A phase 2 trial of zanidatamab in HER2-overexpressed advanced endometrial carcinoma and carcinosarcoma (ZW25-IST-2).

OBJECTIVE: HER2 overexpression is associated with decreased overall survival in metastatic endometrial cancer. Trastuzumab with chemotherapy has demonstrated efficacy for first-line management of advanced HER2+ endometrial carcinoma, but HER2-directed therapy in the recurrent setting is limited. Zanidatamab (ZW25), a humanized, bispecific antibody that simultaneously binds the 2 distinct HER2 epitopes bound by trastuzumab and pertuzumab, has demonstrated safety and activity in HER2+ tumors. Here, we report the results of a phase 2, open-label study evaluating the efficacy and safety of zanidatamab in patients with HER2+ metastatic endometrial carcinoma/carcinosarcoma who received prior treatment. METHODS: We enrolled 16 patients with HER2+ endometrial carcinoma/carcinosarcoma after progression on ≤2 lines of therapy on a single-arm phase 2 study of zanidatamab. The primary endpoint was overall response rate (ORR; complete or partial response) by Response Evaluation Criteria in Solid Tumors version 1.1. HER2 immunohistochemistry and fluorescence in situ hybridization (FISH) were performed on pretreatment samples. Intratumor HER2 genetic heterogeneity was assessed. RESULTS: This study did not meet its primary efficacy endpoint. Although a clinical benefit rate of 37.5% was observed by 24 weeks, only 1 patient achieved a partial response (ORR, 6.2%). Eight patients had HER2 intratumor heterogeneity or lacked HER2 amplification by FISH. Decreased HER2 expression on repeat pretreatment samples was observed in 3 (75%) of 4 patients evaluated. CONCLUSIONS: We observed a low response rate to zanidatamab in recurrent HER2+ endometrial carcinoma/carcinosarcoma, which may be driven by downregulation of HER2 expression. Repeat HER2 testing should be considered prior to second-line HER2-directed therapy. CLINICALTRIALS: govidentifier: NCT04513665.

Tumor lenvatinib addiction and withdrawal rebound response in patients with advanced endometrial cancer.

Combination therapy of lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), plus pembrolizumab, a monoclonal antibody targeting programmed death receptor 1 (PD-1), was recently approved by the Food and Drug Administration for therapy of advanced endometrial cancer. This case series highlights three patients with endometrial serous carcinoma who experienced disease stabilization or slow progression on lenvatinib plus pembrolizumab followed by rapid symptomatic growth of disease after lenvatinib discontinuation, and subsequent repeated response and symptom resolution after lenvatinib re-initiation. All patients died of disease complications 3 to 10 months after retreatment with lenvatinib. These observations highlight an important phenomenon of lenvatinib withdrawal rebound, likely driven by oncogenic signaling pathways upregulated in response to lenvatinib therapy. The findings of this case series represent a potential area for further research into the underlying mechanism for rebound and repeated response to lenvatinib, as well as strategies to mitigate disease flare related to lenvatinib withdrawal.

Phase I Study of a Multivalent WT1 Peptide Vaccine (Galinpepimut-S) in Combination with Nivolumab in Patients with WT1-Expressing Ovarian Cancer in Second or Third Remission.

We examined the safety and immunogenicity of sequential administration of a tetravalent, non-HLA (human leukocyte antigen) restricted, heteroclitic Wilms' Tumor 1 (WT1) peptide vaccine (galinpepimut-S) with anti-PD-1 (programmed cell death protein 1) nivolumab. This open-label, non-randomized phase I study enrolled patients with WT1-expressing ovarian cancer in second or third remission from June 2016 to July 2017. Therapy included six (every two weeks) subcutaneous inoculations of galinpepimut-S vaccine adjuvanted with Montanide, low-dose subcutaneous sargramostim at the injection site, with intravenous nivolumab over 12 weeks, and up to six additional doses until disease progression or toxicity. One-year progression-free survival (PFS) was correlated to T-cell responses and WT1-specific immunoglobulin (Ig)G levels. Eleven patients were enrolled; seven experienced a grade 1 adverse event, and one experienced a grade ≥3 adverse event considered a dose-limiting toxicity. Ten (91%) of eleven patients had T-cell responses to WT1 peptides. Seven (88%) of eight evaluable patients had IgG against WT1 antigen and full-length protein. In evaluable patients who received >2 treatments of galinpepimut-S and nivolumab, the 1-year PFS rate was 70%. Coadministration of galinpepimut-S and nivolumab demonstrated a tolerable toxicity profile and induced immune responses, as indicated by immunophenotyping and WT1-specific IgG production. Exploratory analysis for efficacy yielded a promising 1-year PFS rate.

Durvalumab with or without tremelimumab in patients with persistent or recurrent endometrial cancer or endometrial carcinosarcoma: A randomized open-label phase 2 study.

INTRODUCTION: Our understanding of the biologic heterogeneity of endometrial cancer has improved, but which patients benefit from single-agent versus combination immune checkpoint blockade remains unclear. METHODS: We conducted a single-center, randomized, open-label, phase 2 study of durvalumab 1500 mg (Arm 1) versus durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks (Arm 2) in patients with endometrial carcinoma. The primary endpoints were overall response rate (ORR) and progression-free survival (PFS) at 24 weeks. Patients were stratified by mismatch repair (MMR) status and carcinosarcoma histology. Using a Simon two-stage minimax design, we determined 40 patients per arm would provide 90% power and Type 1 error of 10%. RESULTS: Eighty-two patients were enrolled; 77 were evaluable for toxicity (Arm 1: 38, Arm 2: 39) and 75 evaluable for efficacy (Arm 1: 37, Arm 2: 38). Patient were stratified by MMR status (Arm 1: 5, Arm 2: 4 were MMR-deficient). The ORR in Arm 1 was 10.8% (one-sided 90% CI: 4.8-100%); the ORR in Arm 2 was 5.3% (one-sided 90% CI: 1.4-100%). Since the primary endpoint of ORR was not met, 24-week PFS was not compared to historical controls per protocol specification. No new safety signals were identified. CONCLUSIONS: In these patients with predominantly MMR-proficient endometrial cancer, there was limited response with single-agent and combined immune checkpoint blockade. The pre-specified efficacy thresholds were not met for further evaluation. A deeper understanding of potential mechanisms of resistance to immunotherapy in MMR-proficient endometrial cancer is needed for the development of novel therapeutic approaches.

Waxing and waning pattern of mTOR inhibitor-associated pneumonitis in renal cell carcinoma patients: A retrospective observational study.

OBJECTIVE: mTOR inhibitor-associated pneumonitis is common and often asymptomatic. We describe a waxing and waning pattern of pneumonitis observed on computed tomography (CT) scans of patients with renal cell carcinoma who were being treated with mTOR inhibitor molecular targeted therapy. MATERIALS AND METHODS: In this HIPAA-compliant, IRB-approved retrospective single-institution study, 25 renal cell carcinoma patients were identified who received single-therapy temsirolimus or everolimus between January 2011 and June 2015 and who had chest CT scans available for review both before and after initiation of mTOR inhibitor treatment. A detailed review of the electronic medical record and serial chest CT examinations was performed. RESULTS: Radiologic findings compatible with pneumonitis were identified in 13/25 (52%) patients on mTOR inhibitors in our study. Of the patients with CT findings of pneumonitis, 8/13 (62%) demonstrated a waxing and waning pattern; of whom 7 had clinical symptoms of pneumonitis. Of the 17 patients who received temsirolimus, 9/17 (53%) developed radiologic findings compatible with pneumonitis and 4/9 (44%) developed a waxing and waning pattern. Of the 8 patients who received everolimus, 4/8 (50%) had radiologic findings compatible with pneumonitis and 4/4 (100%) developed a waxing and waning pattern. CONCLUSION: Waxing and waning is an unrecognized pattern of mTOR inhibitor-associated pneumonitis. Recognition of this pattern will promote clinical-radiologic concordance and may facilitate patient management.

A multimodality triage algorithm to improve cytoreductive outcomes in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center team ovary initiative.

OBJECTIVE: To describe outcomes using a multimodal algorithm to triage patients with advanced epithelial ovarian cancer (EOC) to primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT). METHODS: All patients with EOC treated at our institution from 04/2015-08/2018 were identified. We included patients without contraindication to PDS who underwent prospective calculation of a Resectability (R)-score. A low risk score for suboptimal cytoreduction was defined as ≤6, and a high risk score ≥7. Patients were triaged to laparotomy/PDS, laparoscopic evaluation of resectability (LSC), or NACT depending on R-score. RESULTS: Among 299 participants, 226 (76%) had a low risk score and 73 (24%) a high risk score. For patients with a low risk score, management included laparotomy/PDS, 181 (80%); LSC, 43 (19%) (with subsequent triage: PDS, 31; NACT, 12); and NACT, 2 (1%). For patients with a high risk score, management included laparotomy/PDS, 9 (12%); LSC, 51 (70%) (with subsequent triage: PDS, 28; NACT, 23); and NACT, 13 (18%). Overall, 83% underwent PDS, with a 75% CGR rate and 94% optimal cytoreduction rate. Use of the algorithm resulted in a 31% LSC rate and a 6% rate of suboptimal PDS. CONCLUSIONS: The multimodal algorithm led to excellent surgical results; 94% of patients achieved an optimal resection, with a very low rate of suboptimal cytoreduction.

A phase 1 dose-escalation study of intraperitoneal cisplatin, intravenous/intraperitoneal paclitaxel, bevacizumab, and olaparib for newly diagnosed ovarian cancer.

OBJECTIVE: We assessed the safety and maximum tolerated dose (MTD) of the poly ADP-ribose polymerase (PARP) inhibitor olaparib with intravenous (IV)/intraperitoneal (IP) cisplatin/paclitaxel and IV bevacizumab, followed by olaparib and bevacizumab maintenance, in patients with newly diagnosed ovarian cancer who had undergone primary debulking surgery. METHODS: Treatment included: (Cycles 1-6) Day 1, IV paclitaxel 135 mg/m2/3 h + (from Cycle 2 onward) bevacizumab 15 mg/kg; Day 2, IP cisplatin 75 mg/m2; Days 2-8, olaparib (50/100/200 mg BID); Day 8, IP paclitaxel 60 mg/m2 of a 21-day cycle. Maintenance (Cycles 7-22) included: olaparib 300 mg BID and bevacizumab 15 mg/kg Day 1. The primary endpoint was MTD of olaparib, chemotherapy, and bevacizumab. RESULTS: Seventeen women were treated (Cohort 1 [50 mg olaparib], 8 patients; Cohort 2 [100 mg], 3 patients; and Cohort 3 [200 mg], 6 patients). Median age was 57 years (47-73); 94% had stage III disease; 29% had a germline BRCA mutation. Two of 6 patients in Cohort 3 experienced a dose-limiting toxicity (DLT). Grade 3/4 toxicities included: neutropenia (56%), lymphopenia (31%), anemia (25%), and fatigue (19%). Most patients started (88%, 81%) and completed (75%, 50%) maintenance olaparib and bevacizumab, respectively; 36% of patients on olaparib maintenance required a dose reduction. Median PFS was 33 months (26.2-NA). CONCLUSIONS: The MTD of intermittently dosed olaparib with concurrent IV/IP cisplatin/paclitaxel and bevacizumab is 100 mg BID. Non-hematologic toxicities were predominantly low grade. One-third of patients on olaparib maintenance required dose reduction.

Romiplostim Treatment of Chemotherapy-Induced Thrombocytopenia.

PURPOSE: Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment. METHODS: We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/µL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/µL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point. RESULTS: The mean platelet count at enrollment was 62,000/µL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/µL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/µL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT. CONCLUSION: This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.

Rivaroxaban treatment of cancer-associated venous thromboembolism: Memorial Sloan Kettering Cancer Center institutional experience.

BACKGROUND: Low-molecular-weight heparin has been the preferred treatment of cancer-associated thrombosis (CAT); however, emerging data support the use of direct oral anticoagulants (DOACs). OBJECTIVES: The Memorial Sloan Kettering Cancer Center Clinical Pathway has served as the institutional guideline for the use of rivaroxaban to treat CAT since 2014. Key elements are to recommend against use of a DOAC in patients with active gastrointestinal (GI) or genitourinary tract lesions, and a prespecified dose reduction in the elderly (75+ years old). We present our institutional experience for treatment of CAT. METHODS: From January 2014 through September 2016, 1072 patients began rivaroxaban treatment for CAT; 91.9% had a solid tumor, 8.1% had hematologic malignancies, and 75% of patients with solid tumors had metastatic disease. All patients with CAT treated with rivaroxaban were included in this analysis, regardless of adherence to the Clinical Pathway. RESULTS: The 6-month cumulative incidence of recurrent venous thromboembolism and major bleeding were 4.2% (95% confidence interval [CI], 2.7%-5.7%) and 2.2% (95% CI, 1.1%-3.2%), respectively. The incidence of clinically relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days was 5.5% (95% CI,  3.7%-7.1%), and 73.3% of major bleeds occurred in the GI tract. The 6-month cumulative mortality rate was 22.2% (95% CI, 19.4%-24.9%). The elderly had similar rates of recurrent thrombosis and bleeding as those aged under 75 years. CONCLUSION: Our institutional experience suggests that in appropriately selected patients, rivaroxaban may be used for treatment of CAT with promising safety and efficacy.

Models to predict outcomes after primary debulking surgery: Independent validation of models to predict suboptimal cytoreduction and gross residual disease.

OBJECTIVE: Treatment planning requires accurate estimation of surgical complexity (SC) and residual disease (RD) at primary debulking surgery (PDS) for advanced ovarian cancer (OC). We sought to independently validate two published computed tomography (CT) prediction models. METHODS: We included stage IIIC/IV OC patients who underwent PDS from 2003 to 2011. Two prediction models which included imaging and clinical variables to predict RD > 1 and any gross RD, respectively, were applied to our cohort. Two radiologists scored CTs. Discrimination was estimated using the c-index and calibration were assessed by comparing the observed and predicted estimates. RESULTS: The validation cohort consisted of 276 patients; median age of the cohort was 64 years old and majority had serous histology. The validation and model development cohorts were similar in terms of baseline characteristics, however the RD rates differed between cohorts (9.4% vs 25.4% had RD >1 cm; 50.7% vs. 66.6% had gross RD). Model 1, the model to predict RD >1 cm, did not validate well. The c-index of 0.653 for the validation cohort was lower than reported in the development cohort (0.758) and the model over-predicted the proportion with RD >1 cm. The second model to predict gross RD had excellent discrimination with a c-index of 0.762. CONCLUSIONS: We are able to validate a CT model to predict presence of gross RD in an independent center; the separate model to predict RD >1 cm did not validate. Application of the model to predict gross RD can help with clinical decision making in advanced ovarian cancer.

Causes of Avascular Hypoechoic Testicular Lesions Detected at Scrotal Ultrasound: Can They Be Considered Benign?

OBJECTIVE: The purposes of this study were to determine the cause of avascular hypoechoic lesions detected at scrotal ultrasound and to assess usefulness of sonographic and clinical features in differentiating benign from malignant etiologic factors. MATERIALS AND METHODS: This retrospective study included 58 patients with avascular hypoechoic lesions detected at testicular ultrasound. The sonographic features recorded were lesion size and margins and presence of peripheral vascularity and focal calcifications. Also recorded were patient age, symptoms, risk factors, lesion palpability, and levels of serum tumor markers. The reference standard was pathologic results or at least 2-year stability documented with serial follow-up ultrasound studies. Features associated with malignant, including burnt-out, lesions and benign lesions were examined by Fisher exact test, Wilcox-on rank sum test, and the generalized estimating equations method for multivariable models. RESULTS: Sixty-three lesions were identified in 58 patients; 40 of the 63 (63.5%) were benign. Patients with malignant lesions had elevated serum tumor marker levels more often than patients who had benign lesions (26.1% versus 5.7%, p = 0.043). The clinical palpability of lesions and history of testicular cancer were not statistically significantly different between patients with malignant and those with benign lesions. Poorly defined margins of a lesion and focal calcification within the lesion were more often found in malignant lesions. Maximal size of a lesion and peripheral vascularity were not associated with either the benign or the malignant nature of a lesion. CONCLUSION: Although most avascular hypoechoic testicular lesions are benign, a substantial proportion are malignant. The ultrasound characteristics of a lesion, the patient's clinical presentation, and serum tumor marker status may be useful in differentiating malignant from benign lesions.

A multicenter assessment of the ability of preoperative computed tomography scan and CA-125 to predict gross residual disease at primary debulking for advanced epithelial ovarian cancer.

OBJECTIVE: To assess the ability of preoperative computed tomography scan and CA-125 to predict gross residual disease (RD) at primary cytoreduction in advanced ovarian cancer. METHODS: A prospective, non-randomized, multicenter trial of patients who underwent primary debulking for stage III-IV epithelial ovarian cancer previously identified 9 criteria associated with suboptimal (>1cm residual) cytoreduction. This is a secondary post-hoc analysis looking at the ability to predict any RD. Four clinical and 18 radiologic criteria were assessed, and a multivariate model predictive of RD was developed. RESULTS: From 7/2001-12/2012, 350 patients met eligibility criteria. The complete gross resection rate was 33%. On multivariate analysis, 3 clinical and 8 radiologic criteria were significantly associated with the presence of any RD: age≥60years (OR=1.5); CA-125≥600U/mL (OR=1.3); ASA 3-4 (OR=1.6); lesions in the root of the superior mesenteric artery (OR=4.1), splenic hilum/ligaments (OR=1.4), lesser sac >1cm (OR=2.2), gastrohepatic ligament/porta hepatis (OR=1.4), gallbladder fossa/intersegmental fissure (OR=2); suprarenal retroperitoneal lymph nodes (OR=1.3); small bowel adhesions/thickening (OR=1.1); and moderate-severe ascites (OR=2.2). All ORs were significant with p<0.01. A 'predictive score' was assigned to each criterion based on its multivariate OR, and the rate of having any RD for patients who had a total score of 0-2, 3-5, 6-8, and ≥9 was 45%, 68%, 87%, and 96%, respectively. CONCLUSIONS: We identified 11 criteria associated with RD, and developed a predictive model in which the rate of having any RD was directly proportional to a predictive score. This model may be helpful in treatment planning.

Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study.

Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. Rivaroxaban was approved in 2012 for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but no prior studies have been reported specifically evaluating the efficacy and safety of rivaroxaban for cancer-associated thrombosis (CAT). Under a Quality Assessment Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT and now report a validation analysis of our first 200 patients. A 200 patient cohort with CAT (PE or symptomatic, proximal DVT), whose full course of anticoagulation was with rivaroxaban, were accrued. In competing risk analysis, primary endpoints at 6 months included new or recurrent PE or symptomatic proximal lower extremity DVT, major bleeding, clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. In competing risk analysis, the 6 months cumulative incidence of new or recurrent VTE was 4.4 % (95 % CI = 1.4-7.4 %), major bleeding was 2.2 % (95 % CI = 0-4.2 %) and all-cause mortality 17.6 % (95 % CI = 11.7-23.0 %). In this cohort of 200 patients with active cancer and CAT the rates of new or recurrent VTE and major bleeding were comparable to the cancer subgroup analysis from the EINSTEIN studies. The results of our Clinical Pathway provide guidance on Rivaroxaban use for treatment of CAT, and suggest that safety and efficacy is preserved, compared with past-published experience with LMWH.

Is It Time to Centralize Ovarian Cancer Care in the United States?

PURPOSE: The purpose of this article was to broadly review the most up-to-date information pertaining to the centralization of ovarian cancer care in the United States (US) and worldwide. METHODS: Much of the present literature pertaining to disparities in, and centralization of, ovarian cancer care in the US and internationally was reviewed, and specifically included original research and review articles. RESULTS: Data show improved optimal debulking rates, National Comprehensive Cancer Network (NCCN) guideline adherence, and overall survival rates in higher-volume, more specialized hospitals, and amongst higher-volume providers. CONCLUSIONS: Patients with invasive epithelial ovarian cancer, especially those with higher stages (III and IV), are better served by centralized care in high-volume hospitals and by high-volume physicians, who adhere to NCCN guidelines wherever possible. More research is needed to determine the policy changes that can increase NCCN guideline adherence in low-volume hospitals and low-provider caseload scenarios. Policy and future research should be aimed at increasing patient access, either directly or indirectly, to high-volume hospital and high-volume providers, especially amongst Medicare, lower socioeconomic status, and minority patients.

Ovarian vein thrombosis after debulking surgery for ovarian cancer: epidemiology and clinical significance.

OBJECTIVE: Ovarian vein thrombosis is associated with pregnancy and pelvic surgery. Postpartum ovarian vein thrombosis is associated with infection and a high morbidity rate and is treated with anticoagulant and intravenous antibiotic therapy. The natural history of such thrombotic events after debulking surgery for ovarian cancer has not been well described. Our objective was to characterize the presentation and outcomes for patients with this condition at our institution. STUDY DESIGN: We conducted a retrospective study of patients who underwent surgical debulking for ovarian cancer at Memorial Sloan Kettering Cancer Center between the years 2001 and 2010. Patients were included if contrast computed tomography scans of both the abdomen and pelvis were performed within 12 weeks before and 12 weeks after the surgery. The images were reviewed to assess for the presence and extent of a new postoperative ovarian vein thrombosis. When available, subsequent studies were assessed for thrombus progression. Medical records were reviewed to determine whether anticoagulation was used for treatment of the thrombotic episode and to record the occurrence of any new significant venous thromboembolic event in the next year. RESULTS: One hundred fifty-nine patients had satisfactory imaging. New ovarian vein thrombosis was a common complication of debulking surgery, as found in 41 of patients (25.8%). Only 5 women with ovarian vein thrombosis were started on anticoagulation, of which 2 individuals had an independent venous thromboembolic event as indication for treatment. Only 2 of the ovarian vein thromboses (4.9%) progressed to the inferior vena cava or left renal vein on subsequent scan. The estimated cumulative incidence of venous thromboembolism 1 year after the first postoperative scan was 17.1% for patients in the new ovarian vein thrombosis group vs 15.3% of individuals for the group without a postoperative ovarian vein thrombosis (P = .78). CONCLUSION: Ovarian vein thrombosis is commonly encountered after debulking surgery for ovarian cancer. Anticoagulation is usually not indicated, and clinically meaningful thrombus progression rarely occurs.

A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer.

OBJECTIVE: To assess the ability of preoperative computed tomography (CT) scan of the abdomen/pelvis and serum CA-125 to predict suboptimal (>1cm residual disease) primary cytoreduction in advanced ovarian, fallopian tube, and peritoneal cancer. METHODS: This was a prospective, non-randomized, multicenter trial of patients who underwent primary cytoreduction for stage III-IV ovarian, fallopian tube, and peritoneal cancer. A CT scan of the abdomen/pelvis and serum CA-125 were obtained within 35 and 14 days before surgery, respectively. Four clinical and 20 radiologic criteria were assessed. RESULTS: From 7/2001 to 12/2012, 669 patients were enrolled; 350 met eligibility criteria. The optimal debulking rate was 75%. On multivariate analysis, three clinical and six radiologic criteria were significantly associated with suboptimal debulking: age ≥ 60 years (p=0.01); CA-125 ≥ 500 U/mL (p<0.001); ASA 3-4 (p<0.001); suprarenal retroperitoneal lymph nodes >1cm (p<0.001); diffuse small bowel adhesions/thickening (p<0.001); and lesions >1cm in the small bowel mesentery (p=0.03), root of the superior mesenteric artery (p=0.003), perisplenic area (p<0.001), and lesser sac (p<0.001). A 'predictive value score' was assigned for each criterion, and the suboptimal debulking rates of patients who had a total score of 0, 1-2, 3-4, 5-6, 7-8, and ≥ 9 were 5%, 10%, 17%, 34%, 52%, and 74%, respectively. A prognostic model combining these nine factors had a predictive accuracy of 0.758. CONCLUSIONS: We identified nine criteria associated with suboptimal cytoreduction, and developed a predictive model in which the suboptimal rate was directly proportional to a predictive value score. These results may be helpful in pretreatment patient assessment.

Stage IB1 cervical cancer: role of preoperative MR imaging in selection of patients for fertility-sparing radical trachelectomy.

PURPOSE: To determine whether magnetic resonance (MR) imaging evaluation of key morphologic tumor characteristics can improve patient selection for radical trachelectomy. MATERIALS AND METHODS: The institutional review board approved and waived informed consent for this study of 62 patients (mean age, 32 years; age range, 23-42 years) with International Federation of Gynecology and Obstetrics stage IB1 cervical carcinoma who underwent attempted radical trachelectomy between November 2001 and January 2011 and had preoperative MR imaging. Retrospectively, two radiologists reviewed MR images for tumor presence and size, distance between tumor and internal os, and presence of deep cervical stromal invasion. Associations between MR imaging findings and surgery type were tested. RESULTS: Sensitivity and specificity of tumor detection were, respectively, 87% and 100% (reader 1) and 76% and 95% (reader 2). Six of six patients with negative cone biopsy margins and no tumor at postconization MR imaging were without tumor at trachelectomy pathologic analysis. Mean differences between MR imaging and histologic tumor sizes were 0.7 mm (range, -15 to 11 mm) for reader 1 and 2.2 mm (range, -9 to 15 mm) for reader 2. Sensitivities for deep cervical stromal invasion were 75% (reader 1) and 50% (reader 2). For each reader, nine of nine (100%) patients with tumor 5 mm or less from the internal os and three of five (60%) patients with tumor 6-9 mm from the internal os at MR imaging needed radical hysterectomy. For both readers, tumor size of 2 cm or larger (P < .001) and deep cervical stromal invasion (P ≤ .003) at MR imaging were associated with increased chance of radical hysterectomy. CONCLUSION: Pretrachelectomy MR imaging can help identify high-risk patients likely to need radical hysterectomy or confirm the absence of residual tumor in the cervix after a cone biopsy with negative margins.

Phase I trial of weekly and twice-weekly bortezomib with rituximab, cyclophosphamide, and prednisone in relapsed or refractory non-Hodgkin lymphoma.

PURPOSE: To determine the safety and efficacy of substituting weekly or twice-weekly bortezomib for vincristine in the R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen in patients with relapsed/refractory indolent and mantle cell lymphoma (MCL). EXPERIMENTAL DESIGN: Of the 57 patients in this phase I trial, 55 participated in 1 of 2 dosing schedules that included rituximab (375 mg/m(2)) and cyclophosphamide (750 or 1,000 mg/m(2)) administered on day 1 of each 21-day cycle and prednisone (100 mg orally) days 2 to 6. In the once-weekly schedule, bortezomib was administered on days 2 and 8; on the twice-weekly schedule, bortezomib was given on days 2, 5, 9, and 12. Bortezomib and cyclophosphamide were alternately escalated. A separate cohort of 10 patients in the twice-weekly schedule received concurrent pegfilgrastim (PegG) on day 2. RESULTS: Both schedules of R-CBorP (rituximab, cyclophosphamide, bortezomib, and prednisone) were well tolerated. Most toxicities across all dose levels and cycles were grade 1 or 2. The overall response rates for patients on the weekly (n = 13) and twice-weekly (n = 33) schedules were 46% [23% complete response/complete response unconfirmed (CR/CRu)] and 64% (36% CR/CRu), respectively. Concurrent PegG did not increase hematologic toxicities in this regimen. A randomized phase II study is under way to further compare toxicity and efficacy of the 2 dosing schedules. CONCLUSIONS: R-CBorP is a safe and effective regimen in patients with relapsed/refractory indolent and MCLs. Most toxicities were grade 1 or 2, and a promising response rate was seen in this phase I study.

Implementation of evidence-based guidelines for thyroid nodule biopsy: a model for establishment of practice standards.

OBJECTIVE: Multiple studies have defined criteria for the selection of thyroid nodules for biopsy. No set of criteria is sufficiently sensitive and specific. The aim of this study is to develop a method for assessing consistency of practice in an ultrasound group and to determine whether a 5-point malignancy rating scale can be used to select patients for biopsy. MATERIALS AND METHODS: One hundred one nodules (50 benign and 51 malignant) were selected from a thyroid biopsy database. Seven radiologists were educated on evidence-based criteria used to select nodules for biopsy. Using this information, readers graded the likelihood of malignancy using a 5-point malignancy rating scale, where 1 equals the lowest probability of malignancy and 5 equals the highest probability of malignancy, on the basis of overall impression of sonographic findings. Interobserver agreement on biopsy recommendation, reader sensitivity, specificity, and accuracy were determined. RESULTS: The sensitivity and specificity of biopsy recommendation were 96.1% and 52%, respectively. The misclassification rate was 25.7%, and accuracy was 74.3%. Interobserver agreement on biopsy recommendation was fair to substantial (κ, 0.38-0.69). The proportion of agreement was excellent for malignant nodules (0.88-1.0). The risk of malignancy increased with increasing malignancy rating: 4.3% of nodules with a malignancy rating of 1 were malignant versus 93.4% of those assigned a rating of 5. CONCLUSION: Our study illustrates a method to evaluate the standard of practice for thyroid nodule assessment among radiologists within an ultrasound group. Application of a 5-point malignancy rating scale to select nodules for biopsy is feasible and shows good diagnostic accuracy.

Follow-up study of the correlation between postoperative computed tomographic scan and primary surgeon assessment in patients with advanced ovarian, tubal, or peritoneal carcinoma reported to have undergone primary surgical cytoreduction to residual disease of 1 cm or smaller.

INTRODUCTION: We previously reported a 52% correlation between the primary surgeon's assessment and the postoperative computed tomographic (CT) scan findings of residual disease in patients reported to have undergone cytoreduction to residual disease of 1 cm or smaller. This is a follow-up analysis of survival and prognostic factors for patients who had concordant and discordant postoperative CT scan findings. METHODS: Patients scheduled for primary cytoreductive surgery for presumed advanced ovarian carcinoma were offered enrollment in a prospective study evaluating the ability of preoperative CT scan to predict cytoreductive outcome. If cytoreduction to residual disease of 1 cm or smaller was reported, a CT scan was done 7 to 35 days postoperatively. The CT scan findings were graded by protocol radiologists using a qualitative analysis scale from 1 (normal) to 5 (definitely malignant). RESULTS: From January 2001 to September 2006, 285 patients were enrolled; 67 patients were eligible. Postoperative CT scans confirmed the primary surgeon's assessment of no residual disease larger than 1 cm in 38 cases (57%). In 29 cases (43%), the radiologist found residual disease larger than 1 cm and reported it as probably or definitely malignant. Comparing concordant versus discordant findings, there was no significant difference in median progression-free survival (21 vs 17 months; P = 0.365) or overall survival (60 vs 43 months; P = 0.146). Age (P = 0.040), stage (P = 0.038), and residual disease of 0.5 mm or smaller versus 0.6 to 1.0 cm (P = 0.018) were significant for overall survival on multivariate analysis. CONCLUSIONS: On this follow-up analysis, only age, stage, and residual disease were significant prognostic factors for overall survival. Discordant findings between the primary surgeon's assessment and the postoperative CT scan findings of residual disease was not an independent prognostic factor.