Investigating the Current Harmonization Status of Tumor Markers Using Global External Quality Assessment Programs: A Feasibility Study.

BACKGROUND: The harmonization status of most tumor markers (TMs) is unknown. We report a feasibility study performed to determine whether external quality assessment (EQA) programs can be used to obtain insights into the current harmonization status of the tumor markers α-fetoprotein (AFP), prostate specific antigen (PSA), carcinoembryonic antigen (CEA), cancer antigen (CA)125, CA15-3 and CA19-9. METHODS: EQA sample results provided by 6 EQA providers (INSTAND [Germany], Korean Association of External Quality Assessment Service [KEQAS, South Korea], National Center for Clinical Laboratories [NCCL, China], United Kingdom National External Quality Assessment Service [UK NEQAS, United Kingdom], Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek [SKML, the Netherlands], and the Royal College of Pathologists of Australasia Quality Assurance Programs [RCPAQAP, Australia]) between 2020 and 2021 were used. The consensus means, calculated from the measurement procedures present in all EQA programs (Abbott Alinity, Beckman Coulter DxI, Roche Cobas, and Siemens Atellica), was used as reference values. Per measurement procedure, the relative difference between consensus mean for each EQA sample and the mean of all patient-pool-based EQA samples were calculated and compared to minimum, desirable, and optimal allowable bias criteria based on biological variation. RESULTS: Between 19040 (CA15-3) and 25398 (PSA) individual results and 56 (PSA) to 76 (AFP) unique EQA samples were included in the final analysis. The mean differences with the consensus mean of patient-pool-based EQA samples for all measurement procedures were within the optimum bias criterion for AFP, the desirable bias for PSA, and the minimum bias criterion for CEA. However, CEA results <8 µg/L exceeded the minimum bias criterion. For CA125, CA15-3, and CA19-9, the harmonization status was outside the minimum bias criterion, with systematic differences identified. CONCLUSIONS: This study provides relevant information about the current harmonization status of 6 tumor markers. A pilot harmonization investigation for CEA, CA125, CA15-3, and CA19-9 would be desirable.

Laboratory practice is central to earlier myeloma diagnosis: Utilizing a primary care diagnostic tool and laboratory guidelines integrated into haematology services.

Treatment advances have greatly improved survival, but myeloma is among the worst of all cancers for delayed diagnosis, causing serious morbidities and early deaths. This delay is largely because the symptom profile of myeloma has very low specificity, and in primary care, myeloma is rare. However, initiating the journey to diagnosis simply requires considering myeloma and sending blood to test for monoclonal immunoglobulin. Laboratory tests reliably detect monoclonal immunoglobulin, which is present in 99% of myeloma cases, so why do health care systems have such a problem with delayed diagnosis? The Myeloma UK early diagnosis programme has brought together diverse expertise to investigate this problem, and this article was prepared by the programme's working group for laboratory best practice. It reviews evidence for test requesting, analysis and reporting, for which there is large variation in practice across the United Kingdom. It presents a 'GP Myeloma diagnostic tool' and how it can be integrated into laboratory practice alongside a laboratory best practice tool. It proposes improved requesting and integration with haematology services for reporting and interpretation. Here the laboratory has a central role in creating efficient and cost-effective pathways for appropriate and timely bone marrow examination for myeloma diagnosis.

Detection of antinuclear antibodies: recommendations from EFLM, EASI and ICAP.

OBJECTIVES: Antinuclear antibodies (ANA) are important for the diagnosis of various autoimmune diseases. ANA are usually detected by indirect immunofluorescence assay (IFA) using HEp-2 cells (HEp-2 IFA). There are many variables influencing HEp-2 IFA results, such as subjective visual reading, serum screening dilution, substrate manufacturing, microscope components and conjugate. Newer developments on ANA testing that offer novel features adopted by some clinical laboratories include automated computer-assisted diagnosis (CAD) systems and solid phase assays (SPA). METHODS: A group of experts reviewed current literature and established recommendations on methodological aspects of ANA testing. This process was supported by a two round Delphi exercise. International expert groups that participated in this initiative included (i) the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group "Autoimmunity Testing"; (ii) the European Autoimmune Standardization Initiative (EASI); and (iii) the International Consensus on ANA Patterns (ICAP). RESULTS: In total, 35 recommendations/statements related to (i) ANA testing and reporting by HEp-2 IFA; (ii) HEp-2 IFA methodological aspects including substrate/conjugate selection and the application of CAD systems; (iii) quality assurance; (iv) HEp-2 IFA validation/verification approaches and (v) SPA were formulated. Globally, 95% of all submitted scores in the final Delphi round were above 6 (moderately agree, agree or strongly agree) and 85% above 7 (agree and strongly agree), indicating strong international support for the proposed recommendations. CONCLUSIONS: These recommendations are an important step to achieve high quality ANA testing.

Successful pregnancy following chemotherapy in a survivor of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT): A case report and review of literature.

•Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare neoplasm that mostly affects young women.•The chances of future fertility in women are limited due to the aggressive nature of SCCOHT and need for adjuvant therapy.•We report the case of a 26y woman with stage IA SCCOHT who had a successful pregnancy following surgery and chemotherapy.

Continued provision of WHO International Standards for total and free PSA: Content and commutability of replacement preparations.

OBJECTIVES: Replacements are required for the WHO International Standards (IS) for free PSA, coded 96/668 and total PSA (90:10), coded 96/670, which were established in 1999 to support efforts to harmonise PSA assays and address non-equimolarity. An important consideration is that the introduction of the replacements should have minimal impact on PSA measurements. DESIGN AND METHODS: We report the development of a replacement strategy, informed by field assessment of preparations through an external quality assessment scheme and the subsequent evaluation of the candidate ISs in worldwide collaborative studies. RESULTS: By immunoassay, data from participants confirmed the value assigned to the current standards. Robust geometric mean estimates of the free PSA content of the candidate replacement for 96/668 coded 17/102 was 0.533 µg/ampoule (n = 21). The ratio of the content estimates of 17/102:96/668 was 0.516 (GCV 12.5%, n = 21). Robust geometric mean estimates of the total PSA content of the candidate replacement for 96/670, coded 17/100, was 0.505 µg/ampoule (n = 22). The ratio of the content estimates of 17/100:96/670 was 0.490 (GCV 5.3%, n = 22). Through concomitant measurement of a panel of 15 representative patient samples, the candidate ISs were shown to exhibit commutability with patient samples that was comparable with that of the current ISs. CONCLUSION: On the basis of these results, the preparations coded 17/102 and 17/100 were established by the WHO Expert Committee on Biological Standardization as the 2nd ISs for free and total PSA (PSA-ACT+free PSA) respectively, with assigned contents of 0.53 µg/ampoule and 0.50 µg/ampoule.

"PSYCH-PASS": the Development, Adaptation, and Implementation of a Psychiatric Handoff.

OBJECTIVE: The primary purpose of the study was to develop and implement a psychiatry mnemonic PSYCH-PASS for transitions of care in residency training programs. METHODS: The authors examined areas of improvement in the handoff system with residency training administration, service directors, and psychiatry residents to create PSYCH-PASS, a novel mnemonic that could be integrated in the electronic medical record (EMR). The components of PSYCH-PASS are Patient summary, Situational awareness, "whY" is the patient here, Comorbidities, Hemodynamics, Pharmacology/PRNs, Action list, Specifics, and Synthesis. The authors developed a 14 question pre- and post-survey with a 4-point Likert scale measuring five categories. RESULTS: Pre-survey and post-surveys completed by post-graduate year 2 and 3 residents at Montefiore Medical Center (n = 24) noted increased satisfaction, handoff efficiency, handoff efficiency, accessibility, accuracy, communication, awareness, and adherence to PSYCH-PASS, along with a decrease in frequency of errors. CONCLUSIONS: With promising results across a range of metrics indicating resident-reported positive impacts on patient care, further research on the implementation of PSYCH-PASS and its integration into EMR systems is merited. Future directions include gathering objective data from Epic and expansion of the initiative to other psychiatric services and institutions.

Developing a Theoretical Framework for a Complex Maternal-Child Health Intervention: Health Beginning Initiative.

A theoretical framework serves as a roadmap for the implementation and application of a complex, health promotion intervention; is used to test hypotheses; and guides analysis and evaluation of the intervention. The purpose of this article is to demonstrate how a theoretical framework was developed and used to guide the implementation of Healthy Beginning Initiative (HBI) to promote uptake of HIV services in a low-income country. We used the guide for developing a theoretical framework published in Health Promotion Practice. Developing the theoretical framework included seven steps: (1) identifying the essential elements of the intervention; (2) identifying the variables and the context; (3) listing the postulated mechanisms, mediating variables, and postulated outcomes; (4) identifying existing theoretical models supporting the theoretical framework underdevelopment; (5) scripting the theoretical framework into either a figure or sets of statements; (6) conducting content and face validation of the theoretical framework; and (7) revising the theoretical framework. The theoretical framework was developed and used to evaluate HBI's impact on HIV testing, linkage to care and retention in care for pregnant women, their male partners, and newborns. The theoretical framework will also be adapted for other screenings and other settings while remaining true to the essential elements of HBI.

Timely reminder interventions to improve annual Papanicolaou (Pap) smear rates among HIV-infected women in an outpatient center of southern Nevada: a short report.

Current guidelines recommend annual Papanicolaou (Pap) smears for human immunodeficiency virus (HIV)-infected women for cervical cancer screening. Rates for such screening in Nevada are below the national rate. Our cohort includes 485 eligible HIV-infected adult women from an outpatient center in Southern Nevada of which only 12 women had obtained a Pap smear in the past year. An intervention was conducted from June 2015 to September 2015, in which reminders to schedule a Pap smear were sent to the remaining cohort of 473 women via sequential text messaging, followed by phone call attempts. Of all subjects, 94% contacted by text messages and 41% contacted by phone calls were successfully reached. There was an increase in the rate of completed Pap smears from 2.5% (12/485) at baseline to 11.8% (56/473) after interventions (p < 0.0001) in a period of three months. Out of the 68 Pap smear results, 20 (29.4%) were abnormal. Our intervention, utilizing methods of communication such as text messaging and phone calls, markedly increased the rate of completed Pap smear screening in our population.

What do You Need to Get Male Partners of Pregnant Women Tested for HIV in Resource Limited Settings? The Baby Shower Cluster Randomized Trial.

Male partner involvement has the potential to increase uptake of interventions to prevent mother-to-child transmission of HIV (PMTCT). Finding cultural appropriate strategies to promote male partner involvement in PMTCT programs remains an abiding public health challenge. We assessed whether a congregation-based intervention, the Healthy Beginning Initiative (HBI), would lead to increased uptake of HIV testing among male partners of pregnant women during pregnancy. A cluster-randomized controlled trial of forty churches in Southeastern Nigeria randomly assigned to either the HBI (intervention group; IG) or standard of care referral to a health facility (control group; CG) was conducted. Participants in the IG received education and were offered onsite HIV testing. Overall, 2498 male partners enrolled and participated, a participation rate of 88.9%. Results showed that male partners in the IG were 12 times more likely to have had an HIV test compared to male partners of pregnant women in the CG (CG = 37.71% vs. IG = 84.00%; adjusted odds ratio = 11.9; p < .01). Culturally appropriate and community-based interventions can be effective in increasing HIV testing and counseling among male partners of pregnant women.

Effect of a congregation-based intervention on uptake of HIV testing and linkage to care in pregnant women in Nigeria (Baby Shower): a cluster randomised trial.

BACKGROUND: Few effective community-based interventions exist to increase HIV testing and uptake of antiretroviral therapy (ART) in pregnant women in hard-to-reach resource-limited settings. We assessed whether delivery of an intervention through churches, the Healthy Beginning Initiative, would increase uptake of HIV testing in pregnant women compared with standard health facility referral. METHODS: In this cluster randomised trial, we enrolled self-identified pregnant women aged 18 years and older who attended churches in southeast Nigeria. We randomised churches (clusters) to intervention or control groups, stratified by mean annual number of infant baptisms (<80 vs ≥80). The Healthy Beginning Initiative intervention included health education and on-site laboratory testing implemented during baby showers in intervention group churches, whereas participants in control group churches were referred to health facilities as standard. Participants and investigators were aware of church allocation. The primary outcome was confirmed HIV testing. This trial is registered with ClinicalTrials.gov, identifier number NCT 01795261. FINDINGS: Between Jan 20, 2013, and Aug 31, 2014, we enrolled 3002 participants at 40 churches (20 per group). 1309 (79%) of 1647 women attended antenatal care in the intervention group compared with 1080 (80%) of 1355 in the control group. 1514 women (92%) in the intervention group had an HIV test compared with 740 (55%) controls (adjusted odds ratio 11·2, 95% CI 8·77-14·25; p<0·0001). INTERPRETATION: Culturally adapted, community-based programmes such as the Healthy Beginning Initiative can be effective in increasing HIV screening in pregnant women in resource-limited settings. FUNDING: US National Institutes of Health and US President's Emergency Plan for AIDS Relief.

Impact of male partner's awareness and support for contraceptives on female intent to use contraceptives in southeast Nigeria.

BACKGROUND: Despite the growing body of evidence on use of modern contraceptives among women in sub-Saharan African countries, little is known about the broader context in which female decision-making concerning contraceptive use occurs, particularly the role of their male partners' awareness and support of modern contraceptives. METHODS: We conducted a cross-sectional survey of 2468 pregnant women and their male partners enrolled in the Healthy Beginning Initiative (HBI), an intervention to increase HIV testing among pregnant women in Enugu, southeast Nigeria. The aims of this study were to determine: 1) male partners' awareness of, and support for, female contraceptive methods, and 2) influence of male partners' contraceptive awareness and support on pregnant women's expressed desire to use contraception. We used logistic regression models to examine the association between male partners' awareness and support of modern contraceptives on their spouses' desire to use contraceptives. RESULTS: Men's awareness of, and support for, use of modern contraceptives were significantly associated with their female partners' desire to use contraception. A majority of the men who were aware of modern contraceptives (66.5 %) and those who supported their spouses' use of contraception (72.5 %) had partners who expressed a desire to use contraception. Men who were aware of female contraception were 3 times more likely to have spouses who desired to use contraception (AOR = 3.17, 95 % C.I: 2.70-3.75). In addition, men who showed support for their spouses' use of contraception were over 5 times more likely to have spouses who indicated a desire to use contraception (AOR = 5.76, 95 % C.I: 4.82-6.88). Living in a household of 5 or more people (AOR = 1.45, 95 % C.I: 1.23-1.72) and residing in an urban area (AOR = 0.81, 95 % C.I: 0.67-0.97) were also significantly associated with women's expressed desire to use modern contraception. CONCLUSION: Men's awareness of, and support for, use of modern contraceptives were markedly associated with their spouses' desire to use contraception. This underscores the need for men's involvement in programs that seek to address women's uptake of contraception in low and middle income countries.

Floxuridine hepatic arterial infusion associated biliary toxicity is increased by concurrent administration of systemic bevacizumab.

PURPOSE: Systemic bevacizumab (Bev) was added to hepatic arterial infusion (HAI) floxuridine (FUDR)-based chemotherapy in three studies in an attempt to improve outcomes. A specific review of biliary toxicity was carried out. METHODS: This analysis included 203 patients from three prospective studies. The first (study A) was an adjuvant study after liver resection of colorectal metastases in which patients received HAI and systemic chemotherapy (Sys) with or without Bev. Study B comprised unresectable colorectal patients who received HAI and Sys plus Bev. Study C included patients with unresectable cholangiocarcinoma or hepatocellular carcinoma who received HAI plus systematic Bev. The outcome and toxicity of patients in studies B and C were compared with historical controls. RESULTS: In all three studies, the incidence of hyperbilirubinemia and biliary stent placement within 1 year of treatment was increased with the addition of Bev. In the no-Bev versus Bev groups, the placement of biliary stents was as follows: study A, 0 of 38 versus 4 of 35 patients (p = 0.05); study B, 0 of 49 versus 3 of 24 (p = 0.06); and study C, 0 of 34 versus 3 of 22 (p = 0.15). Elevation in bilirubin was noted in the no-Bev versus Bev groups: study A, 0 of 38 versus 5 of 35 patients (p = 0.02); study B, 1 of 49 versus 7 of 24 (p = 0.005); and study C, 2 of 34 versus 5 of 22 (p = 0.10). The addition of Bev did not seem to be associated with improved progression-free or overall survival. CONCLUSIONS: The addition of Bev to HAI FUDR resulted in increased biliary toxicity in three separate studies. Although the sample sizes were small, there was no evidence of improved PFS or OS with the addition of Bev. Bev should not be combined with HAI FUDR.

Hepatic arterial infusion and systemic chemotherapy for breast cancer liver metastases.

Hepatic failure from breast cancer liver metastases (BCLM) is a major cause of morbidity and mortality. We reviewed the treatment histories and outcomes of nine patients with heavily treated BCLM, who received hepatic arterial infusion (HAI) of floxuridine (FUDR)/dexamethasone (Dex) and systemic chemotherapy at our institution. Patients received a median of five (range 1-15) HAI treatments. There were seven (78%) objective responses. Four patients had grade 3 elevations in liver enzymes attributable to HAI. There were no treatment-related deaths. Median hepatic and extrahepatic time to progression on HAI were both 6 months. Median survival after starting HAI was 17 months (range 1-115). Median overall survival from the original breast cancer diagnosis was 110 months (range 52-248). One patient is alive with stable disease on systemic therapy alone. HAI and systemic chemotherapy is feasible and can benefit selected patients with BCLM, who have progressed on prior therapies. Patients require close monitoring for treatment-limiting toxicities.

The role of residue C410 on activation of the human vitamin D receptor by various ligands.

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of genes involved in biologically important processes. The human vitamin D receptor (hVDR) is a member of the NR superfamily and is responsible for maintaining calcium and phosphate homeostasis. This receptor is activated by its natural ligand, 1α, 25-dihydroxyvitamin D(3) (1α, 25(OH)(2)D(3)), as well as bile acids such as lithocholic acid (LCA). Disruption of molecular interactions between the hVDR and its natural ligand result in adverse diseases, such as rickets, making this receptor a good target for drug discovery. Previous mutational analyses of the hVDR have mainly focused on residues lining the receptor's ligand binding pocket (LBP) and techniques such as alanine scanning mutagenesis and site-directed mutagenesis. In this work, a rationally designed hVDR library using randomized codons at selected positions provides insight into the role of residue C410, particularly on activation of the receptor by various ligands. A variant, C410Y, was engineered to bind LCA with increased sensitivity (EC(50) value of 3 µM and a 34-fold activation) in mammalian cell culture assays. Furthermore, this variant displayed activation with a novel small molecule, cholecalciferol (chole) which does not activate the wild-type receptor, with an EC(50) value of 4 µM and a 25-fold activation. The presence of a bulky residue at this position, such as a tyrosine or phenylalanine, may contribute towards molecular interactions that allow for the enhanced activation with LCA and novel activation with chole. Additional bulk at the same end of the pocket, such as in the case of the variant H305F; C410Y enhances the receptor's sensitivity for these ligands further, perhaps due to the filling of a cavity. The effects of residue C410 on specificity and activation with the different ligands studied were unforeseen, as this residue does not line the hVDR's LBP. Further investigating of the structure-function relationships between the hVDR and its ligands, including the mutational tolerance of residues within as well as outside the LBP, is needed for a comprehensive understanding of the functionality and interactions of the receptor with these ligands and for development of new small molecules as potential therapeutic drugs.

Chemotherapy outcomes for the treatment of unresectable intrahepatic and hilar cholangiocarcinoma: a retrospective analysis.

BACKGROUND: Recent clinical trials for "biliary cancers" include a heterogenous group of patients with cholangiocarcinoma, gallbladder, and ampullary cancers. Limited data exist regarding the relative effectiveness of known chemotherapeutic regimens specifically in intrahepatic or hilar cholangiocarcinoma. METHODS: Records of M D Anderson Cancer Center patients with unresectable intrahepatic and hilar cholangiocarcinoma who received first-line chemotherapy from January 1, 2005, to October 31, 2009, were retrospectively reviewed. The primary objective of this research was to determine overall tumor control rates with chemotherapeutic regimens used for first-line treatment of unresectable intrahepatic and hilar cholangiocarcinoma. Secondary objectives included duration of response, overall survival, and prognostic factors. RESULTS: Eighty-five patients met inclusion criteria and were eligible for analysis. The most commonly used regimen was gemcitabine/cisplatin (62%), followed by oxaliplatin and capecitabine (16%). There was no significant difference between tumor control rates with gemcitabine/cisplatin (72% PR + SD) and other regimens (69% PR + SD). There was no significant difference between overall survival with the use of gemcitabine/cisplatin (15.2 months) or alternative regimens (13.9 months). A decrease in overall survival was seen with elevated baseline CA 19-9 (p < .0001), an initial diagnosis of unknown primary tumor (p = .0001), and prior treatment with chemoradiation (p = .0018). CONCLUSION: In this retrospective review, both gemcitabine/cisplatin and alternative doublets (including capecitabine/oxaliplatin, gemcitabine/capecitabine, and gemcitabine/oxaliplatin) were effective regimens in maintaining disease control in intrahepatic and hilar cholangiocarcinoma.

Summary of the causative and treatment factors of diarrhea and the use of a diarrhea assessment and treatment tool to improve patient outcomes.

This article is a review of the causative factors and pharmacologic treatments of diarrhea. This information was incorporated into a Diarrhea Assessment and Treatment Tool (DATT) to guide clinicians on comprehensive diarrhea assessment and current treatment recommendations. The tool was utilized at a university-affiliated oncology institution by a clinical nurse specialist on 26 patients as a performance improvement project. Ease of use and efficacy of DATT were tested. Eighty-one percent of patients were assessed using DATT in 30 minutes or less. Seventy-nine percent of the 57 identified diarrhea classifications were not being treated upon initial assessment. Diarrhea control was achieved in 73% of the patients within 7 days or fewer when DATT was utilized. The premise of diarrhea management is that if all the causative factors are not treated, diarrhea will persist. The conclusions are that this tool will aid the clinician in a comprehensive assessment of diarrhea and provide a systematic approach to diarrhea treatment. The need for research on best practice for management of the various causative factors of diarrhea is needed.

Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma.

PURPOSE To determine the conversion to resectability in patients with unresectable liver metastases from colorectal cancer treated with hepatic arterial infusion (HAI) plus systemic oxaliplatin and irinotecan (CPT-11). PATIENTS AND METHODS Forty-nine patients with unresectable liver metastases (53% previously treated with chemotherapy) were enrolled onto a phase I protocol with HAI floxuridine and dexamethasone plus systemic chemotherapy with oxaliplatin and irinotecan. Results Ninety-two percent of the 49 patients had complete (8%) or partial (84%) response, and 23 (47%) of the 49 patients were able to undergo resection in a group of patients with extensive disease (73% with > five liver lesions, 98% with bilobar disease, 86% with > or = six segments involved). For chemotherapy-naïve and previously treated patients, the median survival from the start of HAI therapy was 50.8 and 35 months, respectively. The only baseline variable significantly associated with a higher resection rate was female sex. Variables reflecting extensive anatomic disease, such as number of lesions or number of vessels involved, were not significantly associated with the probability of resection. CONCLUSION The combination of regional HAI floxuridine/dexamethasone and systemic oxaliplatin and irinotecan is an effective regimen for the treatment of patients with unresectable liver metastases from colorectal cancer, demonstrating a 47% conversion to resection (57% in chemotherapy-naïve patients). Future randomized trials should compare HAI plus systemic chemotherapy with systemic therapy alone to assess the additional value of HAI therapy in converting patients with hepatic metastases to resectability.

A phase I study of gemcitabine given via intrahepatic pump for primary or metastatic hepatic malignancies.

PURPOSE: To determine the maximum tolerated dose and duration of hepatic arterial infusion (HAI) gemcitabine in patients with unresectable hepatic metastases from colorectal cancer or primary hepatic malignancies. METHODS: Patients received weekly gemcitabine via the side-port of an implantable HAI pump for 3 weeks in a 28-day cycle. During the dose escalation phase, increasing doses of HAI gemcitabine (800, 1,000, 1,200, and 1,500 mg/m(2)) were given at a fixed dose-rate of 10 mg/(m(2) min). This was followed by the infusion duration escalation (IDE) phase, in which HAI gemcitabine at 1,000 mg/m(2) was given over increasing lengths of time (200, 300, and 400 min). To estimate hepatic drug extraction, the pharmacokinetics of HAI gemcitabine was compared with those of intravenous gemcitabine given at the same dose-rate to the same patient in the IDE phase. RESULTS: Twenty-eight of 30 patients were evaluable. HAI gemcitabine was well tolerated up to 1,500 mg/m(2) given at 10 mg/(m(2) min) and up to 1,000 mg/m(2) infused over 400 min. There were no protocol-defined dose-limiting toxicities. One patient with cholangiocarcinoma had a partial response. Hepatic extraction of gemcitabine seems highly variable among patients and does not correlate with the length of HAI infusion. CONCLUSIONS: Hepatic arterial infusion of gemcitabine given at doses higher or longer than the recommended systemic dose of 1,000 mg/m(2) over 30 min is well tolerated. For future studies, we recommend an infusion of 1,500 mg/m(2) at a fixed dose-rate of 10 mg/(m(2) min).

Clinical use of anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer.

Abstract Cetuximab and panitumumab, monoclonal antibodies used to target the epidermal growth factor receptor (EGFR), were recently approved by the United States Food and Drug Administration for use as single agents or in combination with other chemotherapy drugs in the treatment of metastatic colorectal cancer. The anti-EGFR monoclonal antibodies, either as single agents or in combination with chemotherapy, have demonstrated clinical activity in this setting. When combined with standard cytotoxic chemotherapy or other targeted agents (e.g., bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody), anti-EGFR monoclonal antibodies have been well tolerated and produced minimal toxicities. However, cetuximab and panitumumab appear to benefit only select patients. Predictive markers of efficacy, including EGFR overexpression, development of skin rash, and the absence of a K-ras mutation, have been evaluated in clinical studies to identify patients likely to respond to anti-EGFR monoclonal antibody therapy. This review discusses recent clinical studies of anti-EGFR monoclonal antibodies in the treatment of metastatic colorectal cancer, predictive markers of their efficacy, and common toxicities associated with their use.

Revised national guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage.

It is crucially important to detect subarachnoid haemorrhage (SAH) in all patients in whom it has occurred to select patients for angiography and preventative surgery. A computerized tomography (CT) scan is positive in up to 98% of patients with SAH presenting within 12 h, but is positive in only 50% of those presenting within one week. Cerebrospinal fluid (CSF) bilirubin spectrophotometry can be used to determine the need for angiography in those few CT-negative patients in whom clinical suspicion of SAH remains high; it may remain positive up to two weeks after the event. A lumbar puncture (LP) should only be performed >12 h after the onset of presenting symptoms. Whenever possible collect sequential specimens. Always ensure that the least blood-stained CSF sample taken (usually the last) is sent for bilirubin analysis. Protect the CSF from light and avoid vacuum tube transport systems, if possible. Always use spectrophotometry in preference to visual inspection. All CSF specimens are precious and should always be analysed unless insufficient sample is received. Centrifuge the specimen at >2000 rpm for 5 min as soon as possible after receipt in the laboratory. Store the supernatant at 4 degrees C in the dark until analysis. An increase in CSF bilirubin is the key finding, which supports the occurrence of SAH but is not specific for this. In most positive cases, bilirubin will occur with oxyhaemoglobin.