An Innovative Technique for Ejaculation-Sparing Prostatic Enucleation with Thulium:YAG Laser.

Purpose: We report our experience with 100 patients who underwent an innovative prostate enucleation technique that spares the complete urethral-plate from the veru montanum to the bladder neck using a low-energy thulium laser emission. The aim of our study was to evaluate the short-term effects of this procedure on ejaculation preservation and urinary obstruction. Materials and Methods: The International Prostate Symptom Index (IPSS), quality of life (QoL), and Male Sexual Health Questionnaire Ejaculatory Dysfunction (MSHQ-EJD) Short Form were used as validated instruments to quantify ejaculatory dysfunction before and 6 months after the surgery. Results: The median IPSS score pre- and postoperatively was 20 and 5, respectively (p < 0.0001); QoL dropped from a median of 4-1 (p < 0.0001); and the mean preoperative maximal flow rate improved significantly (8.5 vs 21.2 mL/min) (p < 0.0001). Furthermore, there was significant reduction in postvoid residual postoperatively (p < 0.0001). Postoperative ejaculatory function was preserved in 92/100 patients (92%). According to the MSHQ-EJD score, patients reported a slight nonsignificant decrease in frequency of ejaculation (item 1), force of expulsion (item 2) and reduction in semen volume during ejaculation (item 3), with the exception of ejaculation discomfort (item 4). Conclusion: According to our results, complete removal of the apical tissue, which has been advocated as an integral part of the so called ejaculatory hood, does not interfere with ejaculation if the ventral lissosphincter remains intact.

Immunohistochemical Markers and TILs Evaluation for Endometrial Carcinoma.

OBJECTIVE: The molecular classification for endometrial cancer (EC) introduced by The Cancer Genome Atlas Research Network (TCGA) and the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) proved the existence of four molecular prognostic subtypes; however, both classifications require costly technology. We suggest a prognostic model for EC based on immunohistochemistry (IHC) and tumor-infiltrating lymphocytes (TILs). STUDY DESIGN: One hundred patients were included. We retrospectively investigated IHC prognostic parameters: mismatch repair (MMR)-deficient tumors, p53 mutation status, progesterone receptors (PgRs), and estrogen receptors (ERs). We further evaluated TILs. These parameters were related to the clinical and morphological features and to the outcome. RESULTS: We classified tumors into three groups (IHC analysis): MMR-deficient, p53-mutated, p53 wild-type. MMR-deficient tumors had a good prognosis, p53 wild-type tumors an intermediate one, and p53-mutated tumors had the poorest outcomes. Disease-free (DFS) and overall survival (OS) were significantly better among PgR+ tumors (respectively p = 0.011 and p = 0.001) and PgR expression is an independent prognostic factor for a better DFS frommultivariate analysis (OR = 0.3; CI: 0.1-0.9; p = 0.03).No significant correlation was observed between DFS and TILs. However, among MMR-deficient tumors, the mean value of TILs was higher than among the other tumors(111 versus 71, p = 0.01) Conclusions: The prognostic model based on IHC markers could potentially be a valid and applicable alternative to the TCGA one. The PgR determination could represent an additional prognostic factor for EC.

Proteomic analysis identifies deregulated metabolic and oxidative-associated proteins in Italian intrahepatic cholangiocarcinoma patients.

BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive disease with poor prognosis. A molecular classification based on mutational, methylation and transcriptomic features could allow identifying tailored therapies to improve CCA patient outcome. Proteomic remains partially unexplored; here, we analyzed the proteomic profile of five intrahepatic cholangiocarcinoma (ICC) derived from Italian patients undergone surgery and one normal bile duct cell line. METHODS: Proteome profile was investigated by using 2D electrophoresis followed by Mass Spectrometry (MS). To validate proteomic data, the expression of four overexpressed proteins (CAT, SOD, PRDX6, DBI/ACBP) was evaluated by immunohistochemistry in an independent cohort of formalin fixed, paraffin-embedded (FFPE) ICC tissues. We also compared proteomic data with those obtained by transcriptomic profile evaluated by microarray analysis of the same tissues. RESULTS: We identified 19 differentially expressed protein spots, which were further characterized by MS; 13 of them were up- and 6 were down-regulated in ICC. These proteins are mainly involved in redox processes (CAT, SODM, PRDX2, PRDX6), in metabolism (ACBP, ACY1, UCRI, FTCD, HCMS2), and cell structure and organization (TUB2, ACTB). CAT is overexpressed in 86% of patients, PRDX6 in 73%, SODM in 100%, and DBI/ACBP in 81% compared to normal adjacent tissues. A concordance of 50% between proteomic and transcriptomic data was observed. CONCLUSIONS: This study pointed out that the impairment of the metabolic and antioxidant systems, with a subsequent accumulation of free radicals, might be a key step in CCA development and progression.

Adrenal Rests in the Uro-genital Tract of an Adult Population.

Ectopic adrenal rests are a rare condition which can be found in various sites, generally in the retroperitoneum or pelvis along the path of gonadal descent. Their real prevalence is unknown. Males are more commonly affected, at least in the pediatric age. Adrenal rests are usually clinically silent and incidentally found in surgical samples, mostly in the pediatric population, and rarely in adults. With the aim of increasing knowledge and estimating the prevalence of ectopic adrenocortical tissue in the adult population, 44 adrenal rests in the urogenital tract of 40 adults are described. These represent approximately 0.07% of the total number of urogenital and gynecological surgeries performed in the 22 considered years. Adrenal rests were identified in the spermatic cord (10 males) and in paraovarian, parasalpingeal, or infundibulopelvic ligament locations (30 females). All but one was incidental findings. One case regarded an adrenocortical carcinoma arisen in adrenal rests. A literature review of adrenal ectopia in the urogenital tract of adults identified 57 reported cases from 53 patients, with similar clinicopathological features as those of our series, with the exception of a lower incidence of parasalpingeal locations. Despite their limited clinical implications, awareness of ectopic adrenal rests is essential also in adults for at least two reasons: (a) to correctly identify sources of adrenocortical hormone production in case of adrenal insufficiency or hormonal imbalance and (b) to avoid misinterpretations in the diagnostic workup of renal cell carcinoma, adrenocortical tumors, and rare gonadal neoplasms, including Sertoli/Leydig cell tumors.

Could a 2D/3D US based model be helpful in the assessment of myometrial invasion at time of intraoperative frozen section? A pilot study.

BACKGROUND: The assessment of myometrial invasion is a pivotal step in the preoperative staging of endometrial cancer. Intraoperative frozen section (FS) represents a reliable tool in directing surgeon's choices. Preoperative transvaginal ultrasound (US) showed high accuracy in evaluating myometrial invasion. This study aimed to understand if the application of a standardized ultrasonographic protocol for the pre-operative evaluation of myometrial invasion can help pathologists in improving the accuracy of FS. Furthermore, the agreement between US and FS in the assessment of myometrial invasion was assessed. METHODS: Sixty-six patients who underwent surgery for endometrial cancer were analyzed. Preoperative 2D/3D ultrasound was performed in all the patients. Myometrial invasion was estimated by subjective assessment and objective measurement techniques. Data from US were reported to pathologists through a prefilled form with depth and site of the maximum myometrial invasion. Diagnostic performance of US and FS were compared having the definitive histological examination as the gold standard. RESULTS: Influenced by the information given by our 3D US-model, FS showed a 90% sensitivity and a 93% specificity, with a 93% PPV and an 89% NPV. The agreement with histology was strong (K=0.824). Myometrial invasion was missed at the level of the isthmus by FS just in one case. Subjective assessment was confirmed as the most reliable ultrasonographic technique in assessing myometrial invasion, with 90% sensitivity, 78% specificity, 80% PPV and 89% NPV. The agreement with histology was substantial (K=0.68). CONCLUSIONS: The application of a preoperative 2D/3D US assessment would seem to help pathologists in detecting myometrial invasion in difficult areas of the uterus such as the isthmus, reducing downstaging and overtreatment.

Ibuprofen enantiomers in premature neonates with patent ductus arteriosus: Preliminary data on an unexpected pharmacokinetic profile of S(+)-ibuprofen.

S(+)-ibuprofen (S-IBU) and R(-)-ibuprofen (R-IBU) concentrations were measured in 16 neonates with patent ductus arteriosus during a cycle of therapy (three intravenous doses of 10-5-5 mg kg-1 at 24-h intervals), at the end of the first infusion and 6, 24, 48, and 72 h later. Data were analyzed with a PK model that included enantiomer elimination rate constants and the R- to S-IBU conversion rate constant. The T½ of S-IBU in the newborn was much longer than in adults (41.8 vs. ≈2 h), whereas the T½ of R-IBU appeared to be the same (2.3 h). The mean fraction of R- to S-IBU conversion was much the same as in adults (0.41 vs. ≈0.60). S-IBU concentrations measured 6 h after the first dose were higher than at the end of the infusion in 10 out of 16 cases, and in five cases, they remained higher even after 24 h. This behavior is unprecedented and may be attributable to a rapid R-to-S conversion overlapping with a slow S-IBU elimination rate. In 13 of the 16 neonates, S-IBU concentrations at 48 and/or 72 h were lower than expected, probably due to the rapid postnatal maturation of the newborn's liver metabolism.

Rare case of uterine cervix lymphoma with spontaneous regression: Case report.

Primary malignant lymphoma rarely occurs in the female reproductive tract, because of that they are often misdiagnosed. Lymphoma spontaneous regression is even rarer, but it is possible behavior of this disease. A case of 54-year-old female patient with a primary diffuse large B-cell lymphoma of the cervix is presented. First assumption was sarcoma or atypical adenocarcinoma; biopsies have been inconclusive and, after a partial spontaneous regression, diagnosis of lymphoma was possible only after surgery. The diagnosis was a real challenge for clinicians, radiologists and pathologists for both localization and behavior. Difficulties in diagnosis led to an over-treatment: a laparotomic bilateral hysteron salpingectomy with lymphadenectomy was performed, while chemotherapy alone would have been the right approach. Considering that prognosis and treatment of primary malignant lymphoma of the cervix are completely different than those of other malignant tumors of the uterus, this disease should be considered in the differential diagnosis.

Predicting steady-state endoxifen plasma concentrations in breast cancer patients by CYP2D6 genotyping or phenotyping. Which approach is more reliable?

In previous studies, steady-state Z-endoxifen plasma concentrations (ENDOss) correlated with relapse-free survival in women on tamoxifen (TAM) treatment for breast cancer. ENDOss also correlated significantly with CYP2D6 genotype (activity score) and CYP2D6 phenotype (dextromethorphan test). Our aim was to ascertain which method for assessing CYP2D6 activity is more reliable in predicting ENDOss. The study concerned 203 Caucasian women on tamoxifen-adjuvant therapy (20 mg q.d.). Before starting treatment, CYP2D6 was genotyped (and activity scores computed), and the urinary log(dextromethorphan/dextrorphan) ratio [log(DM/DX)] was calculated after 15 mg of oral dextromethorphan. Plasma concentrations of TAM, N-desmethyl-tamoxifen (ND-TAM), Z-4OH-tamoxifen (4OH-TAM) and ENDO were assayed 1, 4, and 8 months after first administering TAM. Multivariable regression analysis was used to identify the clinical and laboratory variables predicting log-transformed ENDOss (log-ENDOss). Genotype-derived CYP2D6 phenotypes (PM, IM, NM, EM) and log(DM/DX) correlated independently with log-ENDOss. Genotype-phenotype concordance was almost complete only for poor metabolizers, whereas it emerged that 34% of intermediate, normal, and ultrarapid metabolizers were classified differently based on log(DM/DX). Multivariable regression analysis selected log(DM/DX) as the best predictor, with patients' age, weak inhibitor use, and CYP2D6 phenotype decreasingly important: log-ENDOss = 0.162 - log(DM/DX) × 0.170 + age × 0.0063 - weak inhibitor use × 0.250 + IM × 0.105 + (NM + UM) × 0.210; (R2  = 0.51). In conclusion, log(DM/DX) seems superior to genotype-derived CYP2D6 phenotype in predicting ENDOss.

Neuroendocrine breast carcinoma: a rare but challenging entity.

Breast carcinoma with neuroendocrine differentiation, also known as neuroendocrine breast carcinoma (NEBC), includes a heterogeneous group of rare tumors, which account for 2-5% of all invasive breast carcinomas. Because of their low incidence, most of the current limited knowledge of these tumors derives from anecdotal case reports or small retrospective series. The diagnosis of NEBC is based on the presence of morphological features similar to gastrointestinal and lung NETs and neuroendocrine markers. NEBCs are usually hormone receptors positive and HER2 negative, but despite this luminal phenotype, most recent studies suggested that NEBC could be associated with worse prognosis compared to invasive breast cancer without neuroendocrine differentiation. Due to its rarity and lack of randomized data, there is little evidence to guide the choice of treatment, so NEBC is currently treated as any invasive breast carcinoma not-otherwise specified. Recently, attempts to molecularly characterize NEBC have been made, in order to provide new targets for a more personalized treatment of this uncommon entity.

A Clinically Applicable Approach to the Classification of B-Cell Non-Hodgkin Lymphomas with Flow Cytometry and Machine Learning.

The immunophenotype is a key element to classify B-cell Non-Hodgkin Lymphomas (B-NHL); while it is routinely obtained through immunohistochemistry, the use of flow cytometry (FC) could bear several advantages. However, few FC laboratories can rely on a long-standing practical experience, and the literature in support is still limited; as a result, the use of FC is generally restricted to the analysis of lymphomas with bone marrow or peripheral blood involvement. In this work, we applied machine learning to our database of 1465 B-NHL samples from different sources, building four artificial predictive systems which could classify B-NHL in up to nine of the most common clinico-pathological entities. Our best model shows an overall accuracy of 92.68%, a mean sensitivity of 88.54% and a mean specificity of 98.77%. Beyond the clinical applicability, our models demonstrate (i) the strong discriminatory power of MIB1 and Bcl2, whose integration in the predictive model significantly increased the performance of the algorithm; (ii) the potential usefulness of some non-canonical markers in categorizing B-NHL; and (iii) that FC markers should not be described as strictly positive or negative according to fixed thresholds, but they rather correlate with different B-NHL depending on their level of expression.

DOAC plasma levels measured by chromogenic anti-Xa assays and HPLC-UV in apixaban- and rivaroxaban-treated patients from the START-Register.

INTRODUCTION: To measure direct factor Xa inhibitor (apixaban, edoxaban, rivaroxaban) concentrations, dedicated chromogenic anti-Xa assays are recommended as suitable methods to provide rapid drug quantification. Moreover, the high-performance liquid chromatography with ultraviolet detection (HPLC-UV) is reported as a reliable quantitative technique. We investigated seven anti-Xa assays and an HPLC-UV method for measurement of apixaban and rivaroxaban levels in patients enrolled in the START-Register. METHODS: A total of 127 apixaban and 124 rivaroxaban samples were tested by HPLC-UV and the following anti-Xa assays: Biophen DiXaI and Heparin LRT (Hyphen BioMed), Berichrom and Innovance Heparin (Siemens), STA-Liquid Anti-Xa (Stago Diagnostics), Technochrom anti-Xa (Technoclone), and HemosIL Liquid Anti-Xa (Werfen). Each method was performed in one of the participating laboratories: Bologna, Cremona, Florence, and Padua. RESULTS: Our data confirmed the overestimation of apixaban and rivaroxaban levels by the antithrombin-supplemented anti-Xa method (Berichrom). Performances and reproducibility of the six anti-Xa assays not supplemented with antithrombin and the HPLC-UV method were good, with limits of quantification from 8-39 ng/mL (apixaban) and 15-33 ng/mL (rivaroxaban). The six chromogenic methods showed good concordances with the quantitative HPLC-UV [bias: -26.9-22.3 ng/mL (apixaban), -11.3-18.7 ng/mL (rivaroxaban)]. Higher bias and wider range between limits of agreement were observed at higher concentrations [<100 ng/mL: bias -21.3-4.1 ng/mL (apixaban) and -6.2-3.8 ng/mL (rivaroxaban); >200 ng/mL: bias -42.2-36.8 ng/mL (apixaban) and -20.1-68.9 ng/mL (rivaroxaban)]. CONCLUSION: Overall, the anti-Xa assays not supplemented with antithrombin and the HPLC-UV method proved to be suitable for apixaban and rivaroxaban quantification.

Metastatic Bilateral Strumal Carcinoid: A Case Report and Review of the Literature.

Primary ovarian carcinoids are very rare tumors that belong to the germ cell family of ovarian malignancies. They account for less than 1% of all carcinoid tumors and for less than 0.1% of all ovarian neoplasms. Recurrences are even rarer, with only few cases reported in the literature. Strumal carcinoid has recently been recognized as an extremely rare distinct entity. We report on a patient with bilateral mature cystic teratoma with millimetric foci of ovarian strumal carcinoid who developed lymph node para aortic metastasis after 30 years from primary diagnosis. Our case is thus far the second report of a metastatic strumal carcinoid and the first one in which strumal carcinoid occurred bilaterally and was also metastatic.

PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid.

The hyalinizing trabecular adenoma/tumor is a rare and poorly characterized follicular-derived thyroid neoplasm recently shown to harbor recurrent PAX8-GLIS1 or PAX8-GLIS3 gene fusions. Here we sought to define the repertoire of genetic alterations of hyalinizing trabecular tumors, and whether PAX8-GLIS3 fusions are pathognomonic for hyalinizing trabecular tumors. A discovery series of eight hyalinizing trabecular tumors was subjected to RNA-sequencing (n = 8), whole-exome sequencing (n = 3) or targeted massively parallel sequencing (n = 5). No recurrent somatic mutations or copy number alterations were identified in hyalinizing trabecular tumor, whereas RNA-sequencing revealed the presence of a recurrent genetic rearrangement involving PAX8 (2q14.1) and GLIS3 (9p24.2) genes in all cases. In this in-frame fusion gene, which comprised exons 1-2 of PAX8 and exons 3-11 of GLIS3, GLIS3 is likely placed under the regulation of PAX8. Reverse transcription RT-PCR and/or fluorescence in situ hybridization analyses of a validation series of 26 hyalinizing trabecular tumors revealed that the PAX8-GLIS3 gene fusion was present in all hyalinizing trabecular tumors (100%). No GLIS1 rearrangements were identified. Conversely, no PAX8-GLIS3 gene fusions were detected in a cohort of 237 control thyroid neoplasms, including 15 trabecular thyroid lesions highly resembling hyalinizing trabecular tumor from a morphological standpoint, as well as trabecular/solid follicular adenomas, solid/trabecular variants of papillary carcinoma, and Hurthle cell adenomas or carcinomas. Our data provide evidence to suggest that the PAX8-GLIS3 fusion is pathognomonic for hyalinizing trabecular tumors, and that the presence of the PAX8-GLIS3 fusion in thyroid neoplasms may be used as an ancillary marker for the diagnosis of hyalinizing trabecular tumor, thereby avoiding overtreatment in case of misdiagnoses with apparently similar malignant tumors.

Ultrasound-guided fine needle aspiration cytology in the diagnosis of hepatic and pancreatic perivascular epithelioid cell tumors: A case series.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors that can affect any part of the body. They can be sporadic or arise in the setting of tuberous sclerosis (TSC). In this article, we report a series of three hepatic and two pancreatic PEComas diagnosed preoperatively with ultrasound-guided fine needle aspiration (FNA). All patients were female (age range 28-70), had no personal history of TSC and presented with a single, localized painless mass. Rapid on-site evaluation (ROSE) of cytologic samples was performed for all cases to evaluate for cellular content and adequacy of specimens. Direct smears and cell block preparations revealed a proliferation of medium to large polygonal epithelioid cells, with abundant eosinophilic and vacuolated cytoplasm, arranged in sheets and nests. On immunohistochemistry (IHC), neoplastic cells showed co-expression of melanocytic and smooth muscle markers and a diagnosis of PEComa was rendered. PEComas of the pancreas and liver are rare neoplasms, but should always be considered when examining "clear cell" neoplasms, especially in young female patients. If good quality cytologic samples are obtained by FNA, a correct diagnosis can be achieved with the help of IHC. This is of particular importance in order to plan adequate surgical strategy and to avoid overtreatment.

Nipple-Sparing Mastectomy: Reliability of sub-areolar sampling and frozen section in predicting occult nipple involvement in breast cancer patients.

INTRODUCTION: The oncological safety of nipple-areolar complex (NAC) preservation is a concern in the mastectomies performed for cancer indication. The detection of tumor cells during the intraoperative frozen section examination (IE) of sub-areolar/nipple tissue (SAT) leads to the removal of NAC, but frequently the final histology of the nipple is negative for malignancy. This study aims to evaluate the accuracy of SAT examination in predicting occult NAC involvement in case of Nipple-Sparing Mastectomy (NSM). METHODS: The study includes 76 NSM. We evaluated the concordance between histopathologic features of frozen and paraffin-embedded SAT sections. Moreover, we examined the "true margin" (TM), defined as the measurement of the distance between the tumor margin and the edge of the SAT. A margin >1 mm was considered negative. RESULTS: In 26/76 cases the IE of the SAT was positive. At the final histology, the NAC was negative in 57.7% of cases. The concordance between frozen and paraffin section examination of the SAT was 92.1%. The three false-positives were low-grade DCIS at the IE, and negative or DIN1a on permanent section. A negative TM seems to predict for a negative NAC (6/6). CONCLUSIONS: The detection of a low-grade DCIS at the IE of the SAT may not be confirmed at the permanent section examination; we recommend caution in removing the NAC in these cases. The evaluation of the TM may improve the accuracy of SAT analysis in predicting occult NAC involvement; in our series, a TM wider than 1 mm correlates with a negative NAC.

Alcohol injection into the portal vein prior to ligation increases liver regeneration rate.

BACKGROUND: Failure of portal vein ligation (PVL) to induce hypertrophy is not uncommon. The aim of the study was to evaluate the impact of intraportal alcohol injection prior to ligation on liver regeneration. METHOD: Forty-two patients with colorectal liver metastases who underwent PVL between 01/2004 and 06/2014 were analyzed. Beginning in 09/2011, alcohol was injected prior to PVL. Patients treated with PVL alone (Alc- group) were compared with those treated with alcohol injection plus PVL (Alc+ group). Liver regeneration was assessed by volumetric increase (VI). RESULTS: Alc+ (23 patients) and Alc- (19 patients) groups were similar in terms of age, sex and pre-PVL FLRV. Alc- group had a higher risk of recanalization (12 vs. 1, p < 0.001) and cavernous transformation (7 vs. 2, p = 0.055) of the occluded portal vein. Post-PVL FLRV (43.3 ± 14.3% vs. 34.6 ± 6.4%, p = 0.013) and VI (0.44 ± 0.24 vs. 0.28 ± 0.20, p = 0.029) were higher in Alc+ group. On multivariate analysis male sex (B = -0.149) and alcohol injection (B = 0.143) significantly predicted VI. CONCLUSIONS: Alcohol injection prior to PVL may increase the regeneration of the FLRV by reducing the recanalization of the occluded portal vein.

Pharmacokinetic and pharmacodynamic re-evaluation of a genetic-guided warfarin trial.

PURPOSE: A previous trial failed to demonstrate the superiority of a demographic-genetic algorithm in predicting warfarin (W) dose over a standard clinical approach. The purpose of the present study is to re-analyse the results in subgroups of patients with differing baseline sensitivity to W, integrated with additional pharmacokinetic data. METHODS: The original trial allocated 180 treatment-naïve patients with non-valvular atrial fibrillation to a control arm (CTL, n = 92) or a genetic-guided arm (GEN, n = 88). Before starting anticoagulation treatment, all patients were genotyped for CYP2C9, VKORC1 and CYP4F2 variants and classified into four quartiles (Q1, Q2, Q3, Q4) according to the algorithm-predicted W maintenance dose. International normalised ratios (INR) and plasma concentrations of S-warfarin [S-W]s and R-warfarin [R-W]s were measured at baseline and on days 5, 7, 9, 12, 15 and 19 of therapy. RESULTS: In the lowest dose quartile (Q1), the number of INRs > 3 and mean INR values on days 5 and 7 were significantly higher in CTL than in GEN. In Q3 and Q4, the mean INR values reached therapeutic level (> 2) 2 days later in CTL than in GEN. During follow-up, the mean time courses of INRs and [S-W]s in GEN were remarkably stable in all dose quartiles. Thus, mean changes from starting to final doses were significantly smaller in GEN than in CTL. Plasma concentrations of R-W (a partially active enantiomer) steadily increased from day 5 to day 19 in all Qs in both CTL and GEN, except in the Q1 CTL group, due to the marked dose reduction required. CONCLUSIONS: This analysis showed that the demographic-genetic algorithm used to predict the W dose can identify patients with differing degrees of sensitivity to W and to 'normalise' their average anticoagulant responses. The progressive rise in [R-W]s throughout the 19-day follow-up indicates that the (partial) contribution of R-W to the W anticoagulant effect changes continually during the early phase of treatment.

Mitochondrial DNA "common deletion" in post-fine needle aspiration infarcted oncocytic thyroid tumors.

Thyroid fine needle aspiration (FNA) can rarely induce morphological changes potentially hindering the histopathological diagnosis, especially in Hurthle cell tumors (HCTs), which may easily undergo post-FNA infarction or necrosis. HCTs contain mitochondrion (mt)-rich cells that may bear mtDNA mutations, the most frequent being the so-called common deletion (CD). The aim of this study was to determine the presence and extent of the mtDNA CD in a series of thyroid HCTs that underwent extensive infarction following FNA procedure in comparison with a control series of HCTs lacking post-FNA ischemic/hemorrhagic alterations. Of 257 HCTs with available matched FNA and surgical specimens, 8 cases showed extensive (≥80%) infarction or necrosis in the resected nodule (4 adenomas, 1 carcinoma, 3 HCTs undefined for malignancy). Noninfarcted tumors in the control series included 9 adenomas, 1 carcinoma, and 1 follicular tumor of uncertain malignant potential. These lesions were significantly (P = .03) larger than infarcted nodules. The mtDNA CD was identified using semiquantitative real-time polymerase chain reaction in 2 of 8 (25%) infarcted tumors. In HCTs lacking infarction/necrosis of the control series, the CD was significantly (P = .05) more common (8/11 cases, 72.7%). In 7 of the 10 deleted cases, the CD was present also in the adjacent nonneoplastic parenchyma. In conclusion, the rare oncocytic tumors undergoing extensive infarction are smaller than those lacking ischemic changes and bear the mtDNA CD in a significantly lower proportion compared with control noninfarcted HCTs. This may suggest that mtDNA deletion confers a survival advantage to oncocytic cells in stress conditions, including FNA procedures.

Reversibility of chemotherapy-related liver injury.

BACKGROUND & AIMS: Chemotherapy-associated liver injury (CALI) increases the risk of liver resection and may prejudice further surgery and chemotherapy. The reversibility of CALI is therefore important; however, no data concerning this are available. This study aimed to retrospectively analyze the reversibility of CALI in patients undergoing liver resection for colorectal metastases. METHODS: All resections of colorectal liver metastases after oxaliplatin and/or irinotecan-based chemotherapy were included. First, liver resections were stratified by time between end of chemotherapy and hepatectomy and several possible cut-off values tested. CALI prevalence in various groups was compared. Second, CALI in the two specimens from each patient who had undergone repeat liver resections without interval chemotherapy were compared. RESULTS: Overall, 524 liver resections in 429 patients were analyzed. The median interval chemotherapy-surgery was 56days (15-1264). CALI prevalence did not differ significantly between groups with a chemotherapy-surgery interval <270days. Grade 2-3 sinusoidal dilatation (SOS, 19.4% vs. 40.0%, p=0.022) and nodular regenerative hyperplasia (NRH, 6.5% vs. 20.1%, p=0.063) occurred less frequently in patients with an interval >270days (n=31); prevalence of steatosis and steatohepatitis was similar in all groups. A chemotherapy-surgery interval >270days was an independent protector against Grade 2-3 SOS (p=0.009). Forty-seven patients had repeat liver resection without interval chemotherapy. CALI differed between surgeries only for a chemotherapy-surgery interval >270days (n=15), Grade 2-3 SOS having regressed in 4/5 patients and NRH in 7/8; whereas steatosis and steatohepatitis had persisted. CONCLUSIONS: CALI persists for a long time after chemotherapy. SOS and NRH regress only after nine months without chemotherapy, whereas steatosis and steatohepatitis persist. LAY SUMMARY: The patients affected by colorectal liver metastases often receive chemotherapy before liver resection, but chemotherapy causes liver injuries that may increase operative risks and reduce tolerance to further chemotherapy. The authors analyzed the reversibility of the liver injuries after the chemotherapy interruption. Liver injuries persist for a long time after chemotherapy. Sinusoidal dilatation and nodular regenerative hyperplasia regress only nine months after the end of chemotherapy, whereas steatosis and steatohepatitis persist even after this long interval.

Monitoring Plasma Levels of Donepezil, 5-O-Desmethyl-Donepezil, 6-O-Desmethyl-Donepezil, and Donepezil-N-Oxide by a Novel HPLC Method in Patients With Alzheimer Disease.

BACKGROUND: In humans, donepezil (D) is metabolized to 5-O-desmethyl-donepezil (5DD), 6-O-desmethyl-donepezil (6DD), and donepezil-N-oxide (DNox). Although 6DD and DNox are pharmacologically active, the activity of 5DD is unknown. At present, no routine methods are available to detect D and its 3 metabolites simultaneously. In this study, a novel high-performance liquid chromatography method was developed and applied to a population of patients with Alzheimer disease on stable treatment with the drug. METHODS: Liquid-liquid extraction from plasma was accomplished by means of a solvent mixture of n-hexane/dichloromethane/ethylacetate (45:40:15) after sample alkalinization. Disopyramide was the internal standard. After evaporation, the residue was reconstituted in 200 µL of mobile phase (acetonitrile 85%:1% acetic acid 15%) and 50 µL was injected into the high-performance liquid chromatography column (X-Terra, RP8; flow: 1 mL/min). Photometric and fluorimetric detectors were used in tandem, to maximize the sensitivity of fluorescent compounds (D, 5DD, and DNox) and also to reveal nonfluorescent compounds (6DD and internal standard). RESULTS: The method was linear in the 10-100 ng/mL concentration range. Imprecision (coefficient of variation) varied between 3.2% and 12.6% and inaccuracy (% mean absolute error) between 1.3% and 13.3%, depending on the compound, concentration, and detection mode. The quantitation limits were 0.1-0.3 ng/mL for fluorescent compounds and 1.2-4.3 ng/mL for photometric compounds. D, 5DD, 6DD, and DNox through concentrations were measured in 54 patients with Alzheimer disease on treatment with D (10 mg q.d.). No interfering peaks by endogenous compounds or coadministered drugs were noted. Plasma concentrations were quite variable among patients (D: 10-106 ng/mL; 5DD: 0.07-2.8 ng/mL; 6DD: 1.2-36 ng/mL; DNox: 0.5-45.4 ng/mL). Of note, in 6 patients, the plasma concentrations of the 2 active metabolites (6DD and DNox) were higher than those of the parent drug. CONCLUSIONS: The above method proved to be suitable for therapeutic drug monitoring and may be useful in ascertaining the real contribution of metabolites to the therapeutic effects of donepezil.