Prediction of epilepsy after stroke: Proposal of a modified SeLECT 2.0 score based on posttreatment stroke outcome.

OBJECTIVE: The SeLECT 2.0 score is a prognostic model of epilepsy after ischemic stroke. We explored whether replacing the severity of stroke at admission with the severity of stroke after treatment at 72 h from onset could improve the predictive accuracy of the score. METHODS: We retrospectively identified consecutive adults with acute first-ever neuroimaging-confirmed ischemic stroke who were admitted to the Stroke Unit of the Ospedale Civile Baggiovara (Modena, Italy) and treated with intravenous thrombolysis and/or endovascular treatment. Study outcome was the occurrence of at least one unprovoked seizure presenting >7 days after stroke. RESULTS: Participants included in the analysis numbered 1094. The median age of the subjects was 74 (interquartile range [IQR] = 64-81) years, and 595 (54.4%) were males. Sixty-five (5.9%) subjects developed unprovoked seizures a median of 10 (IQR = 6-27) months after stroke. The median values of the original and modified SeLECT2.0 scores were 3 (IQR = 2-4) and 2 (IQR = 1-3). The modified SeLECT 2.0 score showed better discrimination for the prediction of poststroke epilepsy at 36, 48, and 60 months after stroke compared to the original score according to the area under time-dependent receiver operating characteristic curves. The modified SeLECT 2.0 score had higher values of Harrell C and Somers D parameters and lower values of Akaike and Bayesian information criteria than the original score. The modified SeLECT 2.0 score produced more accurate risk predictions compared to the SeLECT 2.0 score at all evaluated time points from 12 to 60 months after stroke according to the Net Reclassification Index. SIGNIFICANCE: Replacing baseline with posttreatment stroke severity may improve the ability of the SeLECT 2.0 score to predict poststroke epilepsy.

Futile recanalization is associated with increased risk of post-stroke epilepsy.

BACKGROUND: Endovascular treatment (EVT) is the standard of care of ischaemic stroke due to occlusion of large vessels. Although EVT can significantly improve short- and long-term outcomes, functional dependence can persist despite the achievement of a successful recanalization. The evidence about the predictors of post-stroke epilepsy (PSE) in patients with stroke treated by EVT is limited. We aimed to evaluate the relationship between futile recanalization and the risk of PSE. METHODS: We retrospectively identified consecutive adults with first-ever ischaemic stroke of anterior circulation who were treated with EVT. Futile recanalization was defined as poor 3-month functional status (modified Rankin scale score ≥ 3) despite complete or near-complete recanalization. Study outcome was the occurrence of PSE during the follow-up. RESULTS: The study included 327 patients with anterior circulation ischaemic stroke treated with EVT. Futile recanalization occurred in 116 (35.5%) patients and 26 (8.0%) developed PSE during a median follow-up of 35 [interquartile range, 22.7-55.2] months. Futile recanalization was more common among patients who developed PSE compared to those who did not (76.9% versus 31.9%; p < 0.001). Futile recanalization [hazard ratio (HR) = 5.63, 95% confidence interval (CI): 1.88-16.84; p = 0.002], large artery atherosclerosis (HR = 3.48, 95% CI: 1.44-8.40; p = 0.006), cortical involvement (HR = 15.51, 95% CI: 2.06-116.98; p = 0.008), and acute symptomatic status epilepticus (HR = 14.40, 95% CI: 2.80-73.98; p = 0.001) increased the risk of PSE. CONCLUSIONS: Futile recanalization after EVT is associated with increased risk of PSE in patients with ischaemic stroke due to occlusion of large vessel of the anterior circulation.

Fibrinogen Depletion Coagulopathy Predicts Major Bleeding After Thrombolysis for Ischemic Stroke: A Multicenter Study.

BACKGROUND: Symptomatic intracerebral hemorrhage (sICH) and major bleeding can be fatal complications of intravenous thrombolysis (IVT) for acute ischemic stroke. We investigated the impact of early fibrinogen depletion after IVT on major bleeding events. METHODS: This multicenter observational prospective cohort study enrolled 1678 consecutive patients receiving IVT for acute ischemic stroke at 6 Italian centers, undergoing fibrinogen concentration assessment at baseline, 2 hours and 6 hours after IVT. Fibrinogen depletion was defined as a reduction below 200 mg/dL after 2 hours from IVT, or as a reduction below 50% of baseline fibrinogen levels after 2 hours from IVT. Main outcomes were (1) sICH (National Institute of Neurological Disorders and Stroke criteria) and (2) major bleeding defined as fatal bleeding, decrease in the hemoglobin level>2 g/dL/>1 unit transfusion, or bleeding at critical site. Additional outcomes were (1) any ICH, (2) any bleeding, (3) fatal ICH, and (4) sICH according to ECASSII definition. Good functional recovery was defined as modified Rankin Scale score 0 to 2 at 3 months. RESULTS: Overall, 1678 patients were included (mean age 72 years, 46% female). sICH (n=116) and major bleeding (n=297) were associated with lower rate of good functional recovery (P<0.001). Despite similar fibrinogen levels at admission, fibrinogen depletion after 2 hours from IVT was more common in people with sICH, major bleeding and all additional bleeding outcomes. In the backward stepwise multivariable logistic regression model, fibrinogen depletion remained a significant predictor of sICH (OR, 1.55 [95% CI, 1.04-2.32]) and major bleeding (OR, 1.36 [95% CI, 1.03-1.8]). Thirty-one percent of sICH could be attributable to fibrinogen depletion. The association between fibrinogen depletion and worse clinical outcome at 3 months after stroke (P=0.012) was attributable to the higher risk of major bleeding/sICH. CONCLUSIONS: Fibrinogen depletion significantly increases the risk of sICH and major bleeding after IVT for acute ischemic stroke. Fibrinogen depletion represents an independent risk factor for bleeding, and routine assessment could be considered to stratify the risk of ICH. Trials on early fibrinogen repletion are needed to investigate mitigation of bleeding risk.

In-hospital and out-of-hospital stroke in patients with COVID-19: two different diseases?

BACKGROUND: Ischemic stroke is a known complication of COVID-19. It may have a different pathogenesis and worse outcome compared to stroke in patients without COVID-19. Furthermore, patients with COVID-19 and out-of-hospital stroke onset might have different characteristics compared to patients with COVID-19 and in-hospital stroke onset. The aim of our study was to analyze the characteristics of patients with stroke with and without COVID-19 and of patients with COVID-19 with in-hospital and out-of-hospital stroke. METHODS: We performed a retrospective study of all consecutive patients admitted to our hospital with ischemic stroke between October 2020 and February 2021. We compared functional outcome, lab test, demographic, and clinical characteristics between patients with or without COVID-19. We performed a sub-analysis comparing patients with COVID-19 and in-hospital and out-of-hospital stroke onset. RESULTS: We included in the final analysis 137 patients of whom 26 with COVID-19. Half (13) had out-of-hospital stroke and half in-hospital stroke onset. Overall, patients with COVID-19 had higher mortality compared to the control group (27% vs 9%, p: 0.02), and non-significantly lower rate of good functional outcome (50% vs 63%, p: 0.22). Patients with COVID-19 and out-of-hospital stroke had higher rate of good functional outcome (69% vs 39%, p: 0.05), higher lymphocyte count, and lower D-dimer compared with patients with in-hospital stroke onset. CONCLUSIONS: Patients with stroke and COVID-19 had higher mortality compared to patients without COVID-19. Among patients with COVID-19 those with out-of-hospital stroke had better outcome and fewer blood test abnormalities compared to patients with in-hospital stroke.

Platelet Function Monitoring Performed after Carotid Stenting during Endovascular Stroke Treatment Predicts Outcome.

OBJECTIVES: Many studies showed that platelet reactivity testing can predict ischemic events after carotid stenting or ischemic stroke. The aim of our study was to assess the role of early platelet function monitoring in predicting 90-days functional outcome, stent thrombosis and hemorrhagic transformation in patients with ischemic stroke treated with endovascular procedures requiring emergent extracranial stenting. MATERIALS AND METHODS: We performed a retrospective study on consecutive patients with acute anterior circulation stroke admitted to our hospital between January 2015 and March 2020, in whom platelet reactivity testing was performed within 10 days from stenting. Patients were divided according to validated cutoffs in acetylsalicylic acid and Clopidogrel responders and not responders. Group comparison and regression analyses were performed to identify differences between groups and outcome predictors. RESULTS: We included in the final analysis 54 patients. Acetylsalicylic acid resistance was an independent predictor of poor 90 days outcome (OR for modified Rankin scale (mRS) ≤ 2: 0.10 95% CI: 0.02 - 0.69) whereas Clopidogrel resistance was an independent predictor of good outcome (OR for mRS ≤ 2: 7.09 95%CI: 1.33 - 37.72). Acetylsalicylic acid resistance was also associated with increased 90-days mortality (OR: 18.42; 95% CI: 1.67 - 203.14). CONCLUSION: We found a significant association between resistance to acetylsalicylic acid and poor 90-days functional outcome and between resistance to Clopidogrel and good 90-days functional outcome. If confirmed, our results might improve pharmacological management after acute carotid stenting.

Effect of haemoglobin levels on outcome in intravenous thrombolysis-treated stroke patients.

INTRODUCTION: Alterations in haemoglobin levels are frequent in stroke patients. The prognostic meaning of anaemia and polyglobulia on outcomes in patients treated with intravenous thrombolysis is ambiguous. PATIENTS AND METHODS: In this prospective multicentre, intravenous thrombolysis register-based study, we compared haemoglobin levels on hospital admission with three-month poor outcome (modified Rankin Scale 3-6), mortality and symptomatic intracranial haemorrhage (European Cooperative Acute Stroke Study II-criteria (ECASS-II-criteria)). Haemoglobin level was used as continuous and categorical variable distinguishing anaemia (female: <12 g/dl; male: <13 g/dl) and polyglobulia (female: >15.5 g/dl; male: >17 g/dl). Anaemia was subdivided into mild and moderate/severe (female/male: <11 g/dl). Normal haemoglobin level (female: 12.0-15.5 g/dl, male: 13.0-17.0 g/dl) served as reference group. Unadjusted and adjusted odds ratios with 95% confidence intervals were calculated with logistic regression models. RESULTS: Among 6866 intravenous thrombolysis-treated stroke patients, 5448 (79.3%) had normal haemoglobin level, 1232 (17.9%) anaemia - of those 903 (13.2%) had mild and 329 (4.8%) moderate/severe anaemia - and 186 (2.7%) polyglobulia. Anaemia was associated with poor outcome (ORadjusted 1.25 (1.05-1.48)) and mortality (ORadjusted 1.58 (1.27-1.95)). In anaemia subgroups, both mild and moderate/severe anaemia independently predicted poor outcome (ORadjusted 1.29 (1.07-1.55) and 1.48 (1.09-2.02)) and mortality (ORadjusted 1.45 (1.15-1.84) and ORadjusted 2.00 (1.46-2.75)). Each haemoglobin level decrease by 1 g/dl independently increased the risk of poor outcome (ORadjusted 1.07 (1.02-1.11)) and mortality (ORadjusted 1.08 (1.02-1.15)). Anaemia was not associated with occurrence of symptomatic intracranial haemorrhage. Polyglobulia did not change any outcome. DISCUSSION: The more severe the anaemia, the higher the probability of poor outcome and death. Severe anaemia might be a target for interventions in hyperacute stroke. CONCLUSION: Anaemia on admission, but not polyglobulia, is a strong and independent predictor of poor outcome and mortality in intravenous thrombolysis-treated stroke patients.

Clinical features of colorectal cancer patients in advanced age: a population-based approach.

In the immediate future, the number of geriatric patients will continue to rise; consequently we should expect an increase of colorectal cancer, a disease of the elderly population. Through the data of a Cancer Registry, we examined (a) the effect of ageing on the main features of colorectal cancer; (b) changes in management, especially for individuals older than 80 years; and (c) changes in prognosis and survival in subgroups of patients with different age. The Registry provided information on colorectal cancer up to 2010 (27 years). A total of 5293 patients were registered; these were divided into three groups: A (0-64 years), B (65-79) and C (80 or more). Three periods of observation were chosen: 1 (1984-1992), 2 (1993-2001) and 3 (2001-2010). Group A included 1571 patients (29 %), Group B 2539 (48 %) and Group C 1183 (22.3 %). The fraction of old individuals increased during the 27 years of the investigation. In these patients, tumours were predominantly localized to the right colon (42.6 %). The rate of surgery and ratio between curative and palliative approaches were similar among the three groups (p < 0.38). There was disparity (p < 0.002) in the administration of chemotherapy (5.8 % of the elderly vs 34.4 % in remaining patients). Survival increased over time in all three groups. In the elderly, average 5-year survival was 31 % in period 1 and 55 % in period 3. These data show that in Western countries, the standard of care for colorectal cancer diagnosed in geriatric patients has improved over the last 30 years.

Incidence, clinical features and possible etiology of early onset (≤40 years) colorectal neoplasms.

The aim of the study was to investigate the clinical features, including survival, of patients with colorectal malignancies developed at a very early age (≤40 years), together with possible factors involved in the pathogenesis of these rare neoplasms. The study took advantage of the existence of a specialized colorectal cancer Registry active from 1984. 57 patients met the criteria of early onset cancer; main epidemiological data, morphology, stage, familial aggregation, possible role of inheritance and survival were analyzed. Despite the relevant increase over time of all registered patients, joiningpoint analysis of crude incidence rate of early onset colorectal neoplasms revealed a certain stability of these tumors (EAPC: 2.4, CI 14-22) with a constant prevalence of the male sex. Stage at diagnosis did not show significant variations between early onset and maturity onset colorectal neoplasms. Hereditary as well as familial cases were significantly (P < 0.005 and 0.03) more frequent among patients with early onset tumors, although in the majority of them no specific etiological factor could be identified. Survival was more favorable in patients with early onset tumors, though this had to be attributed to the higher presence of some histological types in early onset cases. Survival was significantly more favorable for patients of all ages registered in the last decade. Incidence of early onset colorectal cancer was relatively stable between 1984 and 2008. A male preponderance was evident through the registration period. Hereditary and familial cases were significantly more frequent among early onset case. A well defined etiology could be observed in 16% of the cases (versus 2-3% in older individuals). Five-year survival showed a significant improvement over time.

Disease presentation, treatment and survival for Italian colorectal cancer patients: a EUROCARE high resolution study.

We analysed presentation, treatment and survival in a representative population-based sample of 3753 Italian colorectal cancer cases, diagnosed 2003-05: 70% were >65 years, 44% stage I-II, 27% stage IV and 92% received surgery. Chemotherapy was given to 58% of stage III colon cases, radiotherapy to 25% of rectal cases. Four percent of surgical cases underwent endoscopic polypectomy, and in 57% ≥11 lymph nodes were examined. Five-year relative survival was good (60%), independent of sex and site. Adherence to treatment guidelines was satisfactory, but wider use of faecal blood testing and colonoscopy will anticipate stage at diagnosis and likely improve survival.

Altered expression of apoptosis biomarkers in human colorectal microadenomas.

Human colorectal microadenomas are considered the earliest detectable premalignant lesions in the colon. They can be identified as aggregates of enlarged crypts with thicker epithelial linings and elongated luminal openings on the colonic mucosal surface after methylene blue staining and observation under a dissecting microscope. Multiple lines of evidence suggest that a central role in neoplastic development is played by the inhibition of apoptosis, followed by disruption of DNA repair. Understanding the early mechanisms of colorectal carcinogenesis may help develop new approaches of colorectal cancer prevention and treatment. The aim of the present study was to quantify poly-ADP ribose polymerase 1 (PARP-1)-positive cells and to evaluate apoptotic control mechanisms through Caspase-3 active and Bcl-2 protein expression in human microadenomas and in normal colorectal mucosa using immunofluorescence techniques coupled with confocal microscopy and immunoblot experiments. The mean percentage of PARP-1-positive epithelial cells was 3.0 +/- 0.37% (SD) and 15.67 +/- 0.40% in microadenoma and in normal mucosa, respectively. Proteins involved in programmed cell death were differently expressed in microadenoma and in normal mucosa. Indeed, by semiquantitative immunofluorescence analysis, confirmed by Western blot, microadenoma showed low levels of Caspase-3 active and high levels of Bcl-2 expression, whereas the opposite was true for normal colorectal mucosa [corrected]. In the stroma of normal colorectal mucosa, fibroblast-like cells and neutrophils were the cells that underwent apoptosis to a greater extent. In conclusion, malfunction of the control mechanisms of programmed cell death seems present in the early stages of colorectal cancer development.

Relative role of APC and MUTYH mutations in the pathogenesis of familial adenomatous polyposis.

OBJECTIVE: Familial adenomatous polyposis (FAP) is an interesting model for the study of colorectal tumour. Two genes contribute to the FAP phenotype - APC and MUTYH - but their relative role is still undefined. The objective of this study was to evaluate the contribution of the two genes to the pathogenesis of FAP by means of a series of FAP families. MATERIAL AND METHODS: Sixty-one unrelated families with a diagnosis of FAP and a total of 187 affected individuals were evaluated. After extracting DNA, APC and MUTYH genes were sequenced. RESULTS: In the whole series of patients, colectomy with ileorectal anastomosis was the most frequent surgery, although the number of patients treated by total proctocolectomy and ileoanal anastomosis was increasing. Duodenal and jejunal-ileal adenomas were present in more than half of the patients. Constitutional mutations were detected in 37 of the 45 families (82.2%); there were 33 families with APC and 4 with MUTYH alterations. Age at onset of polyposis and age at surgery were 10-15 years delayed for carriers of MUTYH mutations; cancer at diagnosis was frequent, and extracolonic manifestations were diagnosed in the majority of MUTYH-positive families. MUTYH-associated polyposis showed the horizontal transmission expected for recessive inheritance (at variance with the dominant pattern seen with APC mutations). CONCLUSIONS: At least two genes are associated with the FAP phenotype. APC mutations account for the majority of cases, while MUTYH mutations can be observed in 10% of patients. There are few but definite differences between APC- and MUTYH-associated FAP, such as age at diagnosis and pattern of transmission.

BRAF mutations in multiple sebaceous hyperplasias of patients belonging to MYH-associated polyposis pedigrees.

The characteristics of sebaceous gland hyperplasia (SGH) consist of yellowish or skin-colored papules and nodules. Chronic sun exposure and immunosuppressed conditions are the main environmental risk factors, whereas chronological aging regulated by hormones and molecular changes are the intrinsic risk factors. We have evaluated the contribution of BRAF, K-Ras, and N-Ras mutations to the pathogenesis of SGHs in four patients belonging to three MYH-associated polyposis (MAP) pedigrees. MAP is an autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. Immunohistochemistry of mismatch repair and APC proteins was performed. DNA isolated from blood lymphocytes and formalin-fixed or paraffin-embedded SGHs was PCR amplified and sequenced. In the SGH patients, we detected T1796A heterozygous substitution (V600E) in the BRAF gene. Compound biallelic germline MYH mutations (Y165C/G382D, R168H/379delC, and Y90X/delGGA464) were detected in the MAP patients. In contrast to the majority of melanocytic lesions, activating hotspot mutations in BRAF have not been involved so far in the pathogenesis of SGH. BRAF mutation is not a specific marker of melanocytic cancerogenesis, and it can also be involved in SGHs. In both melanocytic and non-melanocytic skin tumors, BRAF mutation is linked to early tumorigenesis events.

Immunohistochemical expression of MYH protein can be used to identify patients with MYH-associated polyposis.

BACKGROUND & AIMS: MYH-associated polyposis is a recently described, autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. There are only few immunohistochemical studies of the MYH protein. We investigated the expression pattern of the MYH protein to evaluate whether a immunohistochemical approach could be used in clinical practice to screen patients for germline mutations in the MYH gene. METHODS: The expression of MYH, MSH2, MLH1, and MSH6 proteins was studied by immunohistochemistry in 20 samples (colorectal adenomas or cancer) from 18 patients with biallelic MYH mutation, in 11 samples from patients with germline adenomatous polyposis coli (APC) mutations, in 20 samples from patients with sporadic colorectal cancers, and in 10 samples from patients with normal colonic mucosa without malignancies. RESULTS: In all cases the mismatch repair proteins were expressed normally. Nuclear and cytoplasmic immunoreactivity for the MYH protein were observed in normal colorectal mucosa, in sporadic colorectal carcinomas, and in adenomas and carcinomas from patients carrying APC germline mutations. Adenomas and carcinomas from patients with MYH biallelic mutation showed a different pattern of expression: a strong granular cytoplasmic staining was observed without any nuclear expression. The same immunophenotype was observed in the surrounding normal mucosa. CONCLUSIONS: Patients with biallelic MYH mutations showed disappearance of staining from the nucleus, and segregation of immunoreactivity in the cytoplasm, both in neoplastic and surrounding healthy mucosa. Because this pattern of expression seems to be specific for biallelic mutations, it follows that immunohistochemistry might be used in clinical practice to screen patients at risk for MYH-associated polyposis.

Microsatellite instability and colorectal cancer prognosis.

PURPOSE: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy. EXPERIMENTAL DESIGN: In three different institutions, 1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables. RESULTS: Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year-specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non-polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared. CONCLUSIONS: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. The survival benefit for patients with hereditary non-polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.

Molecular genetic alterations and clinical features in early-onset colorectal carcinomas and their role for the recognition of hereditary cancer syndromes.

OBJECTIVES: Colorectal cancer (CRC) occurs rarely in young individuals (<45 yr) and represents one of the criteria for suspecting hereditary cancer families. In this study we evaluated clinical features and molecular pathways (chromosomal instability [CIN] and microsatellite instability [MSI]) in early-onset CRC of 71 patients. METHODS: Detailed family and personal history were obtained for each patient. Expression of APC, beta-catenin, p53, MLH1, MSH2, and MSH6 genes was evaluated by immunohistochemistry. MSI analysis was performed and constitutional main mutations of the mismatch repair (MMR) genes were searched by gene sequencing. RESULTS: Fourteen (19.7%) out of the 71 cases showed both MSI and altered expression of MMR proteins. In the 57 MSI-negative (MSI-) lesions altered expression of APC, beta-catenin, and p53 genes were found more frequently than in MSI-positive(MSI+) tumors. Seven (50%) out of the 14 patients with MSI+ tumors presented clinical features of Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]) and in all but one, constitutional mutations in MLH1 or MSH2 genes could be detected. The same mutations were also found in other family members. CONCLUSIONS: Our study demonstrates the involvement of CIN in a majority of early-onset colorectal tumors. Furthermore, we identified Lynch syndromes in seven cases (50%) of early-onset colorectal carcinomas with impairment of the MMR system. These results suggest that patients with early-onset CRC should be screened for hereditary cancer syndrome through clinical and molecular characterizations.

MDR1 C3435T genetic polymorphism does not influence the response to antiretroviral therapy in drug-naive HIV-positive patients.

P-glycoprotein, a membrane-localized protein transporter, codified by the MDR1 gene, influences the response to pharmacological treatments, including antiretroviral drugs. MDR1 polymorphism C3435T is correlated with the functionality of the protein. We investigated the influence of this polymorphism in the reconstitution of the peripheral CD4 T cell pool in 149 drug-naive HIV-positive patients starting highly active antiretroviral therapy. The MDR1 C3435Tpolymorphism did not influence response to therapy, suggesting no disadvantages for individuals with a different genotype.