Abstract 006: Dysarthria as a Prelude: Capecitabine and Oxaliplatin therapy heralding as Transient Ischemic Attack

Neuropathies associated with oxaliplatin therapy

The phase III ACHIEVE trial conducted in Japan was one of six prospective studies included in the International Duration Evaluation of Adjuvant Therapy collaboration, which explored whether 3 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) therapy would be noninferior to 6 months of treatment in patients with curatively resected stage III colon cancer. We report the final analyses of survival and long-term safety. Eligible patients were randomly assigned (1:1) to either 3 or 6 months of adjuvant chemotherapy (modified [m]FOLFOX6 or CAPOX, as selected by the treating physician). Random assignment was stratified according to number of involved lymph nodes, center, regimen, primary site, and age. The primary end point was disease-free survival, assessed in the modified intention-to-treat population. Overall survival (OS) was a secondary end point. The modified intention-to-treat population comprised 1,291 patients: 641 in the 6-month treatment group and 650 in the 3-month treatment group. Median follow-up for this analysis was 74.7 months. Five-year OS rates were comparable: 87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group (hazard ratio, 0.91; 95% CI, 0.69 to 1.20; P = .51). Subgroup analysis of OS did not reveal a significant interaction between baseline characteristics and treatment duration. Peripheral sensory neuropathy lasting longer than 5 years was more common in the 6- compared with 3-month treatment group (16% v 8%, respectively), and in those receiving mFOLFOX6 compared with CAPOX (14% v 11%, respectively). In Asian patients, shortening adjuvant therapy duration from 6 to 3 months did not compromise efficacy and reduced the rate of long-lasting peripheral sensory neuropathy. In this setting, 3 months of CAPOX therapy is an appropriate adjuvant treatment option.

Past studies have suggested that adjuvant capecitabine and oxaliplatin (CAPOX) provides decreased tumor relapse and longer survival in patients with curatively resected colon cancer. We report the first evidence of the feasibility of adjuvant CAPOX in Japanese patients with early colon cancer. Eligible patients had histologically-confirmed stage II/III colon cancer and received curative resection. The primary endpoint was completion rate of treatment after 8 cycles of adjuvant CAPOX. Thirty-six patients were enrolled in this study. The completion rate of CAPOX and oxaliplatin were 77.8% and 61.1%, respectively. The incidence of grade ≥3 adverse events was neutropenia (n=6), thrombocytopenia (n=3), nausea (n=5), hand-foot syndrome (n=1) and peripheral sensory neuropathy (n=1). Three-year disease-free survival for stage II patients and stage III patients were 100% and 79.3%, respectively. Adjuvant CAPOX can be safely administered to Japanese patients with stage II/III colon cancer.

A number of large-scale clinical trials have demonstrated that using a combination of oxaliplatin and fluoropyrimidines as an adjuvant chemotherapy for stage II/III colon cancer improved the prognosis. However, there has only been experience in Japanese patients with using CapOX therapy, in which capecitabine and oxaliplatin are used in combination. Therefore, our objective was to evaluate the efficacy and safety of CapOX in Japanese patients as an adjuvant chemotherapy for colon cancer in a single institute retrospective study. The efficacy and safety of CapOX as an adjuvant chemotherapy for patients with stage III colon cancer and stage II patients who had a signature for high risk of recurrence were evaluated in patients who had undergone surgery at our institution between December 1, 2009 and March 31, 2013. Forty-one patients received CapOX therapy during the study period: 23 men and 18 women with median age of 68.0 years (35–79 years). Performance status was 0 for 33 patients, and PS 1 for eight patients. The clinical stages were stage II in 14 patients, stage IIIA in 15 patients, and stage IIIB in 12 patients. The median number of CapOX cycles was eight (two to eight courses). The treatment completion rate was 82.9%. Five-year DFS rates were 63.8%. Five-year OS rates were 71.0%. In terms of adverse events, the serious adverse events of grade 3 or higher seen among all patients were neutropenia in four patients, thrombocytopenia in one patient, and peripheral sensory neuropathy in seven patients. However, hand–foot syndrome, which is characteristic of capecitabine, was not observed. Efficacy and tolerability of CapOX in Japanese patients as an adjuvant chemotherapy after colon cancer surgery was demonstrated.

Adjuvant capecitabine and oxaliplatin (CAPOX) therapy is standard strategy for colorectal cancer with risk of recurrence. Early dose reduction (EDR) of CAPOX therapy is commonly used in real-world practice. However, there is limited evidence regarding the effectiveness of CAPOX for patients who had EDR. Therefore, this study aimed to clarify the risks of EDR and its effect on long-term outcomes and body composition factors. Patients who received CAPOX therapy after radical surgery for colorectal cancer between June 2013 and December 2021 were included. EDR was defined as dose reduction within four courses of CAPOX therapy. Body composition factors were measured for 1 year following surgery to determine the EDR effects. Eighty-four patients were included; 35 (42%) of them had EDR. The multivariate analysis revealed that underweight [odds ratio (OR)=4.95, 95% confidence interval (CI)=1.13-21.7, p=0.03] was a risk factor for EDR. Relapse-free survival (RFS) was significantly better in the non-EDR group (p=0.01). The 5-year RFS rates for the non-EDR and EDR groups were 88.7% and 65.4%, respectively. The multivariate analysis revealed that age >65 years [hazard ratio (HR)=3.97; 95% CI=1.16-13.62, p=0.03] and EDR (HR=7.62; 95% CI=1.71-33.91, p=0.005) were associated with poorer RFS. The 1-year body composition analysis revealed decreases in all factors in the EDR group. Preoperative underweight status was associated with EDR, which resulted in decreased RFS and body composition factors when compared with the non-EDR group. Therefore, avoiding EDR and early nutritional intervention after EDR may improve outcomes.

Posterior reversible encephalopathy syndrome (PRES) can cause short-term cerebrovascular complications, such as brain infarction and hemorrhage. We hypothesized that PRES is also associated with an increased long-term risk of stroke. We performed a retrospective cohort study in the United States using statewide all-payer claims data from 2016 to 2018 on all admissions to nonfederal hospitals in 11 states. Adults with PRES were compared with adults with renal colic (negative control) and transient ischemic attack (TIA; positive control). Any stroke and the secondary outcomes of ischemic and hemorrhagic stroke were ascertained using International Classification of Diseases, Tenth Revision, Clinical Modification codes. We excluded prevalent stroke. We used time-to-event statistics to calculate incidence rates and Cox proportional hazards analyses to evaluate the association between PRES and stroke, adjusting for demographics and stroke risk factors. In a sensitivity analysis, outcomes within 2 weeks of index admission were excluded. We identified 1606 patients with PRES, 1192 with renal colic, and 38 216 with TIA. Patients with PRES had a mean age of 56±17 years; 72% were women. Over a median follow-up of 0.9 years, the stroke incidence per 100 person-years was 6.1 (95% CI, 5.0-7.4) after PRES, 1.0 (95% CI, 0.62-1.8) after renal colic, and 9.7 (95% CI, 9.4-10.0) after TIA. After statistical adjustment for patient characteristics and risk factors, patients with PRES had an elevated risk of stroke compared with renal colic (hazard ratio [HR], 2.3 [95% CI, 1.7-3.0]), but lower risk than patients with TIA (HR, 0.67 [95% CI, 0.54-0.82]). In secondary analyses, compared with TIA, PRES was associated with hemorrhagic stroke (HR, 2.0 [95% CI, 1.4-2.9]). PRES was associated with ischemic stroke when compared with renal colic (HR, 1.9 [95% CI, 1.4-2.7]) but not when compared with TIA (HR, 0.49 [95% CI, 0.38-0.63]). Results were similar with 2-week washout. Patients with PRES had an elevated risk of incident stroke.

BackgroundSix months of oxaliplatin-based chemotherapy is the standard adjuvant chemotherapy for completely resected stage III colorectal cancer (CRC). Also, patients with stage II CRC who are considered to be at high risk of disease recurrence often receive the same adjuvant chemotherapy treatment. We prospectively investigated the extent and degree of neuropathy suffered by stage III and high-risk stage II resectable CRC patients who underwent sequential approach involving 3 months of an oxaliplatin-based regimen followed by 3 months of capecitabine.Patients and methodsPatients with completely resected stage III and high-risk stage II CRC aged ≥20 years were eligible. Patients were treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) for 3 months followed by capecitabine (2,500 mg/m2 on days 1–14 every 3 weeks) for 3 months. Primary end points were frequency and the grade of oxaliplatin-induced neurotoxicity as evaluated using the physician-based Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) grading and the patient-based scale, self-reported Patient Neurotoxicity Questionnaire.ResultsNinety-one patients were enrolled and 86 patients assessed. Eighty-four percent of patients completed the planned oxaliplatin-based therapy for 3 months, and 63% of patients completed all treatments for the full 6 months. Overall incidences of grade 3 or 4 peripheral sensory or motor neuropathy according to the CTCAE were 3.5% and 1.2%, respectively. Regarding the peripheral sensory neuropathy, the proportion of Patient Neurotoxicity Questionnaire (grade C–E) and CTCAE (grade 2–4) at months 1.5/3/6 were 11.3/22.1/29.4% and 5.3/4.4/11.3%, respectively (Spearman correlation coefficient: 0.47).ConclusionA sequential approach to adjuvant chemotherapy with 3 months of an oxaliplatin-based regimen followed by 3 months of capecitabine was tolerated by patients and associated with a low incidence of neuropathy.

Microvascular brain injury is well recognized in neuropsychiatric systemic lupus erythematosus (SLE), but cerebral large artery involvement is being debated. Three females with SLE, aged 9 to 14years, had immunosuppressive treatment intensification because of lupus nephritis. Within the following days or weeks, they presented with intense cephalalgia - isolated or associated with neurological symptoms - and no or mild hypertension. Magnetic resonance angiography showed multiple stenoses within the circle of Willis. One patient had subsequent small subcortical cerebral infarction. Two patients were treated for neuropsychiatric SLE; one patient was treated for reversible cerebral vasoconstriction syndrome (RCVS). Angiography normalized within a few weeks in all three patients. Retrospectively, clinical and radiological features suggest that RCVS was the most likely diagnosis in all patients. Multidisciplinary analysis of clinical and angiographic features is recommended, as RCVS is rare in children and its recognition may help to adjust treatment. WHAT THIS PAPER ADDS: Reversible vasoconstriction syndrome was observed in paediatric systemic lupus erythematosus. Thorough imaging analysis was necessary to address this diagnosis in paediatric patients.

An acutely confused young woman

Risk factors in AION

Posterior reversible encephalopathy syndrome (PRES) is a rare neurologic disorder that presents with variable symptoms and symmetrical abnormal white matter signaling most commonly of the occipital and parietal lobes on magnetic resonance imaging (MRI). PRES, also known as reversible posterior leukoencephalopathy syndrome (RPLS) is commonly associated with hypertension. Hypomagnesemia's association with PRES has been rarely reported. Here, we report a patient with severe hypomagnesemia that presented with PRES syndrome that improved with magnesium replacement. Hypomagnesemia should be considered an underlying etiology in patients presenting with PRES syndrome and should be promptly treated. The presentation can often be concerning for acute cerebrovascular accidents with symptoms of dysarthriaand upper motor neuron symptoms, such as facial droop, dysarthria, and gait instability. Differential diagnosis of PRES often includes rostral brainstem infarction, transient ischemic attack, infectious encephalopathy, and metabolic/toxic encephalopathy, which is evaluated in the description of the case.The most common presentation of RPLS/PRES includes altered mental status, drowsiness, seizure, vomiting, alterations in speech including dysarthria, and visual disturbance. The first signs noted are commonly lethargy and somnolence. In this case, the patient presented notably with initial symptoms of dysarthria of speech and facial droop, with serum hypomagnesemia in which symptoms corrected rapidly with the administration of intravenous magnesium sulfate.

Cerebral infarction and prolonged regional hypoperfusion have been described in patients with transient ischemic attacks (TIAs). The aim of this study was to compare the sensitivity of single-photon emission CT (SPECT) with that of brain CT and to evaluate the clinical significance of differentiation of TIA patients with or without focal hypoperfusion. From a hospital-based population, we studied the SPECT and CT findings in 76 consecutive patients, without a stroke history, who presented with TIA in the carotid artery territory. The recorded variables were the time of SPECT, imaging (<36 or > or = 36 hours), clinical presentation, history of previous TIA(s), duration of the presenting attack (<2 or > or = 2 hours), vascular risk factors, and etiology. We used both visual and semiquantitative analyses for the SPECT evaluation. Acetazolamide challenge was not performed. The overall SPECT sensitivity was 36% (27/76). When brain CT and SPECT were performed in the same patients, the SPECT sensitivity was significantly higher than that of CT (19/59 [32%] versus 8/59 [14%]; P=.007). The SPECT sensitivity was not dependent on the time of investigation, duration of attacks, history of TIA(s), or the clinical presentation. The vascular risk and etiologic factors were not significantly different between the patients with or without prolonged focal hypoperfusion. Logistic regression did not identify any variable to discriminate the two groups. Despite its better sensitivity compared with CT, SPECT performed without the acetazolamide test provides no additional clinically useful information on the vascular risk factors and etiology in TIA patients.

Background: Posterior reversible encephalopathy syndrome (PRES), also called the acute hypertensive encephalopathy and reversible leukoencephalopathy syndrome (RPLS), is a clinico-radiological syndrome presents with rapid onset of headache, seizures, loss of consciousness, visual loss and characterized by white matter vasogenic edema affecting parietal and occipital lobes of the brain predominantly. However, the imaging findings are variable and may occur in other locations such as the frontal lobes, thalami, basal ganglia and brainstem. Objective: To study the clinical, imaging spectrum and final disease outcome of PRES Materials And Methods: The study was conducted on 52 patients who presented with clinical features and radiological diagnosis of PRES The clinical, imaging features and outcome of each patient were analyzed Results: The study was conducted on 52 patients with age range from below 10yrs to 65 yrs. Patients presented with various symptoms of which seizures(84.6%) is most common followed by headache(59.6%), vomiting (36.5%), visual disturbances(32.7%), altered sensorium(15.3%), thalamic aphasia (5.7%), hemiparesis(3.8%), paresthesia(3.8%), ataxia(3.8%), Quadriparesis (3.8%) and facial numbness (1.9%) is the least. On MR imaging typical parieto-occipital lobe involvement(98%)is seen in most of the cases, however other atypical regions involved were frontal lobe(52%),temporal lobe (17.3%), cerebellum (27%),thalamus (15.3%), brainstem (13.4%), basal ganglia (9.6%) and corpus callosum (1.9%) Lesions in atypical locations also had lesions in typical locations in all cases except in one case of central PRES. Dominant parieto-occipital pattern was seen in 32%,superior frontal sulcus pattern in 27%,holohemispheric pattern in 34.6%,Partial or asymmetric expression of primary patterns in 5.2% cases Diffusion restriction and postcontrast enhancement was seen in less than 25% cases. Complete resolution of symptoms was seen in 90.5% cases,3.8% of them succumbed to death. On follow up 5.7% of cases showed persistence of symptoms. Conclusion: PRES is a clinico-radiological syndrome with varied clinical and imaging spectrum. Involvement of atypical regions is not uncommon. However lesions in atypical locations often have lesions in typical locations also.Atypical imaging features like restricted diffusion and contrast enhancement are also not uncommon. Knowledge of atypical lesion location, atypical imaging features is necessary for the clinicians and radiologists not to misdiagnose PRES in the appropriate clinical setting

Cardiorespiratory Fitness after Transient Ischemic Attack and Minor Ischemic Stroke: Baseline Data of the MoveIT Study

Sir, In their recent article, published in Frontiers in Neurology, Mullen et al. (2012) demonstrated that anti-phosphatidylserine/prothrombin (PS/PT) antibodies are independently associated with stroke or death in non-antiphospholipid syndrome (APS) patients with transient ischemic attacks (TIA). Despite thorough statistics, the authors mention that these findings should be cautiously interpreted, since only two patients had positive IgG anti-PS/PT antibodies and a clinical event. We have recently assessed the influence of this antiphospholipid antibody (aPL) specificity in the clinical phenotype of systemic lupus erythematosus (SLE) patients. In this regard, we evaluated 35 lupus patients (33 females/2 males, mean age 37.5 ± 8.8 years, mean disease duration 103.8 ± 55.1 months) and one female non-lupus patient (33 years old), according to a previous history of thrombotic complications (arterial and/or venous thrombosis, spontaneous abortions) and other aPL-related manifestations, such as thrombocytopenia and livedo reticularis. Anti-PS/PT antibodies were measured, shortly after the clinical event, by ELISA (AESKULISA, Serin Prothrombin GM, REF 3226). Other aPL specificities, such as anticardiolipin antibodies (ACA), anti-b2GPI antibodies, and lupus anticoagulant (LA) were also assessed. Positive anti-PS/PT antibodies (>18 U/ml) were detected in 11/35 patients (31.4%), 7 with IgG anti-PS/PT, 1 with IgM anti-PS/PT, and 3 with concomitant IgM and IgG anti-PS/PT. From these patients, seven had a recent history of vascular thrombosis, while the remaining four had other aPL-related symptoms and end-stage renal disease (1/11), recurrent serositis (2/11), and false positive serological reactions for syphilis (1/11) respectively. It should be mentioned that these four patients had the lower titers of anti-PS/PT antibodies (marginally positive). Ten out of 11 patients were simultaneously positive for other aPL, such as ACA and anti-b2GPI antibodies. All patients with thrombosis were premenopausal women and had central nervous system involvement (4/7 multiple infarcts, 1/7 psychosis, 1/7 seizures, and 1/7 posterior reversible leukoencephalopathy syndrome, PRES). Of note, the three latter patients had no visible infarcts in brain MRI but detectable cerebral flow abnormalities in single-photon emission computed tomography (SPECT). None of these patients had traditional atherosclerotic risk factors. High titers of anti-PS/PT antibodies (IgM and IgG) were also detected in the sole non-lupus patient in three separate cases. This patient manifested cerebrovascular disease (multiple infarcts), in the absence of atherosclerotic risk factors and other aPL. In this case a diagnosis of APS was made, based in the presence of these antibodies. These findings come in agreement with previous reports demonstrating that the anti-PS/PT antibodies are strongly related to venous and/or arterial thrombotic manifestations in SLE patients and, particularly, cerebral infarctions (Nojima et al., 2006; Nojima et al., 2004). On a pathophysiologic basis, a possible synergistic action of the anti-PS/PT, ACA, and anti-b2GPI antibodies in the induction of ADP-mediated platelet aggregation has been proposed (Nojima et al., 2004). In accordance with these results, Syuto et al. (2009) showed that these antibodies are more frequently (and in higher titers) detected in patients with neuropsychiatric SLE in general. Our results, although restricted in SLE, confirm the findings of Mullen et al. (2012) that anti-PS/PT antibodies may serve as a surrogate marker for unfavorable outcome in TIA and may represent a subsequent stage in disease evolution in lupus patients. Given that, in many patients, TIA may not become clinically apparent, it could be hypothesized that anti-PS/PT antibodies (present in a lupus patient with quiescent TIA) may lead, over time, to multiple infarcts or to subclinical cerebral flow disturbances, which can predispose to the development of other neuropsychiatric SLE features. The authors also underline that it is difficult to determine if the mechanism behind anti-PS/PT antibodies and cerebrovascular events is primarily thrombotic or atherosclerotic. In our study, where all patients were premenopausal women and had no traditional atherosclerotic risk factors, it could be assumed that thrombosis, rather than atherosclerosis, represents the main pathophysiologic mechanism. In conclusion, anti-PS/PT antibodies seem to be strongly related to ischemic/thrombotic cerebrovascular events. Evaluation of their predictive ability and stratification of patients with TIA, in large scale prospective studies, is warranted.