Cognitive and affective complaints are common in patients with primary hyperparathyroidism (PHPT), but few studies have used psychometric testing to document these symptoms and their response to ...parathyroidectomy. The current study sought to clarify the nature of cognitive and affective impairments in PHPT and changes postparathyroidectomy. One hundred eleven patients with PHPT underwent neuropsychological evaluation prior to parathyroidectomy with 68 returning for an early postsurgical evaluation. Changes in cognition were assessed using practice effect corrected reliable change indices. Biochemical and anesthesia variables were compared between groups who improved and declined. In a subset of patients, assessment revealed a significant pattern of cognitive slowing, reductions in psychomotor speed, memory impairment, and depression prior to parathyroidectomy. Postsurgical evaluations revealed a trend for improvements on timed tests and depression but a decline in memory. Older patients responded less well to surgical intervention, as did patients who experienced more dramatic changes in biochemical status following surgery. Cognitive changes early postparathyroidectomy are characterized by improved information processing speed and decline in verbal memory, with younger patients more likely to recover during this acute phase. The need for longer-term follow-up studies and increasing utilization of neuropsychological assessments in this population are discussed.
The nucleoside 3'-c-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis which occurs throughout the cell cycle except for the M phase. TAS-106 is incorporated into cells, is rapidly ...phosphorylated to a monophosphate form, and is preferentially distributed into malignant cells. Preclinical studies showed that TAS-106 has a wide antitumor spectrum against human cancer xenografts. This phase I study was conducted in order to determine the recommended phase II dose of TAS-106 administered once per week for three consecutive weeks, every 28 days in patients with solid tumors.
Patients were enrolled in cohorts of three, starting at 0.22 mg/m(2)/dose. Patients received at least two doses in order to be evaluable in each dose cohort. Dose escalation was stopped if two or more patients experienced dose limiting toxicity at any dose level.
In 20 evaluable patients, TAS-106 was given at the following dose levels (mg/m(2)/dose): 0.22 (3 pts), 0.33 (3 pts), 0.66 (3 pts), 0.99 (1 pt), 1.32 (3 pts), 2.64 (3 pts) and 3.96 (1 pt). Three additional patients were evaluated at 2.64 mg/m(2)/dose for further characterization of toxicity and safety. A total of 16 patients completed courses 1 and 2. All 21 patients enrolled experienced at least one adverse event. The AE attributed to the study drug was grade 2 peripheral neuropathy characterized by peripheral sensory neuropathy, numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes, and feet.
Due to neurotoxicity the MTD was the 2.64 mg/m(2)/dose for the study schedule. No suggested phase II dose was determined. However, at the 1.32 mg/m(2)/dose level, no patients experienced DLTs during course 1 or 2. This could be further studied to determine its viability as a potential phase II dosage.
Trials with interferon-alpha (IFN-alpha) have provided contradictory findings regarding the presence of cognitive side effects. The development of depression in some patients also raises questions ...about whether cognitive dysfunction might be secondary to an organic, interferon-induced mood disorder. Thirty patients with chronic myelogenous leukemia were examined before and during treatment with IFN-alpha alone or IFN-alpha and chemotherapy. Increased depressive symptoms and declines in information processing and executive functions were observed, but depression alone could not account for cognitive dysfunction. There was some evidence suggesting that exposure to chemotherapy and higher cumulative IFN-alpha dose may contribute to cognitive impairment.
Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety ...and optimal dose of the combination regimen and to assess pharmacokinetic interactions.
Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity.
The combination of TNP-470 administered at 60 mg/m(2) three times per week and paclitaxel 225 mg/m(2) administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy.
The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.
This study examined the course of clinically significant cognitive change in hematopoietic stem cell transplant (HSCT), using a Reliable Change Index (RCI). Neuropsychological evaluations were ...administered to 117 patients before HSCT. Thirty-three received subsequent evaluations 6 and 28 weeks later. Of 117 patients, 39% were classified as impaired before HSCT. Of the 33 receiving subsequent evaluations, 47% showed reliable decline at 6-weeks; of these, 33% showed reliable decline again at 28-weeks. Mood and QOL did not account for declines. Verbal learning, psychomotor speed, and executive function showed greatest vulnerability to pre-HSCT impairment, and verbal learning showed greatest likelihood of further, subsequent decline. In conclusion, a subgroup of patients showed cognitive impairment before HSCT, indicating that factors other than HSCT contributed to cognitive deficits. Another subgroup showed further decline after HSCT. This study demonstrated the utility of the RCI in describing cognitive change in HSCT patients.
Interferon (IFN) therapy is associated with neuropsychiatric side effects including cognitive dysfunction and mood syndromes of varying severity. These problems are the most common causes of ...treatment discontinuation. Dose and duration of treatment influence risk of IFN-induced side effects. Rates of IFN-induced depression vary, but approach 50% in recent studies. Presence and severity of depressive symptoms at or before treatment predicts development of mood disorders during IFN therapy. Several possible endocrine and neurotransmitter perturbations may be responsible for IFN neurotoxicity, with recent research suggesting different symptoms clusters are related to different underlying mechanisms. The interpretation of these clusters has been influenced by subjective versus objective evaluation of cognitive function. Effective management of IFN-induced neuropsychiatric side effects should involve pretreatment screening and interval assessment during therapy. Antipsychotic and psychostimulant drugs may be used against cognitive dysfunction. Antidepressants have been shown to be effective against IFN-induced depression and can be very valuable in support of adequate or completed therapy.
Cognitive changes associated with interferon treatment include impaired verbal memory, attention, processing speed, and executive functioning. Pegylated interferon is a relatively new, long-lasting ...form of interferon alpha, but data regarding its cognitive effects in brain tumor patients are limited. Participants in this study were 35 primary brain tumor patients who received pegylated interferon at tumor recurrence. A neuropsychological battery assessed verbal memory, executive functioning, attention, information processing speed, and language functioning. Individual growth curve analyses were used to estimate cognitive change throughout treatment with interferon. Results revealed performance declined on a task of psychomotor speed and upper extremity dexterity. Although decline in a few tests was found, its degree may have been reduced because individuals were tested after tumor recurrence where a substantial amount of cognitive change had already potentially occurred due to surgery, radiation therapy, and chemotherapy. Thus, participants may not have been starting at their baseline cognitive status and the potential neurotoxic effects of interferon may have been obscured by prior treatments. An alternative explanation, however, is that treatment with pegylated interferon did not produce further impairment and patients experienced stability in their cognitive functioning.
This study assessed the neuropsychological outcome of patients after surgical treatment for third ventricle brain tumors. Neuropsychological consequences of surgical intervention can have a major ...impact on patients' quality of life and therefore have important implications for treatment planning.
A retrospective analysis of 33 patients' neuropsychological data was performed. All patients received a comprehensive neuropsychological evaluation after treatment for a primary brain tumor in the third ventricular region. Twenty-six patients underwent surgery, 14 via the transcallosal approach and 12 via a subfrontal, left transcortical, right pterional, or infratentorial supracerebellar approach. Seven patients were not treated by surgical intervention.
There was a significantly elevated frequency of cognitive impairment relative to normative values in memory, executive functioning, and fine manual speed and dexterity. There were no differences in mean neuropsychological scores between patients who underwent surgery and those who did not. There were no differences in mean performance on the basis of surgical approach, tumor infiltration, or history of cranial irradiation. Repeated measures data available for two patients revealed memory impairment before and after surgery, and one patient experienced major improvement after surgery on a measure of mental flexibility and problem solving.
Patients with third ventricle tumors are at risk for developing impairments in memory, executive function, and fine manual speed and dexterity, which are domains associated with frontal subcortical functions. In the current study, different types of treatment were not associated with differential cognitive sequelae, and surgical intervention did not account for cognitive deficits.
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