Endometrial adenocarcinoma presenting as a suprasellar mass: lessons to be learned.

A 66-year-old woman with a history of stage IA mixed endometrioid and serous endometrial cancer presented to our centre with 2 weeks of worsening headaches nearly 4 years after her initial surgery. At admission, she manifested bitemporal hemianopsia, difficulty walking and clinical and laboratory findings of panhypopituitarism, including diabetes insipidus. Magnetic resonance imaging of the brain revealed a 2.7 cm sellar/suprasellar mass compressing the optic chiasm and infiltrating the pituitary stalk. Computerised tomography documented mediastinal, lung, adrenal and liver involvement, including a 2.5 cm palpable left supraclavicular node that on excisional biopsy demonstrated metastatic endometrial adenocarcinoma. Due to the advanced stage of her cancer as well as the presence of multiple metastases, including lung and hepatic metastases causing post-obstructive pneumonia and coagulopathy, the sellar/suprasellar mass was treated with fractionated radiosurgery rather than surgical excision.

Lasting pathologic complete response to chemotherapy for ovarian cancer after receiving antimalarials for dermatomyositis.

Could hydroxychloroquine and quinacrine antimalarial therapy for dermatomyositis later attributed to a paraneoplasic manifestation of an ovarian cancer enhance its subsequent response to chemotherapy? Five months after being diagnosed with dermatomyositis, while somewhat improved with hydroxychloroquine, quinacrine and methotrexate, this 63-year-old woman presented with an advanced intra-abdominal epithelial ovarian cancer documented (but not resected) at laparotomy. Neoadjuvant carboplatin/paclitaxel resulted in remarkable improvement of symptoms, tumour markers and imaging findings leading to thorough cytoreductive surgery at completion of five cycles. No tumour was found in the resected omentum, gynaecologic organs, as well as hepatic and nodal sampling thus documenting a complete pathologic response; a subcutaneous port and an intraperitoneal (IP) catheter were placed for two cycles of IP cisplatin consolidation. She remains free of disease 3 years after such treatment and her dermatomyositis is in remission in the absence of any treatment. We discuss a possible role of autophagy in promoting tumour cell survival and chemoresistance that is potentially reversed by antimalarial drugs. Thus, chemotherapy following their use may subsequently lead to dramatic potentiation of anticancer treatment.

Developing and testing a comprehensive tool to assess family meetings: Empirical distinctions between high- and low-quality meetings.

BACKGROUND: The heterogeneity with regard to findings on family meetings (or conferences) suggests a need to better understand factors that influence family meetings. While earlier studies have explored frequency or timing of family meetings, little is known about how factors (such as what is said during meetings, how it is said, and by whom) influence family meeting quality. OBJECTIVES: (1) To develop an evaluation tool to assess family meetings (Phase 1); (2) to identify factors that influence meeting quality by evaluating 34 family meetings (Phase 2). MATERIALS AND METHODS: For Phase 1, methods included developing a framework, cognitive testing, and finalizing the evaluation tool. The tool consisted of Facilitator Characteristics (i.e., gender, experience, and specialty of the person leading the meeting), and 22 items across 6 Meeting Elements (i.e., Introductions, Information Exchanges, Decisions, Closings, Communication Styles, and Emotional Support) and sub-elements. For Phase 2, methods included training evaluators, assessing family meetings, and analyzing data. We used Spearman's rank-order correlations to calculate meeting quality. Qualitative techniques were used to analyze free-text. RESULTS: No Facilitator Characteristic had a significant correlation with meeting quality. Sub-elements related to communication style and emotional support most strongly correlated with high-quality family meetings, as well as whether "next steps" were outlined (89.66%) and whether "family understanding" was elicited (86.21%). We also found a significant and strong positive association between overall proportion scores and evaluators' ratings (rs=0.731, p<0.001). CONCLUSIONS: We filled a gap by developing an evaluation tool to assess family meetings, and we identified how what is said during meetings impacts quality.

Squamous cell carcinoma of the rectum: a consequence of immunosuppression resulting from inhibiting tumour necrosis factor (TNF)?

Treatment with tumour necrosis factor (TNF) antagonists may lead to enhanced susceptibility to certain malignancies. In particular, an association is seen emerging between TNF antagonists and development of squamous cell carcinomas (SCCs) of the skin (in association with psoriasis), the oral cavity, and in the anogenital areas (possibly related to prior human papilloma virus infection). We present here a case of a 53-year old woman with a history of severe rheumatoid arthritis (RA), most recently treated with the TNF antagonist etanercept plus methotrexate, presented to our service after several months of increasing left pelvis and buttock pain. Evaluation with a computerised tomography (CT)-directed biopsy of a pelvic side wall mass revealed a metastatic SCC. On a fluorodeoxyglucose (FDG) positron-emission tomography (PET) an additional area of uptake was identified in the left posterior rectum corresponding to a 1 cm nodule palpable on digital exam. Colonoscopic biopsy revealed a basaloid SCC of the rectum as the likely primary site. Immunosuppression following TNF antagonist therapy may have given arise to this unrestrained neoplastic growth. It thereby underscores the need for an initial baseline study of risk factors and identification of patients who are at higher risk for development of a malignancy, in order to achieve a diagnosis at an early stage.

Barriers and Facilitators to Initiating and Completing Time-Limited Trials in Critical Care.

OBJECTIVES: A time-limited trial is an agreement between clinicians and patients or surrogate decision makers to use medical therapies over a defined period of time to see if the patient improves or deteriorates according to agreed-upon clinical milestones. Although time-limited trials are broadly advocated, there is little empirical evidence of the benefits and risks of time-limited trials, when they are initiated, when and why they succeed or fail, and what facilitates completion of them. Our study objectives were to 1) identify the purposes for which clinicians use time-limited trials and 2) identify barriers and facilitators to initiating and completing time-limited trials. DESIGN: Semistructured interviews: We analyzed interviews using qualitative description with constant comparative techniques. SETTING: Nine hundred-bed, academic, tertiary hospital in Houston, Texas. Interviewees were from open medical, surgical, neurosurgical, and cardiovascular ICUs. SUBJECTS: Thirty healthcare professionals were interviewed (nine surgeons, 16 intensivists, three nurse practitioners, and two "other" clinicians). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Interviewees reported initiating time-limited trials for three different purposes: to prepare surrogates and clinicians for discussion and possible shifts toward comfort-care only therapies, build consensus, and refine prognostic information. The main barriers to initiating time-limited trials involve clinicians' or surrogate decision makers' disagreement on setting a time limit. Barriers to completing time-limited trials include 1) requesting more time; 2) communication breakdowns because of rotating call schedules; and 3) changes in clinical course. Finally, facilitators to completing time-limited trials include 1) having defined goals about what could be achieved during an ICU stay, either framed in narrow, numeric terms or broad goals focusing on achievable activities of daily living; 2) applying time-limited trials in certain types of cases; and 3) taking ownership to ensure completion of the trial. CONCLUSIONS: An understanding of barriers and facilitators to initiating and completing time-limited trials is an essential first step toward appropriate utilization of time-limited trials in the ICUs, as well as developing educational or communication interventions with clinicians to facilitate time-limited trial use. We provide practical suggestions on patient populations in whom time-limited trials may be successful, the setting, and clinicians likely to benefit from educational interventions, allowing clinicians to have a fuller sense of when and how to use time-limited trials.

Continuous-infusion topotecan and erlotinib: a study in topotecan-pretreated ovarian cancer assessing shed collagen epitopes as a marker of invasiveness.

BACKGROUND: Continuous-infusion topotecan with erlotinib has the potential to reverse topotecan resistance due to drug efflux mechanisms. We assessed the activity of such a regimen in ovarian cancer patients previously failing bolus topotecan. Assay for shed collagen epitopes recognized by antibody HU177 during treatment explored its ability to reflect tumor invasion. METHODS: Topotecan 0.4 mg/m(2) per day was administered by continuous infusion for 9-10 days every 3 weeks. Erlotinib, 150 mg orally, was administered on days 1-10 of each cycle. Cycles were repeated until progression or toxicity. Serum for shed HU177 collagen epitopes was collected weekly. This was a two-stage design to detect a CA-125 response rate of at least 20% in 30 patients after completing two treatment cycles. The trial would be terminated early if there were less than two CA-125 responses in 16 patients. Four or more CA-125 responses in 30 patients would justify further study of this regimen in prior topotecan treatment failures. RESULTS: Six patients were enrolled, with four receiving three or more cycles and one achieving a partial response by cancer antigen 125 (CA-125) criteria. Shed epitope levels became undetectable on at least one measurement in all patients who received three or more cycles (Fig. 1A) and reappeared concomitantly with rises in CA-125 and clinical progression (Fig. 1B). After logistical delays, the trial was closed by the sponsor's decision to stop developing erlotinib in ovarian cancer. FIGURE 1: Monitoring of combination treatment. A, B, C, D, and F refer to patients. (A):: Topotecan and erlotinib. (B):: CA-125 in units/mL. CONCLUSION: Continuous-infusion topotecan with erlotinib was found safe in six pretreated ovarian cancer patients; one met CA-125 criteria for partial response. Serial shed epitope levels to reflect invasiveness deserve further study.

Ovarian cancer in BRCA mutation carriers: improved outcome after intraperitoneal (IP) cisplatin.

BACKGROUND: Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes. METHODS: Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials. RESULTS: Ten patients that were confirmed to have BRCA mutations-all with high-grade and stages IIC to IV disease-survived a median of 10 years (range: 4-18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively. CONCLUSIONS: This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.

Squamous cell carcinoma of the oral cavity in nonsmoking women: a new and unusual complication of chemotherapy for recurrent ovarian cancer?

PURPOSE: To describe occurrences of oral squamous cell carcinoma (SCC) in patients who had received long-term pegylated liposomal doxorubicin (PLD) for ovarian cancer. PATIENTS AND METHODS: In our cohort of patients on maintenance PLD for ovarian and related mullerian epithelial malignancies, we encountered two patients with invasive SCC of the oral cavity (one of them multifocal) and one with high-grade squamous dysplasia. Review of patients at our institution receiving PLD for recurrent ovarian cancer identified three additional patients. The duration of treatment, cumulative PLD dose, human papillomavirus (HPV) positivity, BRCA status, stage at diagnosis, outcome, and other characteristics are reviewed. RESULTS: All five cases were nonsmokers with no known risk factors for HPV and four were negative for p16 expression. Four of the patients had known BRCA mutations whereas one tested negative. Cumulative doses of PLD were >1,600 mg/m2 given over 30-132 months. Three had SCCs staged as T1N0 oral tongue, alveolar ridge (gingival), and multifocal oral mucosa; one had a T2N0 oral tongue; and one had dysplasia. After excision, two were given radiation but recurred shortly thereafter; the others remain well and have had no further exposure to cytotoxic drugs, including PLD. CONCLUSION: Awareness of this possible long-term complication during PLD treatment should enhance the likelihood of early detection of oral lesions in these patients. Decisions to continue maintenance PLD after complete response of the original cancer should perhaps consider the benefits of delaying ovarian cancer recurrence versus the possible risk for a secondary cancer.

Feasibility and cardiac safety of pegylated liposomal doxorubicin plus trastuzumab in heavily pretreated patients with recurrent HER2-overexpressing metastatic breast cancer.

BACKGROUND: Few studies have evaluated concomitant pegylated liposomal doxorubicin (PLD) plus trastuzumab as therapy for HER2-overexpressing metastatic breast cancer (MBC). This open-label, prospective, phase II trial assessed the safety and efficacy of this regimen, with cardiac tolerance as the principal focus. PATIENTS AND METHODS: Women with HER2-overexpressing recurrent MBC, baseline left ventricular ejection fraction >or= 55%, and no history of serious cardiac illness were eligible; preexisting cardiac risk factors, including previous anthracyclines and previous trastuzumab for MBC, were allowed. Patients received weekly trastuzumab and every-3-week PLD until progression, prohibitive toxicity, or patient refusal. Left ventricular ejection fraction was assessed during and after therapy. Grade 3/4 congestive heart failure (CHF) was monitored for premature closure. RESULTS: The trial closed after 2.5 years for slow accrual. Twelve patients were enrolled: 7 had received adjuvant anthracyclines; 9 had received previous MBC treatment, of whom 7 had received trastuzumab in combination with chemotherapy. Patients received a mean of 4.8 cycles of PLD; 8 patients experienced stable disease; 4 patients experienced progression. Mean left ventricular ejection fraction levels did not change substantially: 60.4%, 57%, 60.3%, and 56.8% at baseline, after cycle 2, after cycle 4, and after completion of treatment, respectively. No patients experienced grade 4 CHF. One patient discontinued treatment after grade 3 CHF. Three patients experienced grade 2 left ventricular dysfunction, of whom 2 discontinued treatment. Cardiac function improved in all 4 patients after going off study. Other adverse events were generally mild (grade 1/2) and infrequent. CONCLUSION: Pegylated liposomal doxorubicin plus trastuzumab might be an option for heavily pretreated patients with recurrent HER2-overexpressing MBC.

A phase I and pharmacokinetic study of docetaxel combined with Doxil (pegylated liposomal doxorubicin) without and with granulocyte colony stimulating factor.

The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers.