Factors Affecting Diagnostic Yield of Lesional Bone Biopsy in Hematologic Malignancy Patients.

PURPOSE: To evaluate factors affecting the diagnostic yield (percent of biopsy samples leading to a pathologic diagnosis) of lesional bone biopsies in patients with hematologic malignancies. MATERIALS AND METHODS: This retrospective study included 206 lesional bone biopsies in 182 patients with a hematologic malignancy between January 2017 and December 2022. The parameters that were reviewed to evaluate diagnostic yield included biopsy device type (manual vs. electric-powered drill), number of biopsy cores acquired, core biopsy needle gauge, preliminary intra-procedural sample adequacy (touch preparation cytology determining if samples are adequate for final pathologic examination), lesion morphology on Computed Tomography (CT), and presence of crush artifact. RESULTS: Review of 206 lesional biopsies showed overall diagnostic yield to be 89.8% (185/206). The two statistically significant factors affecting diagnostic yield were biopsy device type and in-room adequacy. 41/42 samples obtained with the electric-powered drill and 144/164 samples obtained using a variety of manual needles were diagnostic (97.6% vs 87.8%, p = 0.03). Of the 192 samples that were assessed for sample adequacy intra-procedurally, 97/102 of the samples that were deemed adequate were diagnostic, and 77/90 of the samples where intra-procedural adequacy was not confirmed were diagnostic (95.1% vs 85.6%, p = 0.018). The remaining factors did not affect diagnostic yield. CONCLUSION: The use of an electric-powered drill bone biopsy device and intra-procedural confirmation of sample adequacy are associated with a higher diagnostic yield of lesional bone biopsies in patients with hematologic malignancies. The presence or absence of crush artifact did not significantly affect the diagnostic yield in these patients.

Colorectal Cancer Liver Metastases: Genomics and Biomarkers with Focus on Local Therapies.

Molecular cancer biomarkers help personalize treatment, predict oncologic outcomes, and identify patients who can benefit from specific targeted therapies. Colorectal cancer (CRC) is the third-most common cancer, with the liver being the most frequent visceral metastatic site. KRAS, NRAS, BRAF V600E Mutations, DNA Mismatch Repair Deficiency/Microsatellite Instability Status, HER2 Amplification, and NTRK Fusions are NCCN approved and actionable molecular biomarkers for colorectal cancer. Additional biomarkers are also described and can be helpful in different image-guided hepatic directed therapies specifically for CRLM. For example, tumors maintaining the Ki-67 proliferation marker after thermal ablation have been particularly resilient to ablation. Ablation margin was also shown to be an important factor in predicting local recurrence, with a ≥10 mm minimal ablation margin being required to attain local tumor control, especially for patients with mutant KRAS CRLM.

Effect of cataract-induced refractive change on intraocular lens power formula predictions.

Cataract-induced refractive change (CIRC) is the change in refraction induced by a cataract. It can amount to several diopters (D). It alters predicted errors in refraction following cataract surgery through changes in axial length measurement. This study determined the effect of CIRC on the accuracy of intraocular lens power formula predictions of refraction in 872 eyes of 662 patients. Regression of results gave -0.030 D prediction error per 1 D of CIRC, i.e. cataract-induced myopia and hyperopia tended to yield postoperative hyperopia and myopia, respectively. Theoretical determinations with a model eye supported this result. There was significant correlation of nuclear cataract opalescence with CIRC. Although these effects are difficult to identify based on changes in refraction, if biometers were able to identify cataract density and automatically adjust axial length measurement, IOL power predictions might improve.

Standardizing sum-of-segments axial length using refractive index models.

Optical biometry uses interferometry to measure the axial length (AL) of the eye. Traditionally, one-variable regression formulas have converted the optical path length measured by a biometer to a geometric AL. An alternate calculation of axial length sums the individual segments of the eye (sum-of-segments AL). This calculation has been shown to improve predictions of some intraocular lens power formulas when used in place of traditional axial length. Sum-of-segments ALs are determined from 13 refractive index models. As measured in 1695 eyes, these yield different ocular axial lengths. A path to standardization from these models is presented.

A comparison of two methods to calculate axial length.

PURPOSE: To compare prediction accuracy with the axial length (AL) calculation method of the Lenstar biometer (traditional AL) and that of the ARGOS biometer (sum-of-segments AL). SETTING: Private practice clinic. DESIGN: Comparative case series. MAIN OUTCOME MEASURE: Mean absolute error (MAE). METHODS: Predictions were developed for nine formulas, grouping them into those derived with ultrasound (US) (SRK/T, Holladay 1 and 2, Hoffer Q, Haigis) and those derived with optical biometry (Barrett, OKULIX, Olsen from PhacoOptics, and Olsen from Lenstar). Formulas were ranked by MAE using sum-of-segments AL and traditional AL, in short eyes (traditional AL <22.0 mm), long eyes (traditional AL >26.0 mm), and all eyes. RESULTS: The study comprised 1442 eyes (54 short eyes and 67 long eyes) of 1070 patients. The best-ranking formula for long eyes was Haigis using sum-of-segments AL. For short eyes and for all eyes, OKULIX using sum-of-segments AL was best. Using sum-of-segments AL instead of traditional AL, Holladay 2 improved the most; Olsen from PhacoOptics worsened the most. CONCLUSIONS: Some biometers used traditional AL, and at least one used sum-of-segments AL. Formula accuracy varied depending on how various commercial biometers internally calculate AL. Using sum-of-segments AL instead of traditional AL improved predictions for formulas designed on US data (SRK/T, Holladay 1, Holladay 2, Hoffer Q, and Haigis), although it worsened the Barrett and Olsen formulas. OKULIX was generally improved with sum-of-segments AL. When ranking by MAE, OKULIX ranked first.

Approximating sum-of-segments axial length from a traditional optical low-coherence reflectometry measurement.

PURPOSE: To present the Cooke-modified axial length (CMALInitial) method, which closely approximates sum-of-segments AL. Notably, sum-of-segments AL has been shown to improve predictions of many intraocular lens (IOL) power formulas; however, calculating this AL requires information that is not readily available. DESIGN: Comparative case series. PATIENTS: Distinct datasets of 215 eyes and 1442 eyes, which were measured before cataract surgery with a commercially available optical biometer (Lenstar LS 900), were identified. The AL measured by this machine was labeled "traditional AL." MAIN OUTCOME MEASURE: Prediction Error. METHODS: The CMALInitial, sum-of-segments AL, and traditional AL methods with Bland-Altman plots and r2 values were compared, along with graphs of prediction errors. RESULTS: The CMALInitial was developed from 215 eyes and evaluated in the 1422-eye validation dataset. The r2 for CMALInitial versus the sum-of-segments AL was 0.99983. The predictions based on CMALInitial were compared with those based on traditional AL using the Hoffer Q, Holladay 1, SRK/T, and Holladay 2 IOL formulas. The CMALInitial produced more accurate predictions in all four formulas (P < .001). Eyes in all datasets were then combined to create the final recommendation: CMALFinal = 1.23853 + 0.95855 × traditional AL - 0.05467 × lens thickness (all measurements in millimeters). CONCLUSIONS: A modified AL method (CMAL) was easy to calculate. Using CMAL improved predictions for at least four IOL power prediction formulas, especially at extreme ALs. Caution is advised if using CMAL with other formulas.

Stereoselective Synthesis and Biological Evaluation of C1-Epimeric and Desmethyl Monomeric Nuphar Analogues.

A class of monomeric nuphar analogues that are either epimeric at C1 and C1' or lack the naturally occurring methyl group at those positions were synthesized and evaluated for biological activity. The syntheses feature enantioselective vinylogous Mukaiyama-Mannich (vM-Mannich) reactions catalyzed by chiral phosphoric acids that proceed with excellent diastereoselectivity. Biological assays reveal that both the desmethyl and C1-epimeric monomeric nuphar analogous are able to induce rapid apoptosis.

Comparison of 9 intraocular lens power calculation formulas.

PURPOSE: To evaluate the accuracy of 9 intraocular lens (IOL) calculation formulas using 2 optical biometers. SETTING: Private practice, Saint Joseph, Michigan, USA. DESIGN: Retrospective consecutive case series. METHODS: Nine IOL power formula predictions with observed refractions after cataract surgery were compared using 1 IOL platform. The performance of each formula was ranked for accuracy by machine and by axial length (AL). The Olsen was further divided by a preinstalled version (OlsenOLCR) and a purchased version (OlsenStandalone). The Holladay 2 was divided by whether a refraction was entered (Holladay 2PreSurgRef) or not (Holladay 2NoRef). The OLCR device used in the study was the Lenstar L5 900 and the PCI device, the IOLMaster. RESULTS: The formulas were ranked by the standard deviation of the prediction error (optical low-coherence reflectometry [OLCR], partial coherence interferometry [PCI]) as follows: OlsenStandalone (0.361, 0.446), Barrett Universal II (0.365, 0.387), OlsenOLCR (0.378, not applicable), Haigis (0.393, 0.401), T2 (0.397, 0.404), Super Formula (0.403, 0.410), Holladay 2NoRef (0.404, 0.417), Holladay 1 (0.408, 0.414), Holladay 2PreSurgRef (0.423, 0.432), Hoffer Q (0.428, 0.432), and SRK/T (0.433, 0.44). CONCLUSIONS: The formulas gave different results depending on which machine measurements were used. The Olsen formula was the most accurate with OLCR measurements, significantly better than the best formula with PCI measurements. The Olsen was better, regardless of AL. If only PCI measurements (without lens thickness) were available, the Barrett Universal II performed the best and the Olsen formula performed the worst. The preinstalled version of Olsen was not as good as the standalone version. The Holladay 2 formula performed better when the preoperative refraction was excluded. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned.

Prediction accuracy of preinstalled formulas on 2 optical biometers.

PURPOSE: To evaluate how well partial coherence interferometry (PCI) (IOLMaster) and optical low-coherence reflectometry (OLCR) (Lenstar LS 900) predict postoperative refractions using only the formulas that come preinstalled on the machines. SETTING: Private practice, Saint Joseph, Michigan, USA. DESIGN: Retrospective consecutive case series. METHODS: Eyes were measured with 2 biometers before cataract surgery. Six formulas were ranked by machine. Formulas were also ranked for extremely long and short eyes by averaging the ranks of 6 statistics (mean error, mean absolute error, standard deviation [SD], maximum error, and percentage of eyes within ±0.5 diopter [D] and ±1.0 D of prediction). RESULTS: Formulas were ranked by the SD of the prediction errors. The OLCR device outperformed the PCI device using the preinstalled formulas. The Olsen formula performed the best (0.378) but was preinstalled on the OLCR device only. Other formulas had the following SDs (OLCR device first, PCI device second): Haigis (0.393, 0.401), Holladay 1 (0.408, 0.414), Hoffer Q (0.428, 0.432), SRK/T (0.433, 0.440), and SRK II (0.623, 0.633). Rankings for long eye were (first to last) were Olsen, Haigis, SRK/T, Hoffer Q, and Holladay 1. Rankings for short eyes were Olsen, Haigis, Holladay 1, SRK/T, and Hoffer Q. CONCLUSIONS: The OLCR device outperformed the PCI device using the Olsen formula. The Olsen formula also ranked first for short eyes and long eyes. Other formulas performed about the same on both machines. The SRK II formula should be avoided.

Interactions between MAP kinase and oestrogen receptor in human breast cancer.

PURPOSE: The oestrogen receptor (ERα) may be activated in a ligand-dependent manner, via oestrogen, or in a ligand-independent manner, via signal transduction pathways. Mitogen Activated Protein Kinase (MAPK) is known to directly phosphorylate ERα at serine 118 in a ligand-independent manner. This study investigated the interaction between MAPK and ERα in breast cancer. MATERIALS & METHODS: Immunohistochemical experiments were undertaken to determine the expression of MAPK, pMAPK and pER(ser118) in breast tumours to determine their clinical relevance. Immunofluorescent experiments were performed, on MCF-7 breast cancer cells, to monitor the phosphorylation and localisation of MAPK and ERα in response to oestrogen, heregulin and a MAPK inhibitor. RESULTS: Oestrogen and Heregulin stimulated phosphorylation of ERα and its nuclear translocation, but heregulin induced this at levels much lower than those observed with oestrogen. Following stimulation with heregulin, but not oestrogen, treatment with MAPK inhibitor reduced the levels of nuclear pER(ser118). In cells treated with both oestrogen and heregulin, nuclear pER(ser118) was visible; but at levels comparable with heregulin treatment alone. CONCLUSION: This study confirms that ligand-mediated phosphorylation is associated with rapid nuclear localisation of ERα, due to oestrogen binding. ERα is phosphorylated at serine 118 in a ligand-independent manner. Preventing nuclear translocation of pMAPK reduced the levels of ligand-independent, but not ligand-dependent phosphorylation of ERα. Co-stimulation with both oestrogen and heregulin suggested that heregulin mediated signalling determines the subcellular localisation of ERα. Activation of ERα by direct phosphorylation may result in its rapid deactivation due to degradation or nuclear export.

Molecular alterations in AKT1, AKT2 and AKT3 detected in breast and prostatic cancer by FISH.

AIMS: The AKT family is implicated in cancer progression. There are three mammalian AKT isoforms located on chromosomes 14, 19 and 1, respectively. The aim of the study was to investigate genetic alterations of AKT in breast and prostatic cancers using fluorescence in situ hybridization (FISH). METHODS AND RESULTS: In oestrogen receptor(ER)-positive breast carcinomas, AKT1 was deleted in five (4.8%) and amplified in one (1%) carcinoma. Deletions of AKT2 were seen in 19 (21.1%) cases. No AKT2 amplifications were identified. Ten (9.9%) AKT3 amplifications but no deletions were seen. In prostatic cancer, AKT1 was amplified in one carcinoma (2.6%). No genetic changes were observed for AKT2 and AKT3. High frequencies of aneusomy for all chromosomes were observed in breast and prostatic carcinomas. CONCLUSIONS: In breast cancer AKT3 amplifications and AKT1 and AKT2 deletions were seen, which, to our knowledge, have not been shown by FISH before. Although these two cohorts cannot be directly compared, only one AKT1 amplification was identified in prostatic carcinomas. This indicates differences in the genetic changes underlying development of breast and prostatic cancers. To evaluate further the role of genetic changes of AKT in breast cancer progression, a cohort of both ER+ and ER- patients should be evaluated.

Is expression or activation of Src kinase associated with cancer-specific survival in ER-, PR- and HER2-negative breast cancer patients?

The aim of the current study was to assess the expression levels of c-Src and phosphorylated Src kinase in human breast cancers and to establish if these are linked to oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status or patient survival. Tissue microarray technology was used to analyze 314 breast cancer specimens. Immunohistochemistry was performed using antibodies to c-Src, Y419Src, and Y215Src, and expression was assessed using the weighted histoscore method. High cytoplasmic c-Src kinase and high membrane phosphorylated activated Y419Src kinase was associated with decreased disease-specific survival. In contrast, phosphorylated activated nuclear and cytoplasmic Y215Src kinase expression levels were significantly associated with improved disease-specific survival. When the cohort was subdivided according to ER/PR/HER2 status, the ER-negative subgroup (105 patients) was associated with improved disease-specific survival and was found to be independent by multivariate analysis with a hazard ratio of 0.4 (interquartile range 0.2-0.8). High cytoplasmic c-Src expression was associated with decreased survival; high expression of activated c-Src (Y215) was associated with improved survival. This was potentiated in the ER/HER2-negative subgroup. Hence, administration of Src kinase inhibitors aiming to decrease phosphorylation should be approached with caution, especially in ER-negative patients. It is therefore essential to appropriately identify with the correct biomarkers which patients are most likely to respond to Src inhibitors.

Locoregional relapse after breast cancer: most relapses occur late and are not clinically detected.

There remains controversy over follow-up after breast cancer. The National Institute for Clinical Excellence (NICE) in the United Kingdom recommends 2-3 years of follow-up for the detection of locoregional relapse. Guidelines in North America advocate much longer follow up periods. Clinicians in the UK have been reluctant to implement the NICE guidelines. Previous studies report that the rate of relapse peaks in the first 3-5 years before falling off. In this study, a retrospective analysis of rate of relapse and method of detection in 198 patients treated with conservation surgery between 1995 and 2001 has been undertaken. Median follow-up was 5.9 years. Rate of relapse is essentially constant for 10 years, with most relapses occurring after 3 years. The majority of relapse in this cohort is detected by means other than routine clinical examination, with only 16.66% of relapse detected this way. The guidelines for follow-up in the UK need revision. If follow-up is to be provided, this needs to continue for at least 10 years, if not beyond. This study casts doubt on the value of routine clinical examination.

Ras/Raf-1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients.

PURPOSE: The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in the development and progression of cancer, and may influence response to treatments such as tamoxifen and chemotherapy. In this study we investigated whether the expression and activation of the key components of this pathway influenced clinical outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women with breast cancer. EXPERIMENTAL DESIGN: Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 [pRaf(ser338) and pRaf(ser259), respectively], MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and overall survival. RESULTS: Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy. Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses. Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen treatment (P=0.03). CONCLUSION: This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies pRaf(ser338) as a potential marker of resistance to estrogen receptor-targeted therapy. In addition, it suggests that expression of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the addition of chemotherapy may be of benefit.

Increasing incidence of breast cancer: distinguishing between the effects of birth cohort and a national breast screening programme.

The incidence of breast cancer in post-menopausal women has been affected by the introduction of national breast screening programmes. The study describes the incidence of breast cancer in Scottish women aged 50-64 by year of birth before, during, and after the prevalent round of screening. Breast cancer registrations in Scotland for women aged 45-69 years from 1977 to 2003 were obtained. Birth cohort incidence rates were calculated and interpreted in the light of screening patterns at particular calendar time points. In the years before screening, there was a small rise in breast cancer incidence by birth cohort in women aged 50-54 which was not seen in other ages. During the prevalent screening round, incidence increased significantly with increasing birth cohort and thereafter continued rises in incidence by birth cohort occurred. The observed rise in breast cancer incidence among post-menopausal women is likely to be due to both screening effects and a true increase in incidence.

A contrast-enhanced ultrasound study of benign and malignant breast tissue.

OBJECTIVE: To determine the diagnostic value of haemodynamic contrast-enhanced ultrasound assessment in benign and malignant breast tissue, using histological examination as the reference standard. METHODS: An HDI 5000 Phillips ultrasound scanner with microvascular imaging software and 2.5 ml SonoVue (Bracco spa, Milan) contrast was used to scan 50 consecutive patients (32 malignant and 18 benign, 49 with histologically confirmed breast lesions). Time-intensity curves of the regions of interest (ROI) placed over the lesional and normal breast tissues were acquired using QLAB software. The area under the curve (AUC), time to peak (TTP), in-flow gradient (IFG) and peak enhancement (PE) were determined in a standardised manner for each focal breast lesion and the control/normal breast. IFG and AUC in the periphery, and PE and AUC in the centre of the lesions, differed significantly between malignant and benign tumours. In a logistical regression model, AUC in the periphery and the ratio of PE at the tumour centre to that of normal breast were independently predictive of malignancy (p < 0.001), achieving a diagnostic sensitivity of 97% and a specificity of 80% in the 41 tumours in which central vessels could be distinguished. CONCLUSION: Haemodynamic contrast-enhanced ultrasound assessment can be used to distinguish between benign and malignant breast lesions.

Expression of tumor necrosis factor alpha converting enzyme in endocrine cancers.

Tumor necrosis factor alpha converting enzyme (TACE) mediates shedding of human epidermal growth factor receptor-4 (HER4). Recent data suggest that released HER4 intracellular domain (4ICD) induces apoptosis in breast cancer. TACE expression, as measured by immunohistochemical analysis, was observed in 183 of 383 breast carcinomas, 39 of 217 ovarian carcinomas, and 16 of 24 and 17 of 24 hormonesensitive and hormone-insensitive prostate carcinomas, respectively. HER4 expression was detected in breast carcinomas by using 2 antibodies recognizing an extracellular or intracellular epitope. TACE expression was predominantly seen in tumors with high levels of 4ICD and membranous HER4. Apoptotic activity was measured by the terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay and cleaved caspase-3 staining in breast carcinomas. There was no significant association between cleaved caspase-3 or TUNEL positivity and 4ICD, whereas TUNEL positivity was seen predominantly in tumors with high levels of internalized HER4. The data presented herein show TACE expression in endocrine cancers and further support a role for TACE in breast cancer apoptosis.

[Oncoplastic approach in breast cancer surgery--a new challenge for the future breast surgeon?]. / Onkoplasztikai szemlélet az emlorák sebészetében--új kihívás a jövo emlosebészeinek?

The future challenge of breast surgery, the so-called oncoplastic approach is reviewed in this article. The authors discuss the most frequently applied surgical techniques as well as their indications. Medline and pubmed search was carried out using the following keywords and cross-references: "oncoplastic breast surgery", "breast reconstruction", "breast conserving surgery" and "reduction mammoplasty". Original and review papers published in English language and their references were included. In the literature surprisingly, a large variety of breast oncoplastic surgical procedures has been described. Although reconstructions with local flaps are relatively easy procedures, proper indications for these are critical in order to improve cosmesis after breast conservation. Applications of pedicled flaps are technically more demanding, and only properly trained oncoplastic breast or plastic surgeons are able to provide the possibly best aesthetic outcome after mastectomy or breast conserving surgery. Finally, carrying out free flap reconstructions after mastectomy should be assigned exclusively to plastic surgeons qualified in microsurgical techniques, and not to surgical oncologists. As conclusions oncoplastic approach will be an integral element of the surgical treatment of breast cancer in the future. Breast oncoplastic training is an interdisciplinary task, which combines surgical oncological management of breast cancers with aesthetic/reconstructive breast surgery.