year follow-up periods. RESULTS: RVFAC deteriorated postoperatively but recovered at follow-up in group T, whereas that in group non-T showed gradual deterioration overtime. RVGLS and TAPSE showed similar temporary deterioration and recovery between groups. Tricuspid E in group T increased postoperatively and showed significant difference, which was kept until follow-up period. Tricuspid e' decreased postoperatively, and recovered slightly in both groups. As a result, postoperative RV diastolic function (tricuspid E/e') showed significant difference between groups. This difference was maintained until follow-up. CONCLUSIONS: RV systolic function deteriorated postoperatively, but there was a tendency to improve at follow-up regardless of tricuspid annuloplasty. RV diastolic function may potentially be impaired when TR was regulated by tricuspid annuloplasty.

[Aortic Valve Translocation for Severe Prosthetic Valve Endocarditis with Aortic Annular Abscess].

We report a case of successful aortic valve translocation in a 71-year-old man with severe prosthetic valve endocarditis and an aortic annular abscess. Six years earlier, the patient had undergone aortic valve replacement for aortic regurgitation and coronary artery bypass grafting to the left anterior descending artery with a saphenous vein. Moreover, 4 years earlier, he had undergone total arch replacement for chronic aortic dissection. He was admitted to our hospital with suspected urinary tract infection. Despite antibiotic therapy, the patient developed a high fever. Transthoracic echocardiography revealed a rocking motion of the prosthetic aortic valve, and an emergency operation was performed. An annular abscess surrounding the prosthetic aortic valve was observed, and the valve was detached. For destruction of the entire aortic annulus, we performed an aortic valve translocation procedure. Revascularization of the left coronary artery was performed by interposing an 8 mm artificial graft between the proximal anastomosis site of the previous venous graft and the composite tube graft. Revascularization of the right coronary artery was performed using a saphenous vein graft. The patient was discharged uneventfully at postoperative day 29 and doing well 1 year after surgery.

[Experiences of Cardioaortic Surgery with Small Anterior Mediastinal Mass on Preoperative Computed Tomography].

Computed tomography(CT) is indispensable for diagnostic imaging. During preoperative assessment for cardioaortic surgery, a CT examination is performed not only for diagnostic purposes but also to decide the surgical strategy. In some cases, CT demonstrates a small abnormal mass in the adipose tissue of the anterior mediastinum. Sometimes radiologists diagnose the image and send the diagnostic report to cardiologists or cardiovascular surgeons. However, they tend to limit their focus to their field of specialty. Thus, they might overlook or underestimate an abnormal mass. Anterior mediastinal masses, though small, may include malignant tumors. Thus, we reviewed 12 cases in which anterior mediastinal masses were found on preoperative CT. Two of these patients were finally diagnosed with malignant tumors. We should pay attention to not only cardiovascular assessment but also mediastinal masses on preoperative CT. In some cases, concomitant surgery for cardioaortic disease and an anterior mediastinal tumor is effective.

Predictors of favorable survival after secondary cytoreductive surgery for recurrent endometrial cancer.

OBJECTIVE: The selection criteria for secondary cytoreductive surgery (SCS) for recurrent endometrial cancer (EC) remain to be defined. The present study aimed to identify predictors for favorable survival after SCS for the disease. METHODS: We retrospectively reviewed the medical records of 112 patients who relapsed by 2016 among 1052 who were diagnosed with primary EC between 1985 and 2014. Characteristics associated with overall survival (OS) after SCS were identified using univariate and multivariate analyses. RESULTS: Twenty-nine of the 112 patients who relapsed underwent SCS. Complete resection was achieved in 18 (62%) patients, whose OS after SCS was significantly better than that of patients receiving incomplete resection (68 vs. 20 months; p = 0.001). Endometrioid histology and performance status (PS) 0 were significant and independent factors for a favorable OS (p = 0.005, and 0.049). The OS of patients with both factors was better than patients with one or no factors (median 75, 19 and 4 months; p = 0.001 and 0.00001). The number of predictors was associated with the rate of complete resection (p = 0.001). CONCLUSIONS: Patients with endometrioid histology and PS 0 should be offered SCS for recurrent EC. Prospective trials are warranted to verify this proposal.

Multiple Spontaneous Iliac and Femoral Arteriovenous Fistulas.

An arteriovenous fistula (AVF) in a limb involves an abnormal connection between a limb artery and vein. It can be due to trauma or iatrogenic injury. Traumatic AVFs can be caused by penetrating or gunshot injuries to the limb, whereas iatrogenic causes include catheter intervention to the groins or open surgery of the inguinal space. By contrast, the occurrence of multiple spontaneous AVFs is rare. We report a case of endovascular therapy for multiple spontaneous AVFs between the iliac artery and the vein, common femoral artery and the vein, superficial artery and the saphenous vein, and deep femoral artery and the vein.

A single-arm study evaluating bevacizumab, cisplatin, and paclitaxel followed by single-agent bevacizumab in Japanese patients with advanced cervical cancer.

BACKGROUND: Adding bevacizumab to chemotherapy for recurrent, persistent or metastatic cervical cancer significantly improved overall survival (primary endpoint), progression-free survival and overall response rate in the randomized Phase III GOG-0240 trial. However, data for bevacizumab-containing therapy are scarce in Japanese patients with advanced cervical cancer. METHODS: The primary objective of the single-arm multicenter Phase II JO29569 study was to evaluate the tolerability of paclitaxel (135 mg/m2 over 24 h or 175 mg/m2 over 3 h), cisplatin (50 mg/m2) and bevacizumab (15 mg/kg), administered every 3 weeks until disease progression or unacceptable toxicity in Japanese patients with stage IVB, persistent or recurrent cervical cancer. RESULTS: The seven treated patients received a median of nine (range 7-12) bevacizumab cycles and six (range 4-12) chemotherapy cycles. None of the predefined adverse events occurred during the tolerability evaluation period. The most common all-grade adverse events were alopecia, hypertension, decreased appetite, nausea and peripheral sensory neuropathy. There were no cases of fistula. The most common grade ≥3 adverse events were hypertension, neutrophil count decreased and neutropenia. Only one patient experienced febrile neutropenia. The overall response rate was 86% (95% confidence interval, 42-100%), including a complete response in one patient. At data cutoff, disease had progressed in one patient; bevacizumab therapy was ongoing in the remaining six. CONCLUSIONS: According to the specified primary objective, a regimen of cisplatin, paclitaxel and bevacizumab was tolerable in Japanese patients and demonstrated encouraging activity in this small single-arm study. Further study is warranted to confirm the safety and effectiveness of bevacizumab in Japanese patients with cervical cancer.

Expression of Tissue Factor in Epithelial Ovarian Carcinoma Is Involved in the Development of Venous Thromboembolism.

OBJECTIVES: Our 2007 study of 32 patients with ovarian cancer reported the possible involvement of tissue factor (TF) in the development of venous thromboembolism (VTE) before treatment, especially in clear cell carcinoma (CCC). This follow-up study further investigated this possibility in a larger cohort. METHODS: We investigated the intensity of TF expression (ITFE) and other variables for associations with VTE using univariate and multivariate analyses in 128 patients with epithelial ovarian cancer initially treated between November 2004 and December 2010, none of whom had received neoadjuvant chemotherapy. Before starting treatment, all patients were ultrasonographically screened for VTE. The ITFE was graded based on immunostaining of surgical specimens. RESULTS: Histological types were serous carcinoma (n = 42), CCC (n = 12), endometrioid carcinoma (n = 15), mucinous carcinoma (n = 53), and undifferentiated carcinoma (n = 6). The prevalence of VTE was significantly higher in CCC (34%) than in non-CCC (17%, P = 0.03). As ITFE increased, the frequencies of CCC and VTE increased significantly (P < 0.001 and P = 0.014, respectively). Multivariate analysis identified TF expression and pretreatment dimerized plasmin fragment D level as significant independent risk factors for VTE development. These factors showed particularly strong impacts on advanced-stage disease (P = 0.021). CONCLUSIONS: The 2007 cohort was small, preventing multivariate analysis. This study of a larger cohort yielded stronger evidence that the development of VTE in epithelial ovarian cancer may involve TF expression in cancer tissues.

Popliteal Artery Pseudoaneurysm Caused by Osteochondroma.

A 16-year-old boy developed pulsating pain and dysesthesia in his right knee. Computed tomography showed a large aneurysm in the right upper popliteal artery and a spiked bone tumor arising from the right distal femoral shaft. Pseudoaneurysm due to osteochondroma was suspected, and the patient underwent emergency surgery. A 2-mm pinhole was detected in the arterial wall behind the tumor. After resection of the tumor, the damaged arterial wall was removed, and the defect was repaired using a saphenous vein patch. We suggest that patch repair is preferable to direct closure or end-to-end anastomosis to prevent recurrent pseudoaneurysm at a later time, even if the defect is small.

Clinicopathologic implications of DNA mismatch repair status in endometrial carcinomas.

OBJECTIVE: Endometrial carcinoma is the most common malignancy in women with Lynch syndrome caused by mismatch repair (MMR) deficiency. We investigated the clinicopathologic significance of deficient MMR and Lynch syndrome presumed by MMR analyses in unselected endometrial carcinomas. METHODS: We analyzed immunohistochemistry of MMR proteins (MLH1/MSH2/MSH6/PMS2) and MLH1 promoter methylation in primary endometrial carcinomas from 221 consecutive patients. Based on these results, tumors were categorized as sporadic or probable Lynch syndrome (PLS). Clinicopathologic variables and prognosis were compared according to MMR status and sporadic/PLS classification. RESULTS: Deficient MMR showed only trends towards favorable overall survival (OS) compared with intact MMR (p=0.13), whereas PLS showed significantly better OS than sporadic (p=0.038). Sporadic was significantly associated with older age, obesity, deep myometrial invasion, and advanced stage (p=0.008, 0.01, 0.02 and 0.03), while PLS was significantly associated with early stage and Lynch syndrome-associated multiple cancer (p=0.04 and 0.001). The trend towards favorable OS of PLS was stronger in advanced stage than in early stage (hazard ratio, 0.044 [95% CI 0-25.6] vs. 0.49 [0.063-3.8]). In the subset receiving adjuvant therapies, PLS showed trends towards favorable disease-free survival compared to sporadic by contrast with patients receiving no adjuvant therapies showing no such trend (hazard ratio, 0.045 [95% CI 0-20.3] vs. 0.81 [0.095-7.0]). CONCLUSIONS: The current findings suggest that analyzing MMR status and searching for Lynch syndrome may identify a subset of patients with favorable survival and high sensitivity to adjuvant therapies, providing novel and useful implications for formulating the precision medicine in endometrial carcinoma.

Proposal for selection criteria of secondary cytoreductive surgery in recurrent epithelial ovarian, tubal, and peritoneal cancers.

BACKGROUND: The selection criteria for secondary cytoreductive surgery (SCS) in recurrent ovarian cancer are yet to be defined. The aim of this study was to propose the selection criteria through identifying predictive factors for successful SCS. METHODS: All patients who underwent SCS for recurrent epithelial ovarian, tubal, and peritoneal cancers between 1982 and 2012 at our institution were identified through our database. Potential prognostic factors were evaluated in univariate and multivariate analyses. Survival after SCS was examined by the grouping model based on the number of prognostic factors. RESULTS: We performed SCS in 80 consecutive patients, 48 (60 %) of whom achieved complete resection. Complete/incomplete resection significantly influenced survival (median 65 vs. 26 months; p = 0.0005). Among favorable prognostic factors determined before SCS, treatment-free interval >12 months, absent distant metastasis, solitary disease, and performance status 0 were independently associated with better survival (p = 0.0009, 0.00003, 0.0004, and 0.015, respectively). Patients with 3-4 of those factors had better survival than those with 2 or 0-1 factors (median 79, 26, and 19 months; p < 0.00001 and <0.0000000001, respectively). Complete resection of visible tumors was achieved in 79 % of patients with 3-4 factors, in 40 % of those with 2 factors, and in 33 % of those with 0-1 factor. Importantly, even when tumor removal was incomplete at SCS, median survival of patients with 3-4 factors was still quite favorable (83 vs. 67.5 months for complete/incomplete resection, respectively), while those of patients with 2 factors (41 vs. 25 months) and 0-1 factor (19 vs. 19 months) were not. CONCLUSION: We strongly recommend SCS for patients with 3-4 of the above favorable factors at recurrence. As for patients with 2 factors, SCS may be considered if complete resection is expected to be achieved. Prospective studies are warranted to validate our proposal.

[Impact of Patent False Lumen at the Descending Aorta after Total Aortic Replacement for Acute type A Aortic Dissection].

OBJECTIVE: Acute type A aortic dissection remains one of the most challenging diseases facing cardiovascular surgeons. It is associated with high mortality and morbidity. However, prevention of disease process progression in the residual dissected aorta is an important aspect of the patient's long-term outcome. The aim of this study was to examine the impact of patent false lumen at the descending aorta after total arch replacement for acute type A aortic dissection. METHODS: Between December 1994 and August 2014, a total of 145 patients underwent total arch replacement for acute type A aortic dissection. The hospital mortality was 5.5%.Of these 145 patients, 33 had patent false lumen at the descending aorta after surgery, and 94 had thrombosed false lumen. The perioperative variables and late results were statistically analyzed. RESULTS: The incidence of residual thoracic patent false lumen was 26.0%.No significant difference was observed in the cumulative survival rate between groups. The patent false lumen group was associated with significant higher risk of the descending aortic event than the thrombosed group. By multivariate analysis, younger age and non-resection of the primary tear were significant prospective factors for the patent false lumen at the descending aorta. CONCLUSIONS: The patent false lumen at the descending aorta was associated with the late aortic critical events after total arch replacement for aortic dissection.

High Pretreatment Plasma D-dimer Levels Are Associated With Poor Prognosis in Patients With Ovarian Cancer Independently of Venous Thromboembolism and Tumor Extension.

OBJECTIVE: Elevated plasma D-dimer (DD) is associated with decreased survival among patients with breast, lung, and colon cancers. The present study clarifies the prognostic significance of pretreatment plasma DD levels in patients with epithelial ovarian cancer (EOC). METHODS: We investigated pretreatment DD levels and other variables for overall survival using univariate and multivariate analyses in 134 consecutive patients with EOC stages II to IV who were initially treated between November 2004 and December 2010. RESULTS: The median follow-up period was 53 (7-106) months. Univariate analysis significantly associated elevated pretreatment DD (≥2.0 µg/mL) levels to poor 5-year overall survival rates irrespective of previously treated venous thromboembolism (72.2% vs 52.6%, P = 0.039). Cancer antigen 125 levels of 200 U/mL or higher (P = 0.011), distant metastases (P = 0.0004), residual tumors (P < 0.0001), and International Federation of Gynecology and Obstetrics stage III/IV (P = 0.0033) were also poor prognostic factors. Multivariate analysis independently associated DD levels of 2.0 µg/mL or higher (P = 0.041), distant metastases (P = 0.013), and residual tumors (P < 0.0001) with poor overall survival. CONCLUSIONS: High pretreatment DD levels are associated with poor overall survival in patients with EOC independently of venous thromboembolism and tumor extension and might comprise a promising prognostic biomarker for patients with EOC.

Clinicopathological features and programmed death-ligand 1 immunohistochemical expression in a multicenter cohort of uterine and ovarian melanomas: a retrospective study in Japan (KCOG-G1701s).

The objective of this study was to propose prognostic factors and optimal treatment strategies by analyzing the clinicopathological features and programmed death-ligand 1 (PD-L1) expression. We analyzed 31 patients diagnosed with uterine or ovarian melanoma between 1997 and 2017 in the Kansai Clinical Oncology Group/Intergroup. Twenty-four and seven patients with cervical and ovarian melanomas were included, respectively. Immune checkpoint inhibitors were used in seven patients, and the objective response rate was 40%. Notably, two patients with objective responses had a high PD-L1 expression. Ten and four patients with cervical and ovarian melanomas, respectively, had high PD-L1 immunohistochemical expressions. Multivariate analysis revealed that tumor stage was an independent prognostic factor for progression-free survival in patients with cervical melanomas. In patients with ovarian melanomas, the 1-year cumulative progression-free and overall survival rates were 0 and 29%, respectively. Kaplan-Meier analyses revealed that age <60 years was associated with poorer progression-free and overall survivals in patients with ovarian melanomas. In patients with cervical melanomas, the 1-, 3-, and 5-year cumulative overall survival rates were 53, 32, and 16%, respectively. Histological atypia was associated with a poorer progression-free survival, but there was no difference in survival between patients who underwent radical hysterectomy and those who did not. The present study is a large cohort study of uterine and ovarian melanomas, which are aggressive tumors with a significantly poor prognosis, even after standard surgery and adjuvant therapy. The use of immune checkpoint inhibitors is a promising and effective treatment option.

Dual aortic aneurysms with coronary artery and multiple cerebrovascular stenoses.

Total debranching thoracic endovascular aortic repair is useful for avoiding neurological complications in cases where cardiopulmonary bypass is difficult and for devising an intraoperative cervical branch reconstruction method.

Rupture of a dissecting thoracoabdominal aortic aneurysm due to Citrobacter freundii infection.

We describe a case of an elderly man with Citrobacter freundii-associated infectious rupture of a dissecting thoracoabdominal aortic aneurysm. We performed an emergency thoracoabdominal aortic replacement using a rifampicin-soaked prosthetic graft and omental flap wrapping. The patient was discharged on postoperative day 255, although he experienced pseudomembranous enteritis and paraplegia.

Mid-term functional recovery after tricuspid annuloplasty concomitant with left-sided valve surgery.

BACKGROUND: To elucidate the impact of tricuspid annuloplasty concomitant with left-sided valve surgery on the right ventricular (RV) function in patients with mild or more tricuspid regurgitation (TR). METHODS: We enrolled 136 patients with mild or more TR who underwent left-sided valve surgery. Seventy-three patients underwent left-sided valve surgery alone (group non-T) and 63 underwent concomitant tricuspid annuloplasty (group T). The echocardiographic data at the latest follow-up (mean 1019 days) were compared using multiple regression analysis to adjust cofounding factors. Propensity score was calculated and included in the analysis as a covariate. In addition, propensity score matching was used for sensitive analysis (12 pairs). RESULTS: In group non-T, there were more aortic valve surgeries, and fewer mitral valve surgeries. At baseline, body surface area, New York Heart Association class, and prevalence of atrial fibrillation were significantly different between groups. On preoperative echocardiography, left and right atrial diameter, RV diameter, and tricuspid annular diameter were larger in group T, whereas there was no significant difference in RV fractional area change. In multiple regression analyses, RV diameter in diastole was significantly lower and RV fractional area change was significantly higher at the follow-up period in group T. These results were not attenuated even in subgroup analysis in patients with only mild TR or mitral valve surgery alone. CONCLUSION: Among patients with mild or more TR, RV dimensional and functional recovery was not obtained with left-sided valve surgery alone. Adding tricuspid annuloplasty may potentially achieve both outcomes.