Investigating the feasibility of a hand-held photoacoustic imaging probe for margin assessment during breast conserving surgery.

Approximately 19 % of breast cancer patients undergoing breast conserving surgery (BCS) must return for a secondary surgery due to incomplete tumour removal. Our previous work demonstrated that the lower lipid content, characteristic of tumour tissue, was observed as regions of hypo-intense photoacoustic (PA) contrast. The goal of this work was to evaluate feasibility of a low-frequency, hand-held PA imaging probe for surgical margin assessment based on lipid content differences. Here, we describe (i) the design of a prototype hand-held PA imaging probe, (ii) the effect of limited-bandwidth on image contrast, (iii) accuracy towards hypo-intense contrast detection, (iv) the limited-view characteristics of the single sensor design, and (iv) early imaging results of an ex-vivo breast cancer specimen. The probe incorporates a single polyvinylidene fluoride acoustic sensor, a 1-to-4 optical fibre bundle and a polycarbonate axicon lens for light delivery. Imaging results on phantoms designed to mimic positive margins demonstrated the ability to detect gaps in optical absorption as small as 1 mm in width. Compared to images from a near full-view PAI system, the hand-held PAI probe had higher signal to noise ratio but suffered from negativity image artifacts. Lumpectomy specimen imaging showed that strong signals can be obtained from the fatty tissue. Taken together, the results show this imaging approach with a hand-held probe has potential for detection of residual breast cancer tissue during BCS; however, more work is needed to reduce the size of the probe to fit within the surgical cavity.

A systematic review of axillary nodal irradiation for the management of the axilla in patients with early-stage breast cancer.

BACKGROUND: Given numerous publications and clinical trials regarding axillary management in breast cancer, we sought to summarize this complex literature to help clarify this field for clinicians. This systematic review focuses on the role of irradiation of the axillary nodes (locoregional nodal irradiation [LRNI]) in the management of the axilla in patients with early-stage breast cancer in various clinical settings. METHODS: We searched MEDLINE and EMBASE databases, the Cochrane library, the proceedings of the ASCO, the ASTRO, the ESMO, the ESTRO, and the San Antonio Breast Cancer Symposium (2016-2019) meetings. The quality of the studies was assessed with design-specific tools. The study was registered in PROSPERO. RESULTS: We included one systematic review, one individual patient data (IPD) meta-analysis, and five randomized controlled trials (RCTs). After axillary lymph node dissection (ALND), LRNI resulted in small benefits in breast cancer specific mortality, locoregional recurrence, and distant metastases-free survival but not overall survival. After a positive sentinel node biopsy (SLNB), LRNI may provide equivalent locoregional control and disease-free survival (DFS) compared to ALND with a lower risk of lymphedema. No randomized data is available for the neoadjuvant setting. CONCLUSIONS: The summary of the role of radiation, is relevant to radiation oncologists for choosing the correct cohort of patient requiring LRNI and to surgeons making clinical decisions regarding the timing and type of breast reconstruction offered to patients.

Consensus statement on tumour bed localization for radiation after oncoplastic breast surgery.

Background: Oncoplastic surgery (ops) is becoming the new standard of care for breast-conserving surgery, leading to some challenges with adjuvant radiation, particularly when accurate tumour bed (tbd) delineation is needed for focused radiation (that is, accelerated partial breast irradiation or boost radiation). Currently, no guidelines have been published concerning tbd localization for adjuvant targeted radiation after ops. Methods: A modified Delphi method was used to establish consensus by a panel of 20 experts in surgical and radiation oncology at the Canadian Locally Advanced Breast Cancer National Consensus Group and in a subsequent online member survey. Results: These are the main recommendations:■ Surgical clips are necessary and should, at a minimum, be placed along the 4 side walls of the cavity, plus 1-4 clips at the posterior margin if necessary.■ Operative reports should include pertinent information to help guide the radiation oncologists.■ Breast surgeons and radiation oncologists should have a basic understanding of ops techniques and work on "speaking a common language."■ Careful consideration is needed when determining the value of targeted radiation, such as boost, in higher-level ops procedures with extensive tissue rearrangement. Conclusions: The panel developed a total of 6 recommendations on tbd delineation for more focused radiation therapy after ops, with more than 80% agreement on each statement. All are summarized, together with the corresponding evidence or expert opinion.

Stereotactic image-guided neoadjuvant ablative single-dose radiation, then lumpectomy, for early breast cancer: the SIGNAL prospective single-arm trial of single-dose radiation therapy.

Background and Purpose: Adjuvant whole-breast irradiation after breast-conserving surgery, typically delivered over several weeks, is the traditional standard of care for low-risk breast cancer. More recently, hypofractionated, partial-breast irradiation has increasingly become established. Neoadjuvant single-fraction radiotherapy (rt) is an uncommon approach wherein the unresected lesion is irradiated preoperatively in a single fraction. We developed the signal (Stereotactic Image-Guided Neoadjuvant Ablative Radiation Then Lumpectomy) trial, a prospective single-arm trial to test our hypothesis that, for low-risk carcinoma of the breast, the preoperative single-fraction approach would be feasible and safe. Methods: Patients presenting with early-stage (T < 3 cm), estrogen-positive, clinically node-negative invasive carcinoma of the breast with tumours at least 2 cm away from skin and chest wall were enrolled. All patients received prone breast magnetic resonance imaging (mri) and prone computed tomography simulation. Treatable patients received a single 21 Gy fraction of external-beam rt (as volumetric-modulated arc therapy) to the primary lesion in the breast, followed by definitive surgery 1 week later. The primary endpoints at 3 weeks, 6 months, and 1 year were toxicity and cosmesis (that is, safety) and feasibility (defined as the proportion of mri-appropriate patients receiving rt). Results: Of 52 patients accrued, 27 were successfully treated. The initial dosimetric constraints resulted in a feasibility failure, because only 57% of eligible patients were successfully treated. Revised dosimetric constraints were developed, after which 100% of patients meeting mri criteria were treated according to protocol. At 3 weeks, 6 months, and 1 year after the operation, toxicity, patient- and physician-rated cosmesis, and quality of life were not significantly different from baseline. Conclusions: The signal trial presents a feasible method of implementing single-dose preoperative rt in early-stage breast cancer. This pilot study did not identify any significant toxicity and demonstrated excellent cosmetic and quality-of-life outcomes. Future randomized multi-arm studies are required to corroborate these findings.

Position statement on defining and standardizing an oncoplastic approach to breast-conserving surgery in Canada.

Although mastectomy is an effective procedure, it can have a negative effect on body image, sense of attractiveness, and sexuality. As opposed to the combination of breast oncologic surgery and plastic surgery, whose primary focus is on replacing lost volume, breast-conserving oncoplastic surgery (ops) redistributes remaining breast tissue in a manner that requires vision, anatomic knowledge, and an appreciation of esthetics, symmetry, and breast function. Modern surgical treatment of breast cancer can be realized only with breast and plastic surgeons working together using oncoplastic techniques to deliver superior cosmetic and cancer outcomes alike. Using this collaborative approach, oncologic and plastic surgeons in Canada have a significant opportunity to improve the care of their breast cancer patients. We propose a tri-level classification for volume displacement procedures to act as a rubric for the training of general surgeons and oncologic breast surgeons in oncoplastic breast-conserving therapy techniques. It is our position that ops enhances outcomes for many women with breast cancer and should become part of the standard repertoire of procedures used by Canadian oncologic surgeons treating breast cancer.

Recurrence and mortality after breast-conserving surgery without radiation.

Background: Breast-conserving surgery (bcs) and radiation therapy (rt) are the standard of care for early breast cancer; studies have demonstrated that adjuvant rt confers a protective effect with respect to recurrence, although no randomized trials have shown a survival benefit. Methods: This retrospective cohort study used Ontario data linked through ices to examine patients treated for breast cancer between 1 April 2007 and 31 March 2014. The primary outcome was death or recurrence. Outcomes were compared between patients who did and did not receive rt. Results: The total cohort size was 26,279. The hazard ratios (hrs) for various outcomes were significantly higher for patients who did not receive rt than for patients who did: recurrence or death combined [hr: 2.49; 95% confidence interval (ci): 2.25 to 2.75], recurrence (hr: 2.33; 95% ci: 1.91 to 2.84), and death (hr: 2.28; 95% ci: 2.03 to 2.56). The hr for death was 1.81 (95% ci: 1.65 to 1.99) for patients having stage ii cancer compared with those having stage i disease. The hr for death was 1.97 (95% ci: 1.74 to 2.22) for patients having high comorbidity compared with those having little comorbidity. Conclusions: Adjuvant rt carries a protective effect with respect to recurrence and survival in patients with early-stage breast cancer. That survival benefit has not been appreciated in previous randomized trials and underscores the importance of rt as a component of breast cancer treatment.

Survival outcome differences based on treatments used and knowledge of the primary tumour site for patients with cancer of unknown and known primary in Ontario.

Introduction: Patients with cancer of unknown primary (cup) have pathologically confirmed metastatic tumours with unidentifiable primary tumours. Currently, very little is known about the relationship between the treatment of patients with cup and their survival outcomes. Thus, we compared oncologic treatment and survival outcomes for patients in Ontario with cup against those for a cohort of patients with metastatic cancer of known primary site. Methods: Using the Ontario Cancer Registry and the Same-Day Surgery and Discharge Abstract databases maintained by the Canadian Institute for Health Information, we identified all Ontario patients diagnosed with metastatic cancer between 1 January 2000 and 31 December 2005. Ontario Health Insurance Plan treatment records were linked to identify codes for surgery, chemotherapy, or therapeutic radiation related to oncology. Multivariable Cox regression models were constructed, adjusting for histology, age, sex, and comorbidities. Results: In 45,347 patients (96.3%), the primary tumour site was identifiable, and in 1743 patients (3.7%), cup was diagnosed. Among the main tumour sites, cup ranked as the 6th largest. The mean Charlson score was significantly higher (p < 0.0001) in patients with cup (1.88) than in those with a known primary (1.42). Overall median survival was 1.9 months for patients with cup compared with 11.9 months for all patients with a known-primary cancer. Receipt of treatment was more likely for patients with a known primary site (n= 35,012, 77.2%) than for those with cup (n = 891, 51.1%). Among patients with a known primary site, median survival was significantly higher for treated than for untreated patients (19.0 months vs. 2.2 months, p < 0.0001). Among patients with cup, median survival was also higher for treated than for untreated patients (3.6 months vs. 1.1 months, p < 0.0001). Conclusions: In Ontario, patients with cup experience significantly lower survival than do patients with metastatic cancer of a known primary site. Treatment is associated with significantly increased survival both for patients with cup and for those with metastatic cancer of a known primary site.

Appropriate treatment receipt after breast-conserving surgery.

Background: Breast-conserving surgery (bcs) and radiation therapy (rt) are the standard of care for early breast cancer, although some women receive ipsilateral mastectomy or adjuvant tamoxifen, both of which can be appropriate alternatives to rt. Objectives of the present study were to determine the proportion of women who are treated appropriately after bcs and to identify factors associated with non-receipt of rt. Methods: This retrospective cohort study used Ontario data linked at the Institute for Clinical and Evaluative Sciences to examine 33,718 patients who received bcs during 2004-2010. Primary outcome was rt receipt. The ipsilateral mastectomy rate and patient, surgeon, and setting variables were measured. Results: Of the study patients, 86.1% received either rt or completion mastectomy; in the cohort less than 70 years of age, 90.8% received rt or completion mastectomy. Among patients less than 70 years of age, 3 risk factors for non-receipt of rt were identified: age less than 46 years, treatment in a non-academic institution, and earlier year of initial bcs. Additionally, in the overall cohort, rt non-receipt was associated with high comorbidity, more than 40 km to the cancer centre, income quintile, and breast care specialization. Conclusions: In Ontario, 90.8% of patients less than 70 years of age are appropriately treated for early breast cancer; approximately 1 in 10 do not receive rt or completion mastectomy. Based on those findings, women less than 46 years of age might be at increased risk of recurrence and death because of incomplete treatment. It also appears that academic centres more effectively treat breast cancer; however, breast cancer care appears to be improving over time in Ontario.

The clinical significance of occult gynecologic primary tumours in metastatic cancer.

OBJECTIVE: We estimated the frequency of occult gynecologic primary tumours (gpts) in patients with metastatic cancer from an uncertain primary and evaluated the effect on disease management and overall survival (os). METHODS: We used Manitoba administrative health databases to identify all patients initially diagnosed with metastatic cancer during 2002-2011. We defined patients as having an "occult" primary tumour if the primary was classified at least 6 months after the initial diagnosis. Otherwise, we considered patients to have "obvious" primaries. We then compared clinicopathologic and treatment characteristics and 2-year os for women with occult and with obvious gpts. We used Cox regression adjustment and propensity score methods to assess the effect on os of having an occult gpt. RESULTS: Among the 5953 patients diagnosed with metastatic cancer, occult primary tumours were more common in women (n = 285 of 2552, 11.2%) than in men (n = 244 of 3401, 7.2%). In women, gpts were the most frequent occult primary tumours (n = 55 of 285, 19.3%). Compared with their counterparts having obvious gpts, women with occult gpts (n = 55) presented with similar histologic and metastatic patterns but received fewer gynecologic diagnostic examinations during diagnostic work-up. Women with occult gpts were less likely to undergo surgery, waited longer for radiotherapy, and received a lesser variety of chemotherapeutic agents. Having an occult compared with an obvious gpt was associated with decreased os (hazard ratio: 1.62; 95% confidence interval: 1.2 to 2.35). Similar results were observed in adjusted analyses. CONCLUSIONS: In women with metastatic cancer from an uncertain primary, gpts constitute the largest clinical entity. Accurate diagnosis of occult gpts early in the course of metastatic cancer might lead to more effective treatment decisions and improved survival outcomes.

Training oncoplastic breast surgeons: the Canadian fellowship experience.

BACKGROUND: Oncoplastic breast surgery combines traditional oncologic breast conservation with plastic surgery techniques to achieve improved aesthetic and quality-of-life outcomes without sacrificing oncologic safety. Clinical uptake and training remain limited in the Canadian surgical system. In the present article, we detail the current state of oncoplastic surgery (ops) training in Canada, the United States, and worldwide, as well as the experience of a Canadian clinical fellow in ops. METHODS: The clinical fellow undertook a 9-month audit of breast surgical cases. All cases performed during the fellow's ops fellowship were included. The fellowship ran from October 2015 to June 2016. RESULTS: During the 9 months of the fellowship, 67 mastectomies were completed (30 simple, 17 modified radical, 12 skin-sparing, and 8 nipple-sparing). The fellow participated in 13 breast reconstructions. Of 126 lumpectomies completed, 79 incorporated oncoplastic techniques. CONCLUSIONS: The experience of the most recent ops clinical fellow suggests that Canadian ops training is feasible and achievable. Commentary on the current state of Canadian ops training suggests areas for improvement. Oncoplastic surgery is an important skill for breast surgical oncologists, and access to training should be improved for Canadian surgeons.

Cost-effectiveness of using a gene expression profiling test to aid in identifying the primary tumour in patients with cancer of unknown primary.

We aimed to investigate the cost-effectiveness of a 2000-gene-expression profiling (GEP) test to help identify the primary tumor site when clinicopathological diagnostic evaluation was inconclusive in patients with cancer of unknown primary (CUP). We built a decision-analytic-model to project the lifetime clinical and economic consequences of different clinical management strategies for CUP. The model was parameterized using follow-up data from the Manitoba Cancer Registry, cost data from Manitoba Health administrative databases and secondary sources. The 2000-GEP-based strategy compared to current clinical practice resulted in an incremental cost-effectiveness ratio (ICER) of $44,151 per quality-adjusted life years (QALY) gained. The total annual-budget impact was $36.2 million per year. A value-of-information analysis revealed that the expected value of perfect information about the test's clinical impact was $4.2 million per year. The 2000-GEP test should be considered for adoption in CUP. Field evaluations of the test are associated with a large societal benefit.

A Canadian national expert consensus on neoadjuvant therapy for breast cancer: linking practice to evidence and beyond.

BACKGROUND: Use of the neoadjuvant approach to treat breast cancer patients has increased since the early 2000s, but the overall pathway of care for such patients can be highly variable. The aim of our project was to establish a multidisciplinary consensus among clinicians with expertise in neoadjuvant therapy (nat) for breast cancer and to determine if that consensus reflects published methods used in randomized controlled trials (rcts) in this area. METHODS: A modified Delphi protocol, which used iterative surveys administered to 85 experts across Canada, was established to obtain expert consensus concerning all aspects of the care pathway for patients undergoing nat for breast cancer. All rcts published between January 1, 1967, and December 1, 2012, were systematically reviewed. Data extracted from the rcts were analyzed to determine if the methods used matched the expert consensus for specific areas of nat management. A scoring system determined the strength of the agreement between the literature and the expert consensus. RESULTS: Consensus was achieved for all areas of the pathway of care for patients undergoing nat for breast cancer, with the exception of the role of magnetic resonance imaging in the pre-treatment or preoperative setting. The levels of agreement between the consensus statements and the published rcts varied, primarily because specific aspects of the pathway of care were not well described in the reviewed literature. CONCLUSIONS: A true consensus of expert opinion concerning the pathway of care appropriate for patients receiving nat for breast cancer has been achieved. A review of the literature illuminated gaps in the evidence about some elements of nat management. Where evidence is available, agreement with expert opinion is strong overall. Our study is unique in its approach to establishing consensus among medical experts in this field and has established a pathway of care that can be applied in practice for patients receiving nat.

Locoregional therapy of locally advanced breast cancer: a clinical practice guideline.

QUESTIONS: In female patients with locally advanced breast cancer (labc) and good response to neoadjuvant chemotherapy (nact), including endocrine therapy, what is the role of breast-conserving surgery (bcs) compared with mastectomy?In female patients with labc, is radiotherapy (rt) indicated for those who have undergone mastectomy?does locoregional rt, compared with breast or chest wall rt alone, result in a higher survival rate and lower recurrence rates?is rt indicated for those achieving a pathologic complete response (pcr) to nact?In female patients with labc who receive nact, is the most appropriate axillary staging procedure sentinel lymph node biopsy (slnb) or axillary dissection? Is slnb indicated before nact rather than at the time of surgery?How should female patients with labc that does not respond to initial nact be treated? METHODS: This guideline was developed by Cancer Care Ontario's Program in Evidence-Based Care (pebc) and the Breast Cancer Disease Site Group (dsg). A systematic review was prepared based on literature searches conducted using the medline and embase databases for the period 1996 to December 11, 2013. Guidelines were located from that search and from the Web sites of major guideline organizations. The working group drafted recommendations based on the systemic review. The systematic review and recommendations were then circulated to the Breast Cancer dsg and the pebc Report Approval Panel for internal review; the revised document underwent external review. The full three-part evidence series can be found on the Cancer Care Ontario Web site. RECOMMENDATIONS: For most patients with labc, modified radical mastectomy should be considered the standard of care. For some patients with noninflammatory labc, bcs can be considered on a case-by-case basis when the surgeon deems that the disease can be fully resected and the patient expresses a strong preference for breast preservation.For patients with labc, rt after mastectomy is recommended.It is recommended that, after bcs or mastectomy, patients with labc receive locoregional rt encompassing the breast or chest wall and local node-bearing areas.It is recommended that postoperative rt remain the standard of care for patients with labc who achieve pcr to nact.It is recommended that axillary dissection remain the standard of care for axillary staging in labc, with the judicious use of slnb in patients who are advised of the limitations of the current data.Although slnb either before or after nact is technically feasible, the data are insufficient to make any recommendation about the optimal timing of slnb with respect to nact. Limited data suggest higher sentinel lymph node identification rates and lower false negative identification rates when slnb is conducted before nact; however, those data must be balanced against the requirement for two operations if slnb is not performed at the time of resection of the main tumour.It is recommended that patients receiving neoadjuvant anthracycline-taxane-based therapy (or other sequential regimens) whose tumours do not respond to the initial agent or agents, or who experience disease progression, be expedited to the next agent or agents of the regimen.For patients who, in the opinion of the treating physician, fail to respond or progress on first-line nact, several therapeutic options can be considered, including second-line chemotherapy, hormonal therapy (if appropriate), rt, or immediate surgery (if technically feasible). Treatment should be individualized through discussion at a multidisciplinary case conference, considering tumour characteristics, patient factors and preferences, and risk of adverse effects.It is recommended that prospective randomized clinical trials be designed for patients with labc who fail to respond to nact so that more definitive treatment recommendations can be developed.

Concurrent chemoradiotherapy for locally advanced breast cancer-time for a new paradigm?

BACKGROUND: In cases of locally advanced breast cancer (labc), preoperative ("neoadjuvant") therapy was traditionally reserved to render the patient operable. More recently, neoadjuvant therapy, particularly chemotherapy, is being used in patients with operable disease to increase the opportunity for breast conservation. Despite the increasing use of preoperative chemotherapy, rates of pathologic complete response, a surrogate marker for disease-free survival, remain modest in patients with locally advanced disease and particularly so when the tumour is estrogen or progesterone receptor-positive and her2-negative. A new paradigm for labc patients is needed. In other solid tumours (for example, rectal, esophageal, and lung cancers), concurrent chemoradiotherapy (ccrt) is routinely used in neoadjuvant and adjuvant treatment protocols alike. RESULTS: The literature suggests that ccrt in labc patients with inoperable disease is associated with response rates higher than would be anticipated with systemic therapy alone. CONCLUSIONS: Ongoing trials in this field are eagerly awaited to determine if ccrt should become the new paradigm.

Evaluating the efficacy of current clinical practice of adjuvant chemotherapy in postmenopausal women with early-stage, estrogen or progesterone receptor-positive, one-to-three positive axillary lymph node, breast cancer.

PURPOSE: We evaluated the benefit of the current clinical practice of adjuvant chemotherapy for postmenopausal women with early-stage, estrogen- or progesterone-receptor-positive (er/pr+), one-to-three positive axillary lymph node (1-3 ln+), breast cancer (esbc). METHODS: Using the Manitoba Cancer Registry, we identified all postmenopausal women diagnosed with er/pr+ 1-3 ln+ esbc during the periods 1995-1997, 2000-2002, and 2003-2005 (n = 156, 161, and 171 respectively). Treatment data were obtained from the Manitoba Cancer Registry and by linkage with Manitoba administrative databases. Seven-year survival data were available for the 1995-1997 and 2000-2002 populations. Using Cox regression, we assessed the independent effect of the clinical practice of adjuvant chemotherapy on disease-free (dfs) and overall survival (os). RESULTS: Clinical breast cancer treatments did not differ significantly between the 2000-2002 and 2003-2005 populations. Adjuvant chemotherapy was administered in 103 patients in the 2000-2002 population (64%) and in 44 patients in the 1995-1997 population [28.2%; mean difference: 36%; 95% confidence interval (ci): 31% to 40%; p < 0.0001]. Compared with 1995-1997, 2000-2002 was not significantly associated with an incremental dfs benefit for patients over a period of 7 years (2000-2002 vs. 1995-1997; adjusted hazard ratio: 0.98; 95% ci: 0.64 to 1.4). CONCLUSIONS: The treatment standard of adjuvant chemotherapy in addition to endocrine therapy may not be effective for all women with er/pr+ 1-3 ln+ esbc. There could be a subgroup of those women who do not benefit from adjuvant chemotherapy as expected and who are therefore being overtreated. Further studies with a larger sample size are warranted to confirm our results.

Driver headway: how close is too close on a motorway?

Driver headway has recently become an important question with much attention being given to unsafe headway or 'tailgating'. This paper reviews a series of recent studies undertaken at the University of Southampton, which have sought to measure and model distance keeping, demonstrating how following distance depends on a wide range of factors, some of which are only recently being explored. These include variations in following distance for any particular driver and the relationship with time to collision, variations in following distances of drivers of differing nationalities and the ability of the driver to 'read the road ahead', which may be affected by interaction with different vehicle types. It is demonstrated that providing clear unequivocal statements regarding car following and safety levels, even after such studies, is still far from straightforward.

Triple "E" syndrome: bilateral locked posterior fracture dislocation of the shoulders.

Bilateral locked posterior fracture dislocation of the shoulders is one of the least common injuries of the shoulder, and this injury has been suggested to be pathognomonic of seizures when diagnosed in the absence of trauma. The authors present a case of idiopathic bilateral locked posterior fracture dislocations of the shoulder, along with a review of the medical literature. The authors also present the "triple E syndrome," describing the possible etiologies of this injury: epilepsy (or any convulsive seizure), electrocution, or extreme trauma.

Primary biliary cirrhosis and hemolytic anemia confusing serum bilirubin levels.

Hemolysis is observed in more than 50% of patients with cirrhosis. However, there has been little documentation of the association of primary biliary cirrhosis with autoimmune hemolytic anemia. Two cases, found within a single practice, of primary biliary cirrhosis coexisting with autoimmune hemolysis and a third case coexisting with hereditary spherocytosis are presented. Anemia in such patients is commonly attributed to chronic disease, and hyperbilirubinemia is attributed to primary biliary cirrhosis. These patients were considered for liver transplantation until the diagnosis of a comorbid hemolytic process was established. This association may be more prevalent than previously recognized. A diagnosis of comorbid hemolysis must always be considered in context with anemia and serum bilirubin levels that rise out of proportion to the severity of the primary biliary cirrhosis.

Examination of the use of fuzzy sets to describe relative speed perception.

In recent years a range of new methods have been proposed with which to describe and evaluate driver behaviour. One such method is that of fuzzy logic, where variables used in the driver decision-making process may be described linguistically, allowing a quantifiable degree of uncertainty to be introduced. This paper explores the use of such a formalism to describe the driver perception of 'closing speed' between two vehicles engaged in 'car-following' on a motorway, and by using data from an instrumented vehicle experiment, it tests a number of models using relative speed, visual angle and the time to collision. Several of these models fit the data quite well, and there is both a small positive perception bias present and a number of reversals in sign judgement. Additionally, a brief examination is made of potential variations on the methodology that may both make data collection easier and/or allow a 'more fuzzy' representation to be made.