A phase Ib/II and pharmacokinetic study of EP0057 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

BACKGROUND: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). METHODS: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. RESULTS: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). CONCLUSIONS: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words.

Vaginal sarcoidosis without other organ involvement in a patient with a history of endometrial cancer: A case report.

•Patient with history of endometrial cancer presented with vaginal discharge.•Biopsy showed non-necrotizing granulomas, potentially sarcoidosis.•She responded to steroids with symptom resolution.

A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: a Gynecologic Oncology Group study.

OBJECTIVES: Vascular endothelial growth factors (VEGF) and their receptors have a critical role in stimulating the growth of ovarian cancer cells. Motesanib is a small molecule inhibitor of multiple receptor tyrosine kinases including VEGF receptors 1-3, as well as c-KIT and platelet-derived growth factor which are related to the VEGF family. PATIENTS AND METHODS: Twenty-two eligible patients with recurrent ovarian, fallopian tube or primary peritoneal carcinoma were treated with an oral daily dose of 125 mg of motesanib. Peripheral blood was analyzed for circulating tumor cells (CTC) and circulating endothelial cells/circulating endothelial progenitors (CEC/CEP), VEGF levels and cell-free circulating DNA (cfDNA). RESULTS: The study was abruptly halted after four patients developed posterior reversible encephalopathy syndrome. One patient had a partial response and seven patients had stable disease at the time they were removed from study treatment. Twelve of the 22 patients (50%) had indeterminate responses at trial closure. Early closure without clinical efficacy data precludes meaningful correlative studies. CONCLUSIONS: The serious central nervous system toxicity observed in patients with recurrent ovarian cancer precluded full examination of this agent in this population. There were no clear cut explanations for the high incidence of this known class effect in the study population compared with patients with other cancers.

Salvage of isolated vaginal recurrences in women with surgical stage I endometrial cancer: a multiinstitutional experience.

The objective of this study was to evaluate the treatment outcomes and risk factors of women with surgical stage I endometrial adenocarcinoma who were initially treated with surgery alone and subsequently developed isolated vaginal recurrences. Patients with surgical stage I endometrial adenocarcinoma diagnosed from 1975 to 2002 were identified from tumor registry databases at seven institutions. All patients were treated with surgery alone including a total hysterectomy, bilateral salpingo-oophorectomy, pelvic (+/- para-aortic) lymph node dissection, and peritoneal cytology and did not receive postoperative radiation therapy. Vaginal recurrences were documented histologically. Metastatic disease in the chest and abdomen was excluded by radiologic studies. Overall survival was calculated by the Kaplan-Meier method. Sixty-nine women with surgical stage I endometrial cancer with isolated vaginal recurrences were identified. Of the 69 patients, 10 (15%) were diagnosed with stage IA disease, 43 (62%) were diagnosed with stage IB disease, and 16 (23%) were diagnosed with stage IC disease. Patients diagnosed with grade 1 disease were 22 (32%), grade 2 disease were 26 (38%), and grade 3 disease were 21 (30%). Among women, 81% with isolated vaginal recurrences were salvaged with radiation therapy. The mean time to recurrence was 24 months, and the mean follow-up was 63 months. Among women, 18% died from subsequent recurrent disease. The 5-year overall survival was 75%. The majority of isolated vaginal recurrences in women with surgical stage I endometrial cancer can be successfully salvaged with radiation therapy, further questioning the role of adjuvant therapy for patients with uterine-confined endometrial cancer at the time of initial diagnosis.

Primary appendiceal cancer: gynecologic manifestations and treatment options.

OBJECTIVE: To determine the presenting symptoms, gynecologic manifestations, and optimal intraoperative management of women with primary appendiceal cancer. METHODS: A multi-institutional investigation was performed to identify female patients with primary appendiceal cancer who were treated from 1990 to present. RESULTS: Forty-eight women with primary appendiceal cancer were identified from the tumor registries of participating institutions. The most common symptoms were abdominal pain (40%) and bloating (23%), but only 8% experienced rectal bleeding. Serum CEA was elevated (>2.5 U/ml) in 67% of patients, and serum Ca-125 was elevated (>35 U/ml) in 50% of patients. Thirty-one patients (65%) presented with a right adnexal or right lower quadrant mass and were operated on initially by a gynecologic oncologist. Ovarian involvement by metastatic appendiceal cancer was documented in 18 patients (38%). All of these patients underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging, but only 8 had a right hemicolectomy at the time of initial surgery. Forty-one patients (85%) presented with advanced stage appendiceal cancer (Stage III or IV) and 19 patients (46%) received postoperative chemotherapy, most commonly with a combination of 5-FU/Leukovorin. Following surgery, 22 patients (46%) experienced disease progression or recurrence, and 14 have died of disease. The most common sites of recurrence were abdominal or pelvic peritoneum (18), colon (2), and ovary (2). Patient survival was 70% at 2 years, and 60% at 5 years. CONCLUSION: Women with primary appendiceal cancer frequently present with ovarian metastases, and initial surgical intervention is often performed by a gynecologic oncologist. All patients with mucinous epithelial ovarian cancer should undergo appendectomy at the time of surgical staging. The appendix should be examined intraoperatively, and if appendiceal carcinoma is identified, a right hemicolectomy and appropriate surgical staging should be considered.

Positron emission tomography in a premenopausal asymptomatic woman: a case report of increased ovarian uptake in a benign condition.

Positron emission tomography (PET) use is increasing; however, optimal utilization in gynecologic oncology remains unclear. PET is expensive, has limited anatomic detail, and it may be difficult to differentiate benign ovarian lesions from malignant lesions when PET is used. A 43-year-old female volunteer's PET scan revealed increased uptake in the left ovary. A subsequent extensive evaluation was entirely normal; however, the patient pursued excision with only a corpus luteum on final pathology. There is a dearth of information regarding PET scan ovarian abnormalities in asymptomatic premenopausal patients, as much of the literature focuses on women with a known ovarian lesion or cancer. Our case represents an increasingly common situation: evaluation and management of an asymptomatic woman with a positive PET scan. As more clinicians encounter PET scan abnormalities, it is imperative that the medical literature documents the limitations of this technology, especially in premenopausal women.

The efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC).

OBJECTIVE: To determine the efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC). METHODS: A retrospective multi-institutional investigation was performed to identify surgically staged patients with Stage I UPSC who were (1) treated after surgery with 3-6 courses of platinum-based chemotherapy without radiation from 1990-2003, and (2) followed for a minimum of 12 months, or until recurrence. RESULTS: Six patients (IA-2, IB-3, IC-1) were treated with carboplatin (AUC 6) or cisplatin (50 mg/m2) alone. One patient recurred to the vagina, was treated with chemo-radiation, and is alive and well at 122 months. One patient recurred to the lung, liver, and brain, and died of disease at 24 months. The remaining 4 patients are alive with no evidence of disease 15-124 months (mean 62 months) after treatment. Two patients (IB-1, IC-1) were treated with cisplatin (50 mg/m2) and cyclophosphamide (1000 mg/m2), and both are alive and well with no evidence of disease 75 and 168 months after treatment. Twenty-one patients (IA-5, IB-13, IC-3) were treated with a combination of carboplatin (AUC 6) and paclitaxel (135 mg/m2-175 mg/m2). One patient recurred to the vagina after 3 cycles of carboplatin/paclitaxel, and was treated with chemo-radiation. She is now without evidence of disease 10 months after treatment. At present, all 21 patients with Stage I UPSC treated following surgical staging with carboplatin/paclitaxel chemotherapy are alive and well with no evidence of disease 10-138 months (mean 41 months) after treatment. CONCLUSION: Combination carboplatin/paclitaxel chemotherapy following surgery is effective in the treatment of Stage I UPSC.

In vitro and in vivo adenovirus-mediated p53 and p16 tumor suppressor therapy in ovarian cancer.

PURPOSE: The objectives of this study were to determine the effects of adenovirus-mediated p16 and p53 on growth and apoptosis in ovarian cancer cells and on survival in nude mice implanted with human ovarian cancer cells. EXPERIMENTAL DESIGN: SKOV-3 ip1 (p53 and p16 null), 2774 (p53 and p16 mutant), and OVCA 420 (p53 and p16 wild-type) cells were used for in vitro studies. SKOV-3 ip1, 2774, and Hey A8 (p53 and p16 wild-type) cells were used in the nude mouse studies. The E1-deleted adenoviruses containing p53, p16, or beta-galactosidase cDNA were transfected into the different cell types or inoculated into the nude mice after injection with ovarian cancer cells. RESULTS: Cell counting, microtetrazolium, and anchorage-independent growth assays on transfected cells demonstrated that p16 and the p16/p53 combination suppressed growth, whereas p53 did not (except in the anchorage-independent growth assay). Although cells infected with the p16/p53 combination had decreased growth compared with cells infected with either tumor suppressor alone, the difference was only statistically significant compared with p53. p16, p53, and the p16/p53 combination all increased apoptosis in the cells. In the nude mice, p16 treatment resulted in the longest survival for all three models, although it only reached statistical significance for the 2774 and SKOV-3 ip1 groups. CONCLUSIONS: Overall, p16 demonstrated greater growth inhibition than p53 both in vivo and in vitro. The p16/p53 combination demonstrated a consistent trend toward increased growth suppression and apoptosis over p16 or p53 alone. Adenovirus-mediated p16 may be a viable future treatment for ovarian cancer.

Expression of Ki-67 in vulvar carcinoma and vulvar intraepithelial neoplasia III: correlation with clinical prognostic factors.

OBJECTIVES: In vulvar carcinoma, the expression of Ki-67 has been previously found to correlate with patient outcome. The objective of the study was to determine whether a specific pattern of expression was associated with occult vulvar cancer in patients with vulvar intraepithelial neoplasia (VIN) III and whether patterns of Ki-67 expression correlated with other clinical prognostic factors. METHODS: 19 women with only VIN III, 16 women with both vulvar cancer and VIN III, and 15 women with only vulvar cancer were identified. Immunostaining, using a monoclonal antibody for Ki-67, was then performed on representative tissue blocks and slides were assessed for diffuse or localized patterns of expression. For the patients with vulvar cancer, the type of staining was correlated with FIGO stage, tumor grade, lymph nodes status, and associated VIN III. RESULTS: All 35 patients with VIN III exhibited a diffuse staining pattern. In the 31 patients with vulvar carcinoma, 11 (35%) expressed a diffuse staining pattern while 20 (65%) showed a localized pattern. Poorly differentiated tumors were associated with a diffuse staining pattern (P = 0.013, RR 3.59, CI 1.59-7.60). For vulvar carcinoma, there were no statistically significant relationships between Ki-67 expression pattern and stage, associated VIN III, or lymph node involvement. CONCLUSION: VIN III, regardless of a concomitant vulvar cancer, always expressed a diffuse pattern; thus Ki-67 staining was not useful as a marker for occult cancer. In women with vulvar carcinoma, however, a diffuse Ki-67 expression was significantly associated with poorly differentiated tumors.

Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence.

OBJECTIVE: To determine the impact of margin status on disease recurrence and the incidence of occult cancer in women diagnosed with vulvar intraepithelial neoplasia (VIN) III and treated with surgical excision. METHODS: Between 1989 and 1995, 73 women were diagnosed preoperatively with VIN III by vulvar biopsy and were treated with surgical resection. Patients were examined postoperatively, and recurrence was diagnosed when a biopsy of suspicious lesions confirmed VIN III. RESULTS: The mean age was 45 years; 81% of the patients were white, and 18% were black. Eighty-two percent of the women had used tobacco, 56% had prior cervical dysplasia, and 37% had prior genital warts. An underlying squamous vulvar cancer was found in 22% of patients at initial treatment for VIN III. Fifty-nine women had follow-up of at least 7 months. Of these, 66% (39 of 59) had positive surgical margins, 31% (18 of 59) had negative margins and 3% had unknown margins (two of 59). With positive margins, 46% (18 of 39) suffered recurrent disease; with negative margins, only 17% (three of 18) had recurrent disease (P = .03). Multifocal disease and a history of genital warts also correlated with VIN III recurrence (P = .03 for both). CONCLUSION: A significant number of women diagnosed initially with VIN III on a vulvar biopsy harbored occult vulvar cancer. Recurrences were almost threefold higher when margins were positive for residual VIN III. We conclude that surgical resection is an appropriate method of treatment of VIN III for both diagnostic and therapeutic purposes.

Improved AIDS surveillance through laboratory-initiated CD4 cell count reporting.

OBJECTIVE: To evaluate laboratory-initiated CD4 reporting (LICR) for AIDS surveillance and for differences in cases found by LICR and traditional surveillance methods (i.e., health care provider or death certificate reports and medical record searches). METHODS: We compared the characteristics of persons reported with AIDS between May 1993 and April 1994 by traditional methods or by LICR reports <200/microl. RESULTS: We received 643 LICR reports and 278 AIDS case reports. HIV status was available on 94% of LICR reports; 96% of these persons were HIV-infected. LICR reports were received on 250 (90%) AIDS cases. Cases found by LICR were less likely to be persons of color and to have opportunistic illnesses and more likely to live in rural areas. Cost of LICR to the health department was less than the salary of one research analyst. CONCLUSIONS: LICR, with a high positive predictive value, is a highly sensitive, timely, and relatively inexpensive method of surveillance and its use should be considered in other jurisdictions.

HIV seroprevalence in emergency department patients: Portland, Oregon, 1988-1991.

OBJECTIVES: In Portland, OR: 1) to determine the changes in HIV seroprevalence for ED patients from 1988 to 1991, 2) to define the characteristics of the HIV-positive ED patient, 3) to determine the hepatitis B seroprevalence of HIV-seropositive ED patients, and 4) to demonstrate the feasibility of an ED population-based surveillance investigation. METHODS: A prospective, multiyear observational, cross-sectional, multicenter, population-based seroprevalence study was performed using seven urban hospital EDs. Serologic testing for HIV and hepatitis B was performed on excess blood obtained from ED patients. Four sampling periods were used at each hospital at 14-month intervals starting June 1988 and ending December 1991. The blood specimens were obtained concurrently at all the participating hospitals. RESULTS: Of 1,681 patients, 17 (1.0%) were HIV-positive. The HIV seroprevalence rate was relatively stable over time: 0.5% (2/444) in 1988, 1.7% (7/396) in 1989, 1% (3/296) in 1990, and 0.9% (5/545) in 1991. Most (94%) HIV patients were men, 100% were white, 81% were > or = 30 years old. Most (59%) of the HIV-positive patients also were positive for hepatitis B core antibody. Many (76%) of the HIV-positive patients were known to be positive by the emergency health care worker. CONCLUSION: HIV seroprevalence among the ED patients in Portland, OR, was generally stable from 1988 to 1991. Many HIV-positive patients also were hepatitis B-positive, thus representing a double occupational infectious disease risk to ED personnel. A significant minority (24%) of the HIV-positive patients were not known to be HIV-positive by the ED personnel. Universal precautions and hepatitis B immunization are paramount for reducing the risk of infectious disease due to exposure to body fluids.

Effects of increasing outpatient diagnosis on AIDS surveillance.

Using AIDS surveillance data, we analyzed trends and correlates of outpatients AIDS diagnosis in Oregon and Washington. The proportion of outpatient diagnoses rose from 24% of cases in 1987 to 51% in 1990. Case characteristics associated with outpatient diagnosis included white race, urban residence, and the exposure category of male homosexual/bisexual contact. AIDS-defining conditions associated with outpatient diagnosis included Kaposi's sarcoma, HIV wasting syndrome, and esophageal candidiasis. Completeness and timeliness of reporting was poorer for cases diagnosed as outpatients compared with inpatients. As outpatient diagnosis becomes more common, modified surveillance methods may be needed to ensure complete case finding and consequent reliability of AIDS surveillance information.

Multicenter HIV and hepatitis B seroprevalence study.

Prior single institutional investigations have found unrecognized HIV seroprevalence in emergency department (ED) patients to range from 0.38% to 4%. A prospective, anonymous study of HIV and hepatitis B (HB) seroprevalence was performed on excess serum of all ED patients over two 48-hour periods in May and August, 1988, from 7 hospitals in the Portland metropolitan area. Demographics were known for 338/444 (76%) of patients. Forty-six percent were male, 85% white, with a median age group of 30-39 years. Ambulance transport, trauma, external blood, presentations requiring ED procedure(s), and acuity resulting in ICU admission were present on 21%, 7%, 10%, 34%, and 14% of patients, respectively. Two of 444 (.45%) patients were HIV +, one previously undiagnosed. Fifty-five of the 444 (12%) and 3 of 444 (0.6%) samples were positive for HBcAB and HBsAG respectively. Risk factor assessment was possible on 180/444 (40%) patients. HBcAB seroprevalence correlated with race (P less than 0.01), IV drug use (P less than 0.0001), and hospital location, (P less than 0.006) but were sensitive in detecting only 14%, 18%, and 38%, respectively, of HBcAB+ patients. HBcAB was not associated with the following factors: sex, area of residence, presence of blood externally, trauma, acuity of illness, ED procedures, or mode of transport. This data strongly support the use of universal body fluid precautions. Hepatitis B poses a significant and distinct risk to all emergency care providers. HB vaccination should be strongly advocated for all ED health care workers (HCWs). Emergency medicine multicenter studies are both desirable and feasible.

Evaluation of active versus passive AIDS surveillance in Oregon.

We searched for unreported AIDS cases in Oregon through death certificate and medical record review, and enhanced infection control practitioner and physician surveillance. Fifty-six AIDS cases diagnosed between February 1, 1986 and January 31, 1987 were reported passively. Twenty-nine additional cases diagnosed during this time were retrospectively identified by active methods. Ninety percent of those 29 cases were diagnosed by physicians and cared for in hospitals that had previously reported cases. Completeness of reporting under the passive system was 64 percent.

Trial of anonymous versus confidential human immunodeficiency virus testing.

Before December, 1986, all public human immunodeficiency virus (HIV) testing in Oregon was done confidentially (using names). In December, clients were offered the option of either anonymous or confidential services. As judged by questionnaire responses, the availability of anonymity increased overall demand for testing by 50%: 125% for homosexual/bisexual (gay) men, 56% for female prostitutes, 17% for intravenous drug users, and 32% for other clients. The number of gay clients who had tests increased from a mean of 42 per month during the 4 months before anonymity was available to 108 per month during the 4 months after, whereas, at public sites in Colorado or California and private sites in Oregon, the number of gay clients tested did not increase. Twice as many seropositive persons were identified during the 3 1/2 months after anonymity became available (n = 85) as in the 3 1/2 months before (n = 36). Thus, availability of anonymous HIV testing and counselling drew gay men who had not sought services under a confidential testing system.

PIP: Before December, 1986, all public human immunodeficiency virus (HIV) testing in Oregon was done using names confidentially. Since December, clients have been offered the option of either anonymous or confidential testing. Clients choosing anonymous testing still received pre-test counseling, but were identified only by number. Demographic and risk factor data were collected, and a self administered questionnaire investigated opinions regarding anonymous testing. There was a sharp increase in the number of individuals seeking testing, from 363 first-time clients in the 3 1/2 months preceding anonymous testing to 1250 in the 3 1/2 months after the change (50% increase). 29% of clients indicated that they would not have come without anonymity, although 11% of these chose confidential testing. Of those who would have come without anonymity, 46% chose anonymity. This was most marked among homosexual men, 49% of whom would not have been tested without anonymity. Anonymous testing is strongly implicated as causing these changes, as there was no sharp increase in the number of people coming for testing in Colorado or California. Neither actual nor perceived antibody status was associated with the choice of anonymous or confidential testing. In the 3 1/2 months after anonymous testing was available 85 seropositive individuals were identified, versus 36 in the 3 1/2 months before. 95% of the client who tested positive after the change (81/85) were gay, and 48% (39/81) would not have come without anonymous testing. Thus, anonymous testing attracted homosexual men who would not have been tested confidentially and resulted in the identification of twice as many seropositive individuals as before.