Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Treatment and outcomes of metastatic colorectal cancer in Australia: defining differences between public and private practice.

BACKGROUND: Prior studies have suggested improved outcomes for cancer patients managed in private centres, despite universal healthcare within Australia. AIMS: To compare patient, disease, treatment and survival data for metastatic colorectal cancer (mCRC) managed in private versus public centres. METHODS: Analysis of prospectively collected registry data for consecutive patients with mCRC managed at 16 participating centres from July 2009. RESULTS: Data for 1065 patients were examined. Age, gender and Charlson comorbidity score were similar for public and private patients. Private patients were more commonly Eastern Cooperative Oncology Group performance score 0-1 (85% vs 78%, P = 0.008), in the highest Index of Relative Socioeconomic Advantage and Disadvantage quintile (57% vs 18%, P < 0.001) or had a single metastatic site (62% vs 54%, P = 0.009). Patients treated in private were more likely to receive chemotherapy (84% vs 70%, P < 0.001), bevacizumab (59% vs 50%, P = 0.008), be treated with curative intent (37% vs 26%, P < 0.001) and undergo metastasectomy (30% vs 22%, P = 0.001). These management differences remained statistically significant after adjusting for baseline characteristics. Management in the private setting was associated with superior overall survival (median 27.9 vs 20 months, hazard ratio 0.7, 95% confidence interval: 0.57 to 0.86, P = 0.001), significant in multivariate analysis adjusting for all baseline covariates. CONCLUSIONS: Significant differences in baseline characteristics were noted for private versus public patients. However, these do not explain the higher rates of treatment delivery in the private setting, which likely contributed towards the observed survival difference. Further studies are required to determine if the increased likelihood of intervention in the private setting is driven by patient, clinician and/or institutional factors.

Early onset metastatic colorectal cancer in Australia.

BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP). METHODS: We reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (≥50 years). RESULTS: Of 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0-1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP. CONCLUSION: Known prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.

Developing a national database for metastatic colorectal cancer management: perspectives and challenges.

BACKGROUND: The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian-centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed. AIMS: To establish a collection of a consensus dataset capturing treatment and outcomes at multiple public and private hospitals across Australia. METHODS: An electronic database was developed by a panel of clinicians, to capture an agreed dataset for patients with newly diagnosed metastatic colorectal cancer. Of particular interest were clinician decision-making, the impact of comorbidities and the frequency of major adverse events. RESULTS: Since July 2009, data collection has been established at six public and eight private hospitals across three Australian states and territories. Successful linkage and analysis, with support from BioGrid Australia, of selected data on the initial 864 patients demonstrates that data can be captured from diverse sites, including public and private practice, that multiple factors impact on treatment delivered and outcomes achieved and that comprehensive data on rare but important adverse events can be captured. As a clinical research tool, the project has been highly successful, generating multiple presentations at national and international conferences related to a diverse range of research questions. CONCLUSIONS: Multistate, project-specific data collection involving large numbers of patients is achievable. Providing invaluable insight into the routine clinical management of metastatic colorectal cancer in the era of targeted therapies, this also creates a significant resource for research, including many questions not being addressed by clinical trials.

Real-world impact of anti-HER2 therapy-related cardiotoxicity in patients with advanced HER2-positive breast cancer.

BACKGROUND: Anti-HER2 therapy-related cardiotoxicity is well described in the context of clinical trials, particularly in the setting of early stage disease, but there is more limited data in advanced breast cancer and in the real world setting. MATERIAL AND METHODS: A prospectively-maintained registry database with 312 consecutive patients diagnosed with HER2 positive advanced breast cancer in Australia was analysed. RESULTS: 287 patients (92%) received anti-HER2 therapy, 17 (6%) experienced anti-HER2 therapy-related cardiotoxicity. Patients who experienced cardiotoxicity were more likely to have ≥2 risk factors for cardiotoxicity (OR 3.9 95% CI 1.4-11.3 p = 0.01). A prior diagnosis of cardiovascular disease was significantly associated with cardiotoxicity (OR 7.1 95% CI 1.3-39.5). Cardiotoxicity resolved on imaging in 65% of patients; there was no association between severity and resolution. 11 patients (65%) received cardiologist input. Of the patients who developed cardiotoxicity, 12 patients (71%) received further anti-HER2 therapy in the first- or second-line setting without recurrent cardiotoxicity. DISCUSSION AND CONCLUSION: Therapy-related cardiotoxicity is an uncommon complication of anti-HER2 therapy in the real world setting. Cardiac toxicity resolved in the majority of affected patients, and further anti-HER2 therapy was administered without recurrence of cardiac issues. Our data suggests anti-HER2 therapy can be safely given in routine care, even in patients with risk factors for toxicity.

Hyperammonaemic encephalopathy associated with rituximab-containing chemotherapy.

Abstract Hyperammonaemic encephalopathy has been infrequently reported after both standard and high-dose chemotherapy for solid and haematological malignancies. It is important to consider this diagnosis for patients with unexplained behaviour changes or encephalopathy and this case report emphasizes this condition and the importance of early diagnosis and is the first reported in association with rituximab-containing chemotherapy.

Postischemic stunning can affect left ventricular ejection fraction and regional wall motion on post-stress gated sestamibi tomograms.

OBJECTIVES: This study was designed to investigate whether left ventricular ejection fraction (LVEF) calculated from post-stress single-photon emission computed tomography (SPECT) reflects the basal value for LVEF or whether post-stress LVEF is reduced in some patients with stress-induced ischemia. BACKGROUND: Automated programs are now commercially available for assessing global left ventricular (LV) function from post-stress technetium-99m sestamibi gated SPECT performed >15 min after completion of exercise. METHODS: Eighty-one sequential patients who underwent a 2-day stress/rest sestamibi imaging protocol and showed perfusion defects on the post-stress tomogram underwent gated acquisition of the second-day rest tomogram. The post-stress and rest tomographic images were read for presence, location, severity and reversibility of defects by consensus of two to three experienced observers with the aid of circumferential count displays. Defects were scored as mild, moderate or severe and as completely or partially reversible or fixed, and a summed defect severity score was calculated. Of these 81 scans, 20 showed nonreversible perfusion defects (group 3), whereas 61 showed reversible perfusion defects. Post-stress and rest LVEF was calculated from the processed gated SPECT data. From 15 additional patients who underwent rest gated SPECT studies on separate days, serial reproducibility of LVEF values calculated from the gated SPECT data was determined to be +/-5.2%. Coronary angiography was performed within 3 months of the scan without intervening events in 47 of 81 patients, including 39 of 61 with reversible perfusion defects. RESULTS: In 22 (36%) of 61 patients with reversible perfusion defects, post-stress LVEF was >5% lower than that at rest (group 2), whereas in the remaining 39 patients, post-stress LVEF was either +/-5% or greater than that at rest (group 1). Segmental chordal shortening analysis performed in group 2 studies showed that differences in chordal shortening between rest and post-stress were significantly greater in the reversible perfusion defect territories than in the nonischemic perfusion defect territories ([mean +/- SD] 0.14 +/- 0.14 vs. 0.02 +/- 0.09, respectively, p < 0.0001). There were no significant differences among groups for any of the following variables: age, gender, previous myocardial infarction and type of stress. Time to imaging and stress and scan variables were correlated with the change in LVEF by univariate analysis, and the two variables that correlated significantly were the summed defect reversibility score on the scan and a left anterior descending coronary artery location of the scan defect. Only summed defect reversibility score was significant on multivariate analysis. CONCLUSIONS: When the only gated sestamibi scan is the post-stress scan, global and regional LV function will not represent basal LV function in all patients with stress-induced ischemia.

Technetium-99m-nitroimadazole uptake in a swine model of demand ischemia.

UNLABELLED: Nitroheterocycles are electron affinic, lipophilic compounds that are retained in hypoxic tissue. This study was designed to test the hypothesis that 99mTc-5-oxa-amine-oxime nitroimadazole (BMS-194796) is retained in ischemic myocardial tissue in a swine model of demand ischemia and that the retained tracer can be imaged in vivo. METHODS: Eighteen domestic swine were anesthetized, intubated and instrumented, including placement of a stenois (80% narrowing) mounted on a catheter into the left anterior descending (LAD) coronary artery. Twelve experiments had complete sets of data for analysis. Each animal was paced at about 200 bpm for 4 min, and 28 mCi of 99mTc BMS-194796 were injected during the last minute of pacing. Dynamic planar imaging was started after pacing and completed at 2.5 hr. In the last 8 experiments, SPECT imaging was performed after planar imaging and completed 3.5 hr after injection. Hemodynamic measurements were made continuously. Blood flow by microspheres and myocardial lactate extraction were measured at control, during pacing and after 2 hr of recovery. The animals were then killed; the risk region was delineated and the hearts were removed, sliced, imaged and stained with triphenyl tetrazolium chloride. RESULTS: Nine of the 12 animals became ischemic (net lactate production) during pacing; 3 did not. None of the 3 nonischemic experiments showed focal uptake on ex vivo or in vivo imaging. All 9 of the ischemic experiments showed focal BMS uptake in the risk region on ex vivo imaged slices; 6 of 9 had uptake in the risk region on in vivo imaging; and 4 of these 6 had small scattered areas of subendocardial necrosis in the risk region on triphenyl tetrazolium chloride staining. Four animals had small infarcts in the distribution of proximal LAD branch vessels occluded by the stenosis catheter. All animals with branch vessel infarcts had positive in vivo images. Overall, 8 of 9 ischemic experiments had positive in vivo images. CONCLUSION: These data support the conclusion that focal myocardial retention of BMS-194796 can be visualized on in vivo imaging in closed chest large animal model after intravenous injection.

The cemented kinematic-II and the non-cemented porous-coated anatomic prostheses for total knee replacement. A prospective evaluation.

One hundred and sixty consecutive total knee arthroplasties were performed in 143 patients: 110 procedures, with a cemented kinematic-II prosthesis and fifty procedures, with a non-cemented porous-coated anatomic prosthesis. Each patient was evaluated before the operation and six weeks and three, six, twelve, and twenty-four months postoperatively. At a minimum twenty-four-month follow-up, the average Hospital for Special Surgery knee-rating score for the patients who had a cemented kinematic-II prosthesis was 9 points higher than the average score for the patients who had a non-cemented anatomic implant (88 points and 79 points). At the same follow-up period, the maximum flexion of the knees that had a cemented kinematic-II prosthesis was greater than that of the knees that had a non-cemented anatomic prosthesis (106 degrees and 97 degrees). In addition, the rate of reoperation for the patients who had a cemented kinematic-II replacement was 4 per cent, compared with 12 per cent for the patients who had a non-cemented anatomic prosthesis. On the basis of this prospective, non-randomized clinical review of unselected patients, we concluded that the results with the cemented kinematic-II prosthesis were superior to those with the non-cemented anatomic prosthesis at a minimum twenty-four month follow-up; however, these superior results may be related to the use of cement or to differences in the designs of the prostheses, the ages of the patients, or the postoperative management of the two groups of patients.

The Miller-Galante knee prosthesis for the treatment of osteoarthrosis. A comparison of the results of partial fixation with cement and fixation without any cement.

In a prospective, non-randomized study of 344 patients who had 392 primary total knee replacements with a Miller-Galante I prosthesis for the treatment of osteoarthrosis, the results of partial fixation with cement (insertion of the tibial and patellar components with cement and of the femoral component without cement) were compared with those of fixation without any cement. Of the 392 knees, 183 (163 patients) had fixation without cement (Group I) and 209 (181 patients), with and without cement (Group II). The average duration of follow-up was three years (range, two to five years). Nine patients died during the follow-up period, but no others were lost to follow-up. Analysis of the knee scores, range of motion of the knee, radiographs, and rates of complications revealed no differences between the outcomes in the two groups during the follow-up period. The rate of complications due to problems related to the extensor mechanism was high in both groups: a reoperation was performed in fifteen (8 per cent) of the knees that had had fixation without cement and in nineteen (9 per cent) of those that had had both types of fixation. Thirteen patients had additional operative treatment for recurrent patellar dislocations; twelve patients, for abnormal wear of the polyethylene of the patellar component: two patients, for avulsion of the patellar ligament from the tibia; and two patients, for unexplained pain in the knee. In addition, there were eight patellar fractures (two of which led to a reoperation) and three deep infections (all of which led to a reoperation).

Results of shockwave lithotripsy for pediatric urolithiasis.

BACKGROUND AND PURPOSE: Shockwave lithotripsy (SWL) is widely practiced in the management of pediatric urolithiasis. However, the efficacy, need for ancillary procedures, and treatment-related complications are not as clearly defined as in the adult population. We reviewed the outcomes of SWL in the pediatric population at our lithotripsy unit. PATIENTS AND METHODS: A retrospective review of all patients

The results of fasciotomy in the management of chronic exertional compartment syndrome.

Twenty-five patients with well-documented clinical history and elevated tissue pressures were subjected to surgical fasciotomy of the respective compartment (anterior, 13; anterior and posterior, 4; deep posterior, 8). The indications for surgery were resting pressures in excess of 15 mmHg and elevated postexercise pressure measurements with delayed normalization. Twenty-two patients were satisfied with the procedure and were able to return to athletics. There were three failures, all of whom had decompression of the deep posterior compartment. This study has demonstrated that fasciotomy of the anterior compartment, when done with the correct indications, gives excellent relief of chronic anterior leg pain. It is recommended that fasciotomy of the deep posterior compartment include a formal release of the tibialis posterior at the time of decompression.

The role of tissue pressure measurement in diagnosing chronic anterior compartment syndrome.

Pressure studies were performed in 55 patients (24 with chronic anterior leg pain and 31 asymptomatic recreational athletes). Pressure measurements were recorded at rest, during, and after exercise, using the slit catheter system. Seventeen of the twenty-four patients with symptomatic anterior leg pain were diagnosed on the basis of tissue pressure studies as having chronic exertional compartment syndrome. The increased tissue pressures at rest and after exercise are most helpful in distinguishing those patients likely to benefit from a surgical fasciotomy.

The use of magnetic resonance imaging in exertional compartment syndromes.

This prospective, double-blind study was carried out to assess the usefulness of magnetic resonance imaging (MRI) as a noninvasive method in the diagnosis of chronic compartment syndrome (CCS). As well, a new radiopharmaceutical known as methoxy isobutyl isonitrile that has been shown to be taken up by muscle in direct proportion to its blood flow was used to illustrate the possible pathophysiology of this syndrome. Twenty patients with a history of chronic leg pain and possible diagnosis of CCS and five normal volunteers had preexercise and postexercise MRI, nuclear medicine imaging, and static and dynamic slit catheter pressure studies. Nine patients had classic symptoms; only five of these nine had abnormal pressure studies. The other 11 patients had an element of pain at rest and had normal pressure studies. The nuclear blood flow studies were normal in all 25 legs tested in this study. Measurement of intrinsic MRI parameters T1 and T2 in the normal legs as well as in those with an atypical history showed a marked elevation with exercise and a gradual return to baseline postexercise that was similar to the pressure curves. In the five patients with a clinical history and elevated pressures, four had abnormal MRI studies with failure of T1 to return to baseline values. Although these results demonstrate the potential of MRI as a tool for noninvasively monitoring muscle status, clinical history and examination remain important in the diagnosis of CCS. This study indicates that the pathophysiology of exertional compartment syndrome does not appear to be related to ischemia.

Thigh pain after cementless hip arthroplasty. Annoyance or ill omen.

A retrospective review of 148 consecutive porous-coated hip arthroplasties (PCA) showed an incidence of thigh pain of 13% one year after surgery, and 22% at two years. Positive correlations were made with femoral stem subsidence (greater than 2 mm) and with distal periosteal and endosteal bone formation. No positive correlations were made with parameters of bone quality or component fit. Resolution of pain occurred in one-third and an anti-inflammatory agent produced partial relief in two-thirds of the patients. We conclude that thigh pain is secondary to stem instability with distal stress transfer in the absence of stable proximal fixation.

The efficacy of tourniquet release in blood conservation after total knee arthroplasty.

One hundred consecutive primary total knee arthroplasties performed by a single surgeon were prospectively randomized into two groups to study the effect of tourniquet release for hemostasis on postoperative blood loss and transfusion requirements. The two groups were comparable. Variables such as antiinflammatory drug use; anesthetic; soft-tissue release; and component fixation were analyzed. There was no significant difference between the groups in terms of perioperative blood loss, decrease in hemoglobin or hematocrit level, transfusion need, or incidence of wound or thromboembolic complications. Tourniquet release for hemostasis is not an effective means of limiting postoperative blood loss or reducing transfusion need after primary total knee arthroplasty.

Total knee arthroplasty in the octogenarian.

Fifty consecutive Miller-Galante (Zimmer, Warsaw, IN) and Kinematic II (Howmedica, Rutherford, NJ) total knee arthroplasties for osteoarthritis in patients 80 years of age and over were compared to 50 arthroplasties in patients aged 65-69 years, with a minimum 2-year follow-up period. Each patient was assessed clinically using the Hospital for Special Surgery knee rating scores and radiographically by an independent observer. Average age of the study group participants was 83 years and of the comparison group, 68 years. Apart from age, the two groups were similar with respect to sex, bilaterality, prosthetic type, and preoperative Hospital for Special Surgery scores. No significant differences were noted for pain, functional level, strength, stability, or range of motion throughout the 2-year follow-up period. More octogenarian patients were found to have a preoperative deformity, and these deformities were larger, on average, than in the retiree group, suggesting a more advanced disease pathophysiology. A larger number of elderly patients required continued use of walking aids. An analysis of the cost-effectiveness data, collected for both groups, showed that although the in-hospital costs and length of stay were the same ($17,160 Can), the cost per patient after discharge was slightly greater ($2,00 Can) in the octogenarian. This prospective clinical study of total knee arthroplasties for osteoarthritis has shown that it is a reliable and cost-effective procedure for the octogenarian.

Management of recurrent dislocation of the patella following total knee arthroplasty.

Fifteen knees with patellar dislocation after total knee arthroplasty had realignment of the extensor mechanism using a modification of the Trillat procedure. The onset of dislocation occurred on average 4.7 months from the time of surgery. After total knee arthroplasty the patients had an average range of motion of 109 degrees. All patients had medialization of the tibial tubercle and lateral release. No patient had a recurrent dislocation after a minimum 2-year follow-up period. The average knee score was 82 and the average flexion arc was 112 degrees. All but one of the osteotomies healed uneventfully.

Kinematic I and Oxford knee arthroplasty. A 5-8-year follow-up study.

Sixty-seven consecutive Oxford Meniscal total knee arthroplasties (TKAs) were compared prospectively with 66 Kinematic I TKAs. At follow-up examination an average of 5.5 (range, 5-8) years later, 20 (30%) of the Oxford Meniscal TKAs had been revised (nine due to aseptic loosenings, seven to aseptic loosening and patellofemoral syndrome, two to patellofemoral syndrome, one to meniscal bearing dislocation, and one to sepsis) and in 16% one or more of the remaining tibial components was radiographically at risk. Three (5%) Kinematic I TKAs had been reoperated upon (one for anterior dislocation, one for a loose patellar component, and one for sepsis) and no component was considered radiographically at risk. The remaining cases demonstrated good and excellent knee ratings (Oxford, 82 +/- 11; Kinematic I, 88 +/- 6; P less than .01; Hospital for Special Surgery). This study suggests that the results of Kinematic I TKA are superior to those of Oxford Meniscal TKA; that patellofemoral resurfacing is advisable; and that Kinematic I TKA yields 5-year data comparable to those of total hip arthroplasty.