Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure.

INTRODUCTION: Acquired resistance to TKI is an important unmet need in the management of EGFR mutated lung cancer. Recent clinical trial IMPower150 suggested that combination approach with VEGF inhibitor, check point inhibitor immunotherapy and platinum-based chemotherapy was effective in oncogene driven lung cancer. The current trial examined the efficacy of a modified regimen in an EGFR mutated cohort. METHODS: An open-labelled, single arm, phase II study was conducted in patients with EGFR mutated NSCLC who had progressed on at least one EGFR TKI. For those with T790M mutation, radiological progression on osimertinib was required for enrolment. Patients were treated with combination atezolizumab (1200 mg), bevacizumab (7.5 mg/kg), pemetrexed (500 mg/m2) and carboplatin (AUC 5) given once every 3 weeks until progression. RESULTS: Forty patients were enrolled. Median age was 62 (range 45-76) years. More than one half (23/40, 57.5%) had progressed on osimertinib. PD-L1 expression was < 1% in 52.5%. Median follow-up time was 17.8 months. ORR was 62.5%. Median PFS was 9.4 months (95% CI: 7.6 - 12.1). One year OS was 72.5% (95% CI: 0.56-0.83). Treatment related grade 3 or above adverse events (AE) occurred in 37.5% (15/40). Immune-related AE occurred in 32.5% (13/40) patients. Quality of life measures of function and symptoms did not change significantly throughout the course of treatments. Post-trial rechallenge with EGFR TKI containing regimen resulted in PFS of 5.8 months (95% CI 3.9-10.0 months). CONCLUSION: Combination approach of atezolizumab, bevacizumab, pemetrexed and carboplatin achieved promising efficacy in metastatic EGFR mutated NSCLC after TKI failure. The results were comparable with taxane based regimen of IMPower150 while toxicity profile was improved.

Integrative Palliative Cancer Care in Hong Kong: An Overview and an Example from the East.

Cancer is the most common cause of mortality worldwide. Although recent advances of multiple modality cancer management have significantly improved the cure and control rates, a significant proportion of patients are still refractory to the standard and available treatments. Early initiation of palliative care can reduce cancer suffering, improve health-related quality of life and possibly prolong survival. It also allows patients and their caretakers to perceive the trajectory of their cancer, so that better and advanced care planning can be contemplated and implemented. The traditional beliefs and perceptions of cancer also differ significantly between the East and the West, which may also affect the preferential approach to palliative care. This review provides an overview of palliative care services in Hong Kong, as compared with other parts of the world. In addition, we shall also explore how cancer perceptions affect the decision-making on palliative care.

Disorder in Pixel-Level Edge Directions on T1WI Is Associated with the Degree of Radiation Necrosis in Primary and Metastatic Brain Tumors: Preliminary Findings.

BACKGROUND AND PURPOSE: Co-occurrence of local anisotropic gradient orientations (COLLAGE) is a recently developed radiomic (computer extracted) feature that captures entropy (measures the degree of disorder) in pixel-level edge directions and was previously shown to distinguish predominant cerebral radiation necrosis from recurrent tumor on gadolinium-contrast T1WI. In this work, we sought to investigate whether COLLAGE measurements from posttreatment gadolinium-contrast T1WI could distinguish varying extents of cerebral radiation necrosis and recurrent tumor classes in a lesion across primary and metastatic brain tumors. MATERIALS AND METHODS: On a total of 75 gadolinium-contrast T1WI studies obtained from patients with primary and metastatic brain tumors and nasopharyngeal carcinoma, the extent of cerebral radiation necrosis and recurrent tumor in every brain lesion was histopathologically defined by an expert neuropathologist as the following: 1) "pure" cerebral radiation necrosis; 2) "mixed" pathology with coexistence of cerebral radiation necrosis and recurrent tumors; 3) "predominant" (>80%) cerebral radiation necrosis; 4) predominant (>80%) recurrent tumor; and 5) pure tumor. COLLAGE features were extracted from the expert-annotated ROIs on MR imaging. Statistical comparisons of COLLAGE measurements using first-order statistics were performed across pure, mixed, and predominant pathologies of cerebral radiation necrosis and recurrent tumor using the Wilcoxon rank sum test. RESULTS: COLLAGE features exhibited decreased skewness for patients with pure (0.15 ± 0.12) and predominant cerebral radiation necrosis (0.25 ± 0.09) and were statistically significantly different (P < .05) from those in patients with predominant recurrent tumors, which had highly skewed (0.42 ± 0.21) COLLAGE values. COLLAGE values for the mixed pathology studies were found to lie between predominant cerebral radiation necrosis and recurrent tumor categories. CONCLUSIONS: With additional independent multisite validation, COLLAGE measurements might enable noninvasive characterization of the degree of recurrent tumor or cerebral radiation necrosis in gadolinium-contrast T1WI of posttreatment lesions.

Discontinuation and non-publication of neurodegenerative disease trials: a cross-sectional analysis.

BACKGROUND AND PURPOSE: Trial discontinuation and non-publication represent major sources of research waste in clinical medicine. No previous studies have investigated non-dissemination bias in clinical trials of neurodegenerative diseases. METHODS: ClinicalTrials.gov was searched for all randomized, interventional, phase II-IV trials that were registered between 1 January 2000 and 31 December 2009 and included adults with Alzheimer's disease, motor neurone disease, multiple sclerosis or Parkinson's disease. Publications from these trials were identified by extensive online searching and contact with authors, and multiple logistic regression analysis was performed to identify characteristics associated with trial discontinuation and non-publication. RESULTS: In all, 362 eligible trials were identified, of which 12% (42/362) were discontinued. 28% (91/320) of completed trials remained unpublished after 5 years. Trial discontinuation was independently associated with number of patients (P = 0.015; more likely in trials with ≤100 patients; odds ratio 2.65, 95% confidence interval 1.21-5.78) and phase of trial (P = 0.009; more likely in phase IV than phase III trials; odds ratio 3.90, 95% confidence interval 1.41-10.83). Trial non-publication was independently associated with blinding status (P = 0.005; more likely in single-blind than double-blind trials; odds ratio 5.63, 95% confidence interval 1.70-18.71), number of centres (P = 0.010; more likely in single-centre than multi-centre trials; odds ratio 2.49, 95% confidence interval 1.25-4.99), phase of trial (P = 0.041; more likely in phase II than phase IV trials; odds ratio 2.88, 95% confidence interval 1.04-7.93) and sponsor category (P = 0.001; more likely in industry-sponsored than university-sponsored trials; odds ratio 5.05, 95% confidence interval 1.87-13.63). CONCLUSIONS: There is evidence of non-dissemination bias in randomized trials of interventions for neurodegenerative diseases. Associations with trial discontinuation and non-publication were similar to findings in other diseases. These biases may distort the therapeutic information available to inform clinical practice.

Can an Immediate 2-stage Breast Reconstruction Be Performed After Previous Conservative Surgery and Radiotherapy?

BACKGROUND: Prosthetic breast reconstruction is generally considered contraindicated after previous breast irradiation. As a result, patients undergoing a salvage mastectomy for recurrent breast cancer or "risk-reducing" mastectomies after previous conservative surgery and radiotherapy (CS + RT) are usually offered autologous breast reconstruction. However, not all such patients are suitable candidates for a major flap reconstruction. The purpose of this study is to review our results of immediate 2-stage prosthetic breast reconstruction after CS + RT. METHODS: A retrospective review was undertaken for 671 consecutive patients with prosthetic-only breast reconstruction performed by a single surgeon over a 12.5-year period. Twenty-two patients who qualified for the criteria were audited. Outcomes examined include complications, loss of tissue expander or implant, revisional surgery, and aesthetic result. RESULTS: Twenty-two patients underwent 33 mastectomies and immediate 2-stage breast reconstructions after previous CS + RT (15 for recurrent cancer and seven "risk-reduction") and 11 contralateral risk-reducing mastectomies. One patient died due to extensive metastatic disease. There was no reconstruction failure. The average breast implant size was 491.7 g (range 220 -685g). Seroma was the most common complication and occurred in 3 of 22 patients (13.6%) after stage 1 and 3 of 21 patients (14.3%) after stage 2 reconstruction. The revisional surgery rate was 28.6%. Aesthetic result was rated as excellent in 9.5%, good in 76.2%, and fair in 14.3%. CONCLUSIONS: For selected patients, immediate 2-stage prosthetic breast reconstruction can be performed successfully after a salvage mastectomy subsequent to a recurrence after CS + RT.

Epidemiology and outcome of Candida bloodstream infection in an intensive care unit in Hong Kong.

OBJECTIVE: To study the epidemiology of Candida bloodstream infection in the Intensive Care Unit. DESIGN: Retrospective study. SETTING: A 22-bed, mixed medical and surgical Intensive Care Unit of a 1400-bed university teaching hospital in Hong Kong. PATIENTS: All adult patients (>18 years) who had at least one blood culture positive for Candida. RESULTS: During the 9 years of the study period, there were 128 patients with episodes of candidaemia (point prevalence, 9.6 per 1000 Intensive Care Unit admissions), 72 entailed albicans candidaemia and 56 non-albicans candidaemia. Albicans was still the predominant species, but the incidence of tropicalis was increasing. The median lengths of hospital and Intensive Care Unit stays prior to taking of the culture revealing candidaemia were 15 and 6 days, respectively. In all, 61% of patients did not have Candida colonisation within 2 weeks of their candidaemia. The main anti-fungal agents used were fluconazole and amphotericin B, but only 89 (70%) of the patients received appropriate anti-fungal treatment. Intensive Care Unit and hospital mortalities were 70% and 78%, respectively. Patients who did not receive appropriate treatment within 3 days had a worse outcome than those who did. CONCLUSIONS: Our data showed a high point prevalence of candidaemia in the Intensive Care Unit. Albicans was still the predominant species. Candidaemia occurred early during Intensive Care Unit stay, and a significant proportion of patients did not have prior fungal colonisation. Candidaemia in the Intensive Care Unit was associated with high morbidity and mortality. Many patients did not receive appropriately early anti-fungal therapy, and endured higher mortality than in the remainder.

Radiation-induced peripheral nerve neurofibromata in a patient receiving hypofractionated radiation therapy.

Radiation-induced peripheral nerve tumor, in particular a benign entity such as a neurofibroma, is rare, with only a few cases being reported so far. We demonstrate a case of radiation-induced neurofibromata along the left cervical nerve roots in a man with a background of localized targeted hypofractionated radiation therapy as adjuvant treatment for left cervical nodal metastasis complicating nasopharyngeal carcinoma. The toxicity of high-dose radiation in a hypofractionated regime is also stressed.

Regeneration of nerve fibres across a colonic anastomosis in the guinea-pig.

Resection and re-anastomosis of the bowel interrupts enteric neuronal pathways. The reestablishment of neuronal connections across a colonic anastomosis was studied using immunohistochemical, retrograde tracing and physiological techniques. In control guinea-pig proximal colon, retrograde labelling with 1,1'-didodecyl-3,3,3,3'-tetramethylindocarbocyanine perchlorate (DiI) revealed that enteric neurons with anally-directed projections are more numerous and have longer axons than orally-projecting neurons. In resected bowel, up to 26 weeks after re-anastomosis, descending neuronal pathways were substantially interrupted. Immunohistochemical labelling of nerve fibres revealed that some enteric nerve fibres did regenerate across narrow regions of the anastomosis, growing preferentially in the oral to anal direction. However, nerve fibres immunoreactive for neurofilament protein triplet were substantially depleted in myenteric ganglia anal to the anastomosis, even after the longest recovery periods, demonstrating that axonal regrowth was limited. This was confirmed in retrograde tracing studies, as no nerve cell bodies oral to an anastomosis were labelled when DiI was placed on myenteric ganglia just anal to the anastomosis. Physiological studies confirmed that regrowth of nerve fibres across the anastomosis occurred and that it was asymmetric, as electrical stimulation led to aboral conduction across the anastomosis more reliably than oral conduction, as measured by circular muscle contraction. After resection and re-anastomosis of the colon, the disruption of neuronal pathways in the enteric nervous system was observed, with limited and preferential re-establishment of aborally-directed long connections.

Variations in rupture site and surface strains at failure in the maturing rabbit medial collateral ligament.

The relationship between the pattern of surface strain and the site of failure in maturing rabbit ligaments was studied in vitro. Bone-medial collateral ligament (MCL)-bone complexes of 24 female New Zealand White rabbits at 3, 6, 9 and 12 months of age (n = 6 rabbits, 12 MCLs per group) were tested in tension to failure. A video dimension analysis (VDA) system was used to map the surface strain at failure across the width and along the length of the medial side of each MCL during testing. Results showed that the highest strains were consistently located at the femoral insertion decreasing towards the midsubstance, with the highest strain occurring in the anterior portion of the MCL immediately adjacent to the femoral insertion. Strains of the complex at failure increased with rabbit maturation. The strain distribution however, did not change dramatically, even though the locations of MCL failure changed from exclusively tibial avulsion in the three month old rabbits to predominantly midsubstance failures in the 12 month old rabbits. In the six month old rabbits, there was a particular dissociation with all MCLs failing near the tibial insertion while femoral strains were apparently the highest. These results suggest two possibilities beyond that of some unknown artifacts of optical strain measurement. First, since failure sites rarely correlated with areas of maximum surface strain in this study, it seems possible that higher strains could exist deeper in the tissue, particularly at the bone-ligament interface of the tibial insertion in immature animals and somewhere within the midsubstance of the MCL in the adult. Secondly, it is possible that the ligament material may be heterogeneous.

A cure for xerostomia? Free jejunal patch graft in oral reconstruction.

A case of oral carcinoma associated with extensive leukoplakia and severe xerostomia is presented. The advantage of using a free jejunal patch graft to restore large intra-oral mucosal defects and concurrently eradicate xerostomia is demonstrated. Further, it is recommended that a tracheostomy be used routinely in such cases to avoid postoperative aspiration of the graft secretions. Following healing the use of osseointegrated implants can complete oral rehabilitation without compromising the graft.

Does squatting reduce pelvic floor descent during defaecation?

Neurogenic faecal and urinary incontinence result from a stretch-induced injury to the pelvic nerves, from difficult childbirth or from chronic straining at stool. It has been suggested that the condition occurs less frequently in societies where the squatting position is used during defaecation, and that squatting may minimize pelvic floor descent. This is a prospective study which evaluates the position of the pelvic floor during defaecation straining in 52 patients. The position of the perineum was measured at rest and during maximal defaecation straining using a perineometer, with the patient in the left lateral, sitting and squatting positions. There was a significant difference in the position of the perineum at rest and on straining between the left lateral position and both the sitting and squatting positions. However, there was no significant difference at rest or on straining between the sitting and squatting positions. These results show that squatting does not reduce pelvic floor descent during defaecation straining, and imply that squatting would not help reverse stretch-induced pudendal nerve damage.

Changes in the cyclic and static relaxations of the rabbit medial collateral ligament complex during maturation.

There is at present no information on how the viscoelastic properties of bone-ligament-bone complexes change during maturation. Changes in the static and the cyclic relaxation behaviours of rabbit bone-medial-collateral-ligament-bone complexes at 3, 6, 9 and 12 months of age are described. These ages cover maturation and initial ageing of this complex. The specimens were subject to 30 cycles of uniaxial tension between zero and 0.68 mm extension at 10 mm min-1. Immediately after the cyclic test, the specimens were held at a constant 0.68 mm extension for 1200 s. The results showed that in both the cyclic and the static tests, specimens from 3-month-old animals relaxed significantly more than specimens at 6, 9 or 12 months of age, whereas those 6, 9 and 12 months old were not significantly different from each other. When the results of the cyclic tests were compared to those of the static tests, cyclic relaxation was higher than static relaxation for each of the 6-, 9- and 12-month-old specimens. For specimens 3 months of age, the opposite was observed. An explanation is offered whereby the total relaxation is suggested to be comprised of two parts: a material relaxation and a water flux component. Differing contributions by each of the two components at particular ages can explain the observed results.

Calibration characteristics of a video dimension analyser (VDA) system.

A comprehensive calibration and error analysis of a video dimension analyser (VDA) system was carried out to determine the effects of various parameters relevant to actual test conditions on the characteristics of the system. The parameters considered were: (1) varying distances or angles between the test specimen and the camera; (2) refractive effects of glass tank and physiologic solutions; and (3) dynamic response of the VDA system. The error analysis shows that, at low strain levels, the strain computed by the VDA is sensitive to camera placement and orientation as well as the media through which the object is observed. Very large errors can occur at small nominal strains, depending on the system parameters (e.g. 80% error at 1% nominal strain for one set of parameters). At higher strain levels, the sensitivity of the system is reduced, and the strain computed by the VDA system approaches the nominal strain (10% error at 10% nominal strain).

Anastomotic complications after esophagectomy for cancer. A comparison of neck and chest anastomoses.

Leakage, tumor recurrence, and stricture formation at the anastomosis are serious problems after esophagectomy for cancer of the esophagus or cardia. Because the prevalence of these postoperative complications may be affected by whether an anastomosis is made in the neck or in the chest, a comparison was made between anastomoses made at these two sites. During a period of some 7 years, we studied prospectively 411 patients who underwent resection for cancer of the esophagus or cardia and, after immediate reconstruction, had an anastomosis made in the neck or chest. The anastomotic leak rate for the neck anastomosis group was 4.3% and for the chest anastomosis group, 3.7% (p = not significant). The difference between leak rates of anastomoses fashioned by hand-sewn (5.0%) or stapled (3.0%) techniques was also not significant. The median upper resection margins in the neck and chest anastomosis groups were 4.5 cm and 3.5 cm, respectively. The corresponding rates of anastomotic tumor recurrence were 6.1% and 8.1% (p = not significant). The prevalence of benign stricture formation was significantly higher in the chest anastomosis group (19.2%) than in the neck anastomosis group (9.0%) (p = 0.002). This difference was a reflection of a significantly increased prevalence of stricture formation when an anastomosis was made by the stapler technique than with the hand-sewn method, and whereas most of the anastomoses in the neck were hand sewn (90%) the majority of those in the chest were stapled (80%). There were thus no statistically significant differences between the sites in terms of anastomotic leak and tumor recurrence rates, and the higher stricture rate in the chest anastomosis group was the result of more stapled anastomoses.

Surgical management of anal incontinence.

The complex nature of the continence mechanism is reflected in the difficulties experienced in the surgical management of patients with faecal incontinence. Apparent anatomical abnormalities may be identified but the functional outcome following surgery may be unsatisfactory. It is therefore important to improve both the selection of patients as well as the surgical procedures themselves. Selection of patients for appropriate treatment should be based on clinical findings as well as anorectal physiology tests. Most patients referred for assessment fall into one of six categories: incontinence with a normal sphincter; minor incontinence due to local anal conditions; direct sphincter injury; neurogenic ("idiopathic") incontinence; rectal prolapse; generalised neurological condition. Minor anal conditions causing incontinence must be carefully identified for appropriate treatment. A large amount of work has been done over the past ten years on the pathophysiology of major incontinence and new surgical procedures have been developed. A common difficulty is deciding whether anterior sphincter attenuation or neurogenic weakness is the dominant lesion causing incontinence; overlapping sphincter repair is indicated for the former and postanal repair for the latter. Anorectal physiology studies can be helpful in differentiating these conditions and are now used routinely in the assessment of patients.

Hypotension and endoscopic stigmata of recent haemorrhage in bleeding peptic ulcer: risk models for rebleeding and mortality.

Clinical and endoscopic data were collected prospectively in 1050 patients with bleeding peptic ulcer admitted between September 1985 and July 1989 to the care of one surgical team. Seventy-nine patients underwent therapeutic endoscopy soon after admission and in 129 patients either immediate or early elective surgery was performed. Eight hundred and forty-two patients, in whom therapeutic endoscopy was not performed at any stage, underwent initial conservative management and data from this latter group are now presented. Shock on admission was defined as systolic blood pressure (BP) less than or equal to 100 mmHg on presentation. There were 10 deaths of 147 shocked patients (6.8%) compared with only 25 deaths of 695 patients (3.6%) not in shock (P less than 0.08). Bleeding recurred in 30 patients (20.4%) shocked on presentation but in only 96 (13.8%) with a BP greater than 100 mmHg (P less than 0.05). Twenty-one of 358 patients (5.9%) with endoscopic stigmata of recent haemorrhage (ESRH) died, but only 14 of 484 patients (2.9%) without such stigmata (P less than 0.05) died. In shocked patients rebleeding was evident in 21 of 73 (28.8%) cases with ESRH but in only 9 of 74 (12.2%) patients in whom ESRH were absent (P less than 0.02). In the absence of fresh blood at endoscopy rebleeding occurred in 22 of 124 (17.8%) shocked patients and only 74 of 629 (11.8%) of those not shocked on presentation (P less than 0.07). When ulcer size was documented rebleeding rates for ulcers less than or equal to 1 cm, less than or equal to 2 cm and greater than 2 cm in size were 54 of 485 (11.1%), 30 of 142 (21.2%) and 12 of 44 (27.3%) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)