Sample size re-estimation for clinical trials with longitudinal negative binomial counts including time trends

In some diseases, such as multiple sclerosis, lesion counts obtained from magnetic resonance imaging (MRI) are used as markers of disease progression. This leads to longitudinal, and typically overdispersed, count data outcomes in clinical trials. Models for such data invariably include a number of nuisance parameters, which can be difficult to specify at the planning stage, leading to considerable uncertainty in sample size specification. Consequently, blinded sample size re-estimation procedures are used, allowing for an adjustment of the sample size within an ongoing trial by estimating relevant nuisance parameters at an interim point, without compromising trial integrity. To date, the methods available for re-estimation have required an assumption that the mean count is time-constant within patients. We propose a new modeling approach that maintains the advantages of established procedures but allows for general underlying and treatment-specific time trends in the mean response. A simulation study is conducted to assess the effectiveness of blinded sample size re-estimation methods over fixed designs. Sample sizes attained through blinded sample size re-estimation procedures are shown to maintain the desired study power without inflating the Type I error rate and the procedure is demonstrated on MRI data from a recent study in multiple sclerosis.     

Increased alpha suppression with age during involuntary memory retrieval

Recent work suggests that while voluntary episodic memory declines with age, involuntary episodic memory, which comes to mind spontaneously without intention, remains relatively intact. However, the neurophysiology underlying these differences has yet to be established. The current study used electroencephalography (EEG) to investigate voluntary and involuntary retrieval in older and younger adults. Participants first encoded sounds, half of which were paired with pictures, the other half unpaired. EEG was then recorded as they listened to the sounds, with participants in the involuntary group performing a sound localization cover task, and those in the voluntary group additionally attempting to recall the associated pictures. Participants later reported which sounds brought the paired picture to mind during the localization task. Reaction times on the localization task were slower for voluntary than involuntary retrieval and for paired than unpaired sounds, possibly reflecting increased attentional demands of voluntary retrieval and interference from reactivation of the associated pictures respectively. For the EEG analyses, young adults showed greater alpha event-related desynchronization (ERD) during voluntary than involuntary retrieval at frontal and occipital sites, while older adults showed pronounced alpha ERD regardless of intention. Additionally, older adults showed greater ERD for paired than unpaired sounds at occipital sites, likely reflecting visual reactivation of the associated pictures. Young adults did not show this alpha ERD memory effect. Taken together, these data suggest that involuntary memory is largely preserved with age, but this may be due to older adults' greater recruitment of top-down control even when demand for such control is limited.     

Presentation and management of traumatic occipital spur fracture

Occipital spur is an abnormal bony outgrowth of the external occipital protuberance (EOP). We describe an interesting and previously unreported case of fracture of an occipital spur following trauma. Our 20-year-old male patient was treated in the emergency department (ED) and discharged home without complication. Neurosurgical consultation was obtained but is not requisite for these injuries. Greater awareness of this unique presentation may help to expedite future emergency department treatment.     

The 5-year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy

The use of adjuvant radiation therapy in breast cancer patients treated with mastectomy and adjuvant chemotherapy has been controversial. In order to assess the necessity and effectiveness of adjuvant radiation therapy in this setting, we reviewed the results in 510 patients with T1-T3 tumors and pathologically positive nodes or tumors larger than 5 cm and negative nodes who were treated with adjuvant chemotherapy. Patients with four or more positive nodes or at least one positive apical node were randomized to receive either five or ten cycles of cyclophosphamide/Adriamycin (Adria Laboratories, Columbus, OH) (CA) and patients with one to three positive nodes or operable tumors larger than 5 cm and pathologically negative nodes were randomized to receive eight cycles of either cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) or methotrexate and 5-FU (MF) chemotherapy. Two hundred six of these patients were subsequently rerandomized to receive either no further treatment or adjuvant radiotherapy. Thirty-five patients withdrew after randomization, including 34 who declined to receive radiotherapy. Radiation therapy consisted of 4,500 cGy in 5 weeks to the chest wall and appropriate draining lymph nodes. Median follow-up from chemotherapy randomization is 45 months for patients in the CA arm and 53 months for those in the CMF/MF arm. The crude rate of local failure (chest wall or draining lymph node areas) as first site of failure for patients randomized to receive chemotherapy only was 14%; for those randomized to receive both chemotherapy and radiotherapy it was 5% (P = .03). For patients in the CMF/MF arm, the rate of local failure as the first site of failure was nearly the same for patients randomized to chemotherapy only as for those randomized to adjuvant radiotherapy as well (5% v 2%). For patients in the CA arm, the crude rate of local failure was 20% for patients randomized to receive chemotherapy only, and 6% for those randomized to both types of adjuvant treatment (P = .03). Among the 43 patients treated with CA who actually received radiotherapy, there was only one local failure, compared with 12 local failures among the 59 patients (20%) who actually did not receive radiotherapy (P = .007). No significant difference was seen in disease-free survival or overall survival in either the CA or the CMF/MF arm between patients randomized to receive radiation therapy and those randomized to no further treatment.(ABSTRACT TRUNCATED AT 400 WORDS)