Survival of COVID-19 Patients With Respiratory Failure is Related to Temporal Changes in Gas Exchange and Mechanical Ventilation.

Background: Respiratory failure due to coronavirus disease of 2019 (COVID-19) often presents with worsening gas exchange over a period of days. Once patients require mechanical ventilation (MV), the temporal change in gas exchange and its relation to clinical outcome is poorly described. We investigated whether gas exchange over the first 5 days of MV is associated with mortality and ventilator-free days at 28 days in COVID-19. Methods: In a cohort of 294 COVID-19 patients, we used data during the first 5 days of MV to calculate 4 daily respiratory scores: PaO2/FiO2 (P/F), oxygenation index (OI), ventilatory ratio (VR), and Murray lung injury score. The association between these scores at early (days 1-3) and late (days 4-5) time points with mortality was evaluated using logistic regression, adjusted for demographics. Correlation with ventilator-free days was assessed (Spearman rank-order coefficients). Results: Overall mortality was 47.6%. Nonsurvivors were older (P < .0001), more male (P = .029), with more preexisting cardiopulmonary disease compared to survivors. Mean PaO2 and PaCO2 were similar during this timeframe. However, by days 4 to 5 values for all airway pressures and FiO2 had diverged, trending lower in survivors and higher in nonsurvivors. The most substantial between-group difference was the temporal change in OI, improving 15% in survivors and worsening 11% in nonsurvivors (P < .05). The adjusted mortality OR was significant for age (1.819, P = .001), OI at days 4 to 5 (2.26, P = .002), and OI percent change (1.90, P = .02). The number of ventilator-free days correlated significantly with late VR (-0.166, P < .05), early and late OI (-0.216, P < .01; -0.278, P < .01, respectively) and early and late P/F (0.158, P < .05; 0.283, P < .01, respectively). Conclusion: Nonsurvivors of COVID-19 needed increasing intensity of MV to sustain gas exchange over the first 5 days, unlike survivors. Temporal change OI, reflecting both PaO2 and the intensity of MV, is a potential marker of outcome in respiratory failure due to COVID-19.

Continued In-Hospital Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use in Hypertensive COVID-19 Patients Is Associated With Positive Clinical Outcome.

BACKGROUND: This study investigated continued and discontinued use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) during hospitalization of 614 hypertensive laboratory-confirmed COVID-19 patients. METHODS: Demographics, comorbidities, vital signs, laboratory data, and ACEi/ARB usage were analyzed. To account for confounders, patients were substratified by whether they developed hypotension and acute kidney injury (AKI) during the index hospitalization. RESULTS: Mortality (22% vs 17%, P > .05) and intensive care unit (ICU) admission (26% vs 12%, P > .05) rates were not significantly different between non-ACEi/ARB and ACEi/ARB groups. However, patients who continued ACEi/ARBs in the hospital had a markedly lower ICU admission rate (12% vs 26%; P = .001; odds ratio [OR] = 0.347; 95% confidence interval [CI], .187-.643) and mortality rate (6% vs 28%; P = .001; OR = 0.215; 95% CI, .101-.455) compared to patients who discontinued ACEi/ARB. The odds ratio for mortality remained significantly lower after accounting for development of hypotension or AKI. CONCLUSIONS: These findings suggest that continued ACEi/ARB use in hypertensive COVID-19 patients yields better clinical outcomes.

Impact of advanced endoscopic imaging on Barrett's esophagus in daily clinical practice.

BACKGROUND AND AIMS: Several advanced imaging techniques have been proposed to improve the visualization of dysplastic regions within Barrett's epithelium, with some evidence for the use of narrow-band imaging (NBI) and acetic acid chromoendoscopy (AAC). METHODS: We retrospectively analyzed consecutive cases of Barrett's esophagus, diagnosed using white-light endoscopy and confirmed histologically by the presence of intestinal metaplasia, between April 2007 and April 2010 in a large community hospital. A change in practice was then instituted, whereby a Barrett's team consisting of specialist endoscopists was formed in an attempt to standardize and improve the quality of surveillance. Barrett's epithelium was inspected with both white-light imaging and NBI in all patients. Where the length of Barrett's epithelium was 3 cm or more, AAC was also used. One and a half percent acetic acid was sprayed onto the Barrett's segment and loss of aceto-whitening observed after a 2-minute period. Any abnormal areas noted during advanced imaging underwent target biopsy sampling. We subsequently compared the dysplasia detection rate in Barrett's epithelium identified between April 2011 and April 2014 after these changes. Observed differences between the cohorts were analyzed with the Fisher exact test and the Student t test. RESULTS: From 2007 to 2010 Barrett's esophagus was identified during 560 gastroscopies in 392 individual patients. The mean maximal Barrett's esophagus recorded length was 4.4 cm (range, 1-10), with an average of 4.7 esophageal biopsy specimens taken per endoscopy. In comparison, from 2011 to 2014 Barrett's esophagus was identified during 856 endoscopies in 630 patients. From 2011 to 2014 the Barrett's team performed 85% of all procedures using the aforementioned techniques. The mean maximal Barrett's esophagus length was 3.8 cm (range, 1-16), with an increased average of 5.8 biopsy specimens per endoscopy taken (P < .01). Both cohorts were comparable in age and gender distribution. Our data demonstrated no significant difference in the relative frequencies of occurrence of dysplasia detected between both cohorts of patients. From 2007 to 2010 dysplasia was detected in 11.0% (n = 43) of patients. This consisted of low-grade dysplasia in 7.7% of patients and high-grade dysplasia or cancer 3.3%. From 2011 to 2014 this compared with dysplasia in 11.3% (n = 71) of patients, with low-grade dysplasia in 9.4% and high-grade dysplasia or cancer in 1.9%. CONCLUSIONS: Our data show that the use of NBI and AAC in the imaging of Barrett's esophagus did not result in an increased detection rate of dysplasia in routine clinical practice. These findings concur with the recommendations of existing Barrett's esophagus surveillance guidelines, which advocate the continued use of quadratic biopsy sampling within general surveillance programs.

Cerebral Oximetry During Cardiac Arrest: A Multicenter Study of Neurologic Outcomes and Survival.

OBJECTIVES: Cardiac arrest is associated with morbidity and mortality because of cerebral ischemia. Therefore, we tested the hypothesis that higher regional cerebral oxygenation during resuscitation is associated with improved return of spontaneous circulation, survival, and neurologic outcomes at hospital discharge. We further examined the validity of regional cerebral oxygenation as a test to predict these outcomes. DESIGN: Multicenter prospective study of in-hospital cardiac arrest. SETTING: Five medical centers in the United States and the United Kingdom. PATIENTS: Inclusion criteria are as follows: in-hospital cardiac arrest, age 18 years old or older, and prolonged cardiopulmonary resuscitation greater than or equal to 5 minutes. Patients were recruited consecutively during working hours between August 2011 and September 2014. Survival with a favorable neurologic outcome was defined as a cerebral performance category 1-2. INTERVENTIONS: Cerebral oximetry monitoring. MEASUREMENTS AND MAIN RESULTS: Among 504 in-hospital cardiac arrest events, 183 (36%) met inclusion criteria. Overall, 62 of 183 (33.9%) achieved return of spontaneous circulation, whereas 13 of 183 (7.1%) achieved cerebral performance category 1-2 at discharge. Higher mean ± SD regional cerebral oxygenation was associated with return of spontaneous circulation versus no return of spontaneous circulation (51.8% ± 11.2% vs 40.9% ± 12.3%) and cerebral performance category 1-2 versus cerebral performance category 3-5 (56.1% ± 10.0% vs 43.8% ± 12.8%) (both p < 0.001). Mean regional cerebral oxygenation during the last 5 minutes of cardiopulmonary resuscitation best predicted the return of spontaneous circulation (area under the curve, 0.76; 95% CI, 0.69-0.83); regional cerebral oxygenation greater than or equal to 25% provided 100% sensitivity (95% CI, 94-100) and 100% negative predictive value (95% CI, 79-100); regional cerebral oxygenation greater than or equal to 65% provided 99% specificity (95% CI, 95-100) and 93% positive predictive value (95% CI, 66-100) for return of spontaneous circulation. Time with regional cerebral oxygenation greater than 50% during cardiopulmonary resuscitation best predicted cerebral performance category 1-2 (area under the curve, 0.79; 95% CI, 0.70-0.88). Specifically, greater than or equal to 60% cardiopulmonary resuscitation time with regional cerebral oxygenation greater than 50% provided 77% sensitivity (95% CI,:46-95), 72% specificity (95% CI, 65-79), and 98% negative predictive value (95% CI, 93-100) for cerebral performance category 1-2. CONCLUSIONS: Cerebral oximetry allows real-time, noninvasive cerebral oxygenation monitoring during cardiopulmonary resuscitation. Higher cerebral oxygenation during cardiopulmonary resuscitation is associated with return of spontaneous circulation and neurologically favorable survival to hospital discharge. Achieving higher regional cerebral oxygenation during resuscitation may optimize the chances of cardiac arrest favorable outcomes.

A feasibility study of cerebral oximetry during in-hospital mechanical and manual cardiopulmonary resuscitation*.

OBJECTIVE: A major hurdle limiting the ability to improve the quality of resuscitation has been the lack of a noninvasive real-time detection system capable of monitoring the quality of cerebral and other organ perfusion, as well as oxygen delivery during cardiopulmonary resuscitation. Here, we report on a novel system of cerebral perfusion targeted resuscitation. DESIGN: An observational study evaluating the role of cerebral oximetry (Equanox; Nonin, Plymouth, MI, and Invos; Covidien, Mansfield, MA) as a real-time marker of cerebral perfusion and oxygen delivery together with the impact of an automated mechanical chest compression system (Life Stat; Michigan Instruments, Grand Rapids, MI) on oxygen delivery and return of spontaneous circulation following in-hospital cardiac arrest. SETTING: Tertiary medical center. PATIENTS: In-hospital cardiac arrest patients (n = 34). MAIN RESULTS: Cerebral oximetry provided real-time information regarding the quality of perfusion and oxygen delivery. The use of automated mechanical chest compression device (n = 12) was associated with higher regional cerebral oxygen saturation compared with manual chest compression device (n = 22) (53.1% ± 23.4% vs 24% ± 25%, p = 0.002). There was a significant difference in mean regional cerebral oxygen saturation (median % ± interquartile range) in patients who achieved return of spontaneous circulation (n = 15) compared with those without return of spontaneous circulation (n = 19) (47.4% ± 21.4% vs 23% ± 18.42%, p < 0.001). After controlling for patients achieving return of spontaneous circulation or not, significantly higher mean regional cerebral oxygen saturation levels during cardiopulmonary resuscitation were observed in patients who were resuscitated using automated mechanical chest compression device (p < 0.001). CONCLUSIONS: The integration of cerebral oximetry into cardiac arrest resuscitation provides a novel noninvasive method to determine the quality of cerebral perfusion and oxygen delivery to the brain. The use of automated mechanical chest compression device during in-hospital cardiac arrest may lead to improved oxygen delivery and organ perfusion.

Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.

Undetectable SARS-CoV-2 in a nasopharyngeal swab but persistent viral RNA from deep lung swabs: findings from an autopsy.

During the global pandemic of COVID-19 accurate diagnosis of the infection by demonstrating SARS-CoV-2 viral RNA by PCR in specimens is crucial for therapeutic and preventative interventions. There have been instances where nasal and throat swabs have been negative despite the patient having typical clinical and radiological findings compatible with the disease. We report a case of a man in his late 50s, brought to the hospital following a cardiac arrest and prolonged unsuccessful resuscitation. The history was typical for COVID-19 with fever for 10 days and worsening shortness of breath. His throat and nasal swabs (after death) were negative for SARS-CoV-2. A limited diagnostic autopsy was performed after 27 days, and lung swabs confirmed presence of SARS-CoV-2. This case highlights the importance of lung swabs when initial upper respiratory tract swabs are negative and proves that the virus can be detected from dead human tissue almost a month later.

Deep learning prediction of likelihood of ICU admission and mortality in COVID-19 patients using clinical variables.

BACKGROUND: This study aimed to develop a deep-learning model and a risk-score system using clinical variables to predict intensive care unit (ICU) admission and in-hospital mortality in COVID-19 patients. METHODS: This retrospective study consisted of 5,766 persons-under-investigation for COVID-19 between 7 February 2020 and 4 May 2020. Demographics, chronic comorbidities, vital signs, symptoms and laboratory tests at admission were collected. A deep neural network model and a risk-score system were constructed to predict ICU admission and in-hospital mortality. Prediction performance used the receiver operating characteristic area under the curve (AUC). RESULTS: The top ICU predictors were procalcitonin, lactate dehydrogenase, C-reactive protein, ferritin and oxygen saturation. The top mortality predictors were age, lactate dehydrogenase, procalcitonin, cardiac troponin, C-reactive protein and oxygen saturation. Age and troponin were unique top predictors for mortality but not ICU admission. The deep-learning model predicted ICU admission and mortality with an AUC of 0.780 (95% CI [0.760-0.785]) and 0.844 (95% CI [0.839-0.848]), respectively. The corresponding risk scores yielded an AUC of 0.728 (95% CI [0.726-0.729]) and 0.848 (95% CI [0.847-0.849]), respectively. CONCLUSIONS: Deep learning and the resultant risk score have the potential to provide frontline physicians with quantitative tools to stratify patients more effectively in time-sensitive and resource-constrained circumstances.

Outcomes of Introducing a Mobile Interactive Learning Resource in a Large Medical School Course.

Mobile devices are an integral part of modern medical education, as convenient platforms for access to online interactive learning resources; students' use of textbooks has correspondingly declined. We designed an interactive iBook© for pre-clinical students encompassing the content of the pulmonary segment in an organ-based multidisciplinary course. We found, via a survey-based study, that students preferred the iBook to other faculty-supplied materials (PowerPoints and PDFs), mainly due to its interactive images, animations, and study questions. Students' test performance did not change significantly after introducing the iBook. This study suggests that expanded use of interactive learning resources may enhance students' engagement with pre-clinical courses.

Prediction model and risk scores of ICU admission and mortality in COVID-19.

This study aimed to develop risk scores based on clinical characteristics at presentation to predict intensive care unit (ICU) admission and mortality in COVID-19 patients. 641 hospitalized patients with laboratory-confirmed COVID-19 were selected from 4997 persons under investigation. We performed a retrospective review of medical records of demographics, comorbidities and laboratory tests at the initial presentation. Primary outcomes were ICU admission and death. Logistic regression was used to identify independent clinical variables predicting the two outcomes. The model was validated by splitting the data into 70% for training and 30% for testing. Performance accuracy was evaluated using area under the curve (AUC) of the receiver operating characteristic analysis (ROC). Five significant variables predicting ICU admission were lactate dehydrogenase, procalcitonin, pulse oxygen saturation, smoking history, and lymphocyte count. Seven significant variables predicting mortality were heart failure, procalcitonin, lactate dehydrogenase, chronic obstructive pulmonary disease, pulse oxygen saturation, heart rate, and age. The mortality group uniquely contained cardiopulmonary variables. The risk score model yielded good accuracy with an AUC of 0.74 ([95% CI, 0.63-0.85], p = 0.001) for predicting ICU admission and 0.83 ([95% CI, 0.73-0.92], p<0.001) for predicting mortality for the testing dataset. This study identified key independent clinical variables that predicted ICU admission and mortality associated with COVID-19. This risk score system may prove useful for frontline physicians in clinical decision-making under time-sensitive and resource-constrained environment.

Early changes in functional dynamic magnetic resonance imaging predict for pathologic response to neoadjuvant chemotherapy in primary breast cancer.

PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows noninvasive, in vivo measurements of tissue microvessel perfusion and permeability. We examined whether DCE-MRI done after two cycles of neoadjuvant chemotherapy could predict final clinical and pathologic response in primary breast cancers. EXPERIMENTAL DESIGN: Thirty-seven patients with primary breast cancer, due to receive six cycles of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy, were examined using DCE-MRI before neoadjuvant chemotherapy and after two cycles of treatment. Changes in DCE-MRI kinetic parameters (K(trans), k(ep), v(e), MaxGd, rBV, rBF, MTT) were correlated with the final clinical and pathologic response to neoadjuvant chemotherapy. Test-retest variability was used to determine individual patient response. RESULTS: Twenty-eight patients were evaluable for response (19 clinical responders and 9 nonresponders; 11 pathologic responders and 17 nonresponders). Changes in the DCE-MRI kinetic parameters K(trans), k(ep), MaxGd, rBV, and rBF were significantly correlated with both final clinical and pathologic response (P < 0.01). Change in K(trans) was the best predictor of pathologic nonresponse (area under the receiver operating characteristic curve, 0.93; sensitivity, 94%; specificity, 82%), correctly identifying 94% of nonresponders and 73% of responders. Change in MRI-derived tumor size did not predict for pathologic response. CONCLUSION: Changes in breast tumor microvessel functionality as depicted by DCE-MRI early on after starting anthracycline-based neoadjuvant chemotherapy can predict final clinical and pathologic response. The ability to identify nonresponders early may allow the selection of patients who may benefit from a therapy change.

Use of student feedback to drive quality improvement (QI) in a preclinical U.S. medical school course.

Medical educators are continually looking for ways to enhance integrated learning and help students see how the material taught in their various courses is inter-related. . At Stony Brook School of Medicine, we embarked on a school-wide new curriculum called the Learning focused, Experiential, Adaptive, Rigorous and Novel (LEARN) curriculum and developed several integrated courses that were not based in specific departments. As part of this process, the pre-clinical (Phase-1) curriculum was shortened to 17 months to accommodate an expanded set of clinical offerings. The new structure called for teachers from different departments to lead and conduct the integrated blocks of pre-clinical courses. In this paper, we describe our discouraging experience with the first iteration of an integrated course in Cardiology, Pulmonology and Renal organ systems (CPR), and its transformation into a highly successful second iteration. This involved a systematic course quality improvement (QI) process within the context of a larger school wide curricular reform. As a result, student overall satisfaction with the course increased from 22% (28 of 127 responders) to 83% (111 of 134 responders); the mean score on a standardized NBME content exam increased by 6.7%. We report the systematic process we used to collect data from students and faculty that helped facilitate quality improvement in a key course in Phase-1 of our LEARN curriculum.

Exercise Capacity in Unilateral Diaphragm Paralysis: The Effect of Obesity.

PURPOSE: Healthy patients with unilateral diaphragm paralysis (UDP) are often asymptomatic; those with UDP and comorbidities that increase work of breathing are often dyspneic. We report the effect of obesity on exercise capacity in UDP patients. METHODS: All obese and nonobese patients with UDP undergoing cardiopulmonary exercise testing (CPET) during a 32-month period in the exercise laboratory of an academic hospital were compared to a retrospectively identified cohort of obese and nonobese controls without UDP, matched for key features. CPET used a modified Bruce treadmill protocol with breath-to-breath expired gas analysis. O2 uptake, minute ventilation, exercise time, and work rate were recorded at peak exercise. Static pulmonary functions were measured. Kruskal-Wallis, Wilcoxon rank sum, and Fisher's exact tests were used to compare continuous and categorical variables, respectively. Stratified linear regression was used to quantify the effect of UDP and obesity on CPET variables. RESULTS: Twenty-two UDP patients and 46 controls were studied. The BMI of obese and nonobese patients was 33.0±4.2 and 25.8±2.4 kg/m2, respectively. UDP subjects with obesity, compared to controls with neither condition, showed significantly reduced peak O2 uptake normalized to actual body weight (1.57±0.64 versus 2.01±0.88 L/min), shorter exercise time (5.7±2.0 versus 8.5±2.9 minutes), and lower peak ventilation. This was not observed in UDP alone or obesity alone. Peak work rate trended lower in the combined UDP-obesity group. CONCLUSION: Neither UDP nor obesity alone significantly reduced exercise capacity. Superimposed UDP and obesity interact to create a ventilatory limitation to exercise, with reduced peak-VO2, exercise time, and work rate.

Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit.

CONTEXT: In critically ill intubated patients, signs of respiratory infection often persist despite treatment with potent systemic antibiotics. OBJECTIVE: The purpose of this study was to determine whether aerosolized antibiotics, which achieve high drug concentrations in the target organ, would more effectively treat respiratory infection and decrease the need for systemic antibiotics. DESIGN: Double-blind, randomized, placebo-controlled study performed from 2003 through 2004. SETTING: The medical and surgical intensive care units of a university hospital. PATIENTS: Critically ill intubated patients were randomized if: 1) > or = 18 yrs of age, intubated for a minimum of 3 days, and expected to survive at least 14 days; and 2) had ventilator-associated tracheobronchitis defined as the production of purulent secretions (> or = 2 mL during 4 hrs) with organism(s) on Gram stain. Of 104 patients monitored, 43 consented for treatment and completed the study. No patients were withdrawn from the study for adverse events. INTERVENTION: Aerosol antibiotic (AA) or aerosol saline placebo was given for 14 days or until extubation. The responsible clinician determined the administration of systemic antibiotics (SA). Patients were followed for 28 days. MAIN OUTCOME MEASURES: Primary: Centers for Disease Control National Nosocomial Infection Survey diagnostic criteria for ventilator-associated pneumonia (VAP) and clinical pulmonary infection score. Secondary: white blood cell count, SA use, acquired antibiotic resistance, and weaning from mechanical ventilation. RESULTS: Most patients had VAP at randomization. With treatment, the AA group had reduced signs of respiratory infection: reduced Centers for Disease Control National Nosocomial Infection Survey VAP (14/19; 73.6%) to (5/14; 35.7%) vs. placebo (18/24; 75%) to (11/14; 78.6%), reduction in clinical pulmonary infection score, lower white blood cell count at day 14, reduced bacterial resistance, reduced use of SA, and increased weaning (all p < or = .05). CONCLUSIONS: In critically ill patients with ventilator-associated tracheobronchitis, AA decrease VAP and other signs and symptoms of respiratory infection, facilitate weaning, and reduce bacterial resistance and use of systemic antibiotics.

Adjacent thoracic lymph node metastases originating from two separate primary cancers: case report.

Reported is an unusual case of adjacent thoracic lymph nodes demonstrating metastases from two different primary malignancies. A 51 year-old woman with a previous history of bilateral breast cancer underwent a radical gastro-oesophagectomy for adenocarcinoma of the lower third of the oesophagus. The resection specimen demonstrated breast and oesophageal metastases in adjacent thoracic lymph nodes. Mechanisms for this phenomenon, including the known local immune suppression on lymphoid cells by oesophageal carcinoma cells, are discussed.

Collision of adenocarcinoma and gastrointestinal stromal tumour (GIST) in the stomach: report of a case.

A 78-year-old woman was diagnosed with a proximal gastric adenocarcinoma and underwent an elective D2 total gastrectomy with splenectomy. Subsequent histopathology revealed the presence of another tumour at the gastric antrum. This was a small benign gastrointestinal stromal tumour (GIST) mixed with gastric adenocarcinoma cells similar to those of the main gastric tumour i.e. a collision tumour. The literature has only few previous reports of this very rare association. It is not known whether this synchronicity is incidental or there is a causative factor inducing the development of tumours of different histotypes in the same organ. Pathologists, oncologists and surgeons should be aware of this interesting condition.

Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial.

PURPOSE: Accelerated repopulation is a main reason for locoregional failure after fractionated radiotherapy for head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor (EGFR) is a key controller of cellular proliferation in HNSCC, which stimulated the current study to look for a direct link between EGFR status and a possible clinical advantage of accelerated radiotherapy. PATIENTS AND METHODS: Immunohistochemical staining for EGFR was performed in 304 patients with available pretreatment tumor biopsy material among 918 patients randomized to receive continuous hyperfractionated accelerated radiotherapy versus conventionally fractionated radiotherapy. The EGFR index was estimated as the proportion of tumor cells with EGFR membrane staining. RESULTS: Significant benefit in locoregional tumor control from continuous hyperfractionated accelerated radiotherapy was seen in patients with HNSCC with high EGFR expression (2P = .010) but not in those with low EGFR expression (2P = .85). EGFR status had no significant effect on survival or rate of distant metastases. The EGFR index was significantly associated with histologic grade and microvessel density. There was moderate support for an association between EGFR status and subsite within the head and neck region but no significant association with Ki-67 index, Ki-67 pattern, p53 index, p53 intensity, bcl-2 expression, or cyclin D1 index. CONCLUSION: This study indicates a key role for the EGFR receptor in determining the proliferative cellular response to fractionated radiotherapy in HNSCC. It also shows that we can select the dose-fractionation regime that has the greatest chance of benefiting the patient. These results also encourage further development of EGFR targeting combined with fractionated radiotherapy in HNSCC.

Evaluation of Ki-67 proliferation and apoptotic index before, during and after neoadjuvant chemotherapy for primary breast cancer.

INTRODUCTION: Biological markers that reliably predict clinical or pathological response to primary systemic therapy early during a course of chemotherapy may have considerable clinical potential. This study evaluated changes in Ki-67 labeling index and apoptotic index (AI) before, during, and after neoadjuvant anthracycline chemotherapy. METHODS: Twenty-seven patients receiving neoadjuvant FEC (5-fluorouracil, epirubicin, and cyclophosphamide) chemotherapy for operable breast cancer underwent repeat core biopsy after 21 days of treatment. Tissue from pre-treatment biopsy, day 21 and surgery was analysed for Ki-67 index and AI. RESULTS: The objective clinical response rate was 56%. Eight patients (31%) achieved a pathological response by histological criteria; two patients had a near-complete pathological response. A reduction in Ki-67 index was observed in 68% of patients at day 21 and 72% at surgery; Ki-67 index increased between day 21 and surgery in 54%. AI decreased in 50% of tumours by day 21, increased in 45% and was unchanged in one patient; 56% demonstrated rebound increases in AI by the time of surgery. Neither pre-treatment nor post-chemotherapy median Ki-67 index nor median AI at all three time points or relative changes at day 21 and surgery differed significantly between clinical or pathological responders and non-responders. Clinical responders had lower median Ki-67 indices at day 21 (11.4% versus 27.0%, p = 0.02) and significantly greater percentage reductions in Ki-67 at day 21 than did non-responders (-50.6% versus -5.3%, p = 0.04). The median day-21 Ki-67 was higher in pathological responders (30.3% versus 14.1%, p = 0.046). A trend toward increased AI at day 21 in pathological responders was observed (5.30 versus 1.68, p = 0.12). Increased day-21 AI was a statistically significant predictor of pathological response (p = 0.049). A strong trend for predicting pathological response was seen with higher Ki-67 indices at day 21 and AI at surgery (p = 0.06 and 0.06, respectively). CONCLUSION: The clinical utility of early changes in biological marker expression during chemotherapy remains unclear. Until further prospectively validated evidence confirming the reliability of predictive markers is available, clinical decision-making should not be based upon individual biological tumour marker profiles.

Pre-treatment proliferation and the outcome of conventional and accelerated radiotherapy.

This study investigated the influence of pre-treatment proliferation characteristics, assessed by Ki-67 staining, in patients treated in the CHART trial of accelerated radiotherapy in head and neck cancer. Histological material from 402 patients was collected and stained for the presence and pattern of Ki-67 staining. Locoregional control and overall survival were the main clinical endpoints. Increasing Ki-67 positivity was associated with decreasing differentiation (P < 0.001) and increasing N-stage (P < 0.004). Increasing N-stage was also associated with the progression of proliferation pattern from marginal to random (P < 0.001). Using a multivariate model, a trend was seen towards a greater benefit from CHART in the lower Ki-67 tumours (P = 0.08); this became significant by pooling the low and intermediate Ki-67 groups in comparison with the high Ki-67 group (P = 0.032). Tumours with marginal proliferation pattern showed a lower hazard ratio with CHART versus conventional for locoregional control (P = 0.005). The data presented in this study do not support that a high pre-treatment Ki-67 is associated with a therapeutic benefit from accelerated radiotherapy.