Stage I Breast Cancer in the Modern Era: A Retrospective Cohort Study of 328 Patients Diagnosed from 2002 to 2006 with a 14-Year Median Follow-Up.

INTRODUCTION: This study aimed to evaluate the long-term outcomes of stage I breast cancer (BC) patients diagnosed during the current era of screening mammography, immunohistochemistry receptor testing, and systemic adjuvant therapy. METHODS: A retrospective cohort study was conducted on 328 stage I BC patients treated consecutively in a single referral center with a follow-up period of at least 12 years. The primary endpoints were invasive disease-free survival (IDFS) and overall survival (OS). The influence of tumor size, grade, and subtype on the outcomes was analyzed. RESULTS: Most patients were treated by lumpectomy, sentinel node biopsy, and adjuvant endocrine therapy, and most (82%) were of subtype luminal A. Adjuvant chemotherapy was administered to 25.6% of our cohort. Only 24 patients underwent gene expression testing, which was introduced toward the end of the study period. Mean IDFS was 14.64 years, with a 15-year IDFS of 75.6%. Mean OS was 15.28 years with a 15-year OS of 74.9%. In a Cox multivariate analysis, no clinical or pathologic variable impacted on OS and only tumor size (<1 cm vs. 1-2 cm) impacted significantly on IDFS. During follow-up, 20.1% of the cohort developed second primary cancers, including BC. The median time to diagnosis of a second BC was 6.49 years. CONCLUSION: The study results emphasize the importance of long-term follow-up and screening for subsequent malignancies of patients with stage I BC and support the need for using prognostic and predictive indicators beyond the routine clinicopathological characteristics in luminal A patients.

Epidemiological, clinical, and pathological characteristics of invasive breast cancer in Bedouin and Jewish women in southern Israel: a retrospective comparative study.

BACKGROUND: Invasive breast cancer (IBC) is a leading cause of cancer-related death among women in Israel, regardless of ethnicity. This study compared IBC epidemiological, clinical, and pathological characteristics in Bedouin and Jewish patients in southern Israel. METHODS: Medical records of 1514 Jewish and 191 Bedouin women with IBC treated at Soroka University Medical Center between 2014 and 2021 were analyzed retrospectively. Baseline measures and tumor characteristics were compared between groups. Overall survival (OS) and disease-free survival (DFS) were analyzed using log-rank test. Multivariate analysis was performed using the Cox proportional hazard model. RESULTS: Bedouin patients exhibited a significantly younger age at diagnosis (median 48 vs. 62 years, p < 0.001), larger tumor size (median 2.5 vs. 2.13 cm, p < 0.001), and higher metastasis rate (18.8% vs. 12.7%, p = 0.03) compared to Jewish patients. In early-stage (non-metastatic) disease, Jewish and Bedouin patients had comparable overall survival (OS) rates (127 vs. 126 months, p = 0.2), consistent across stages 1 to 3. However, among patients with metastatic disease, Bedouins exhibited significantly longer OS (76.6 vs. 37.8 months, p = 0.006). Disease-free survival (DFS) showed no ethnic differences (not reached vs. 122 months, p = 0.31). There were no significant differences in OS between Bedouin and Jewish patients undergoing various treatment modalities for early-stage disease: surgery, adjuvant radiotherapy, chemotherapy, and systemic neoadjuvant therapy. CONCLUSION: Breast cancer among Bedouin women in southern Israel manifests at a younger age, with larger tumors and more advanced stages than in Jewish women. However, recent data indicate no differences in OS and DFS between the ethnic groups despite past disparities in prognosis.

Probing lipids relaxation times in breast cancer using magnetic resonance spectroscopic fingerprinting.

OBJECTIVES: To investigate the clinical relevance of the relaxation times of lipids within breast cancer and normal fibroglandular tissue in vivo, using magnetic resonance spectroscopic fingerprinting (MRSF). METHODS: Twelve patients with biopsy-confirmed breast cancer and 14 healthy controls were prospectively scanned at 3 T using a protocol consisting of diffusion tensor imaging (DTI), MRSF, and dynamic contrast-enhanced (DCE) MRI. Single-voxel MRSF data was recorded from the tumor (patients) - identified using DTI - or normal fibroglandular tissue (controls), in under 20 s. MRSF data was analyzed using in-house software. Linear mixed model analysis was used to compare the relaxation times of lipids in breast cancer VOIs vs. normal fibroglandular tissue. RESULTS: Seven distinguished lipid metabolite peaks were identified and their relaxation times were recorded. Of them, several exhibited statistically significant changes between controls and patients, with strong significance (p < 10-3) recorded for several of the lipid resonances at 1.3 ppm (T1 = 355 ± 17 ms vs. 389 ± 27 ms), 4.1 ppm (T1 = 255 ± 86 ms vs. 127 ± 33 ms), 5.22 ppm (T1 = 724 ± 81 ms vs. 516 ± 62 ms), and 5.31 ppm (T2 = 56 ± 5 ms vs. 44 ± 3.5 ms, respectively). CONCLUSIONS: The application of MRSF to breast cancer imaging is feasible and achievable in clinically relevant scan time. Further studies are required to verify and comprehend the underling biological mechanism behind the differences in lipid relaxation times in cancer and normal fibroglandular tissue. KEY POINTS: •The relaxation times of lipids in breast tissue are potential markers for quantitative characterization of the normal fibroglandular tissue and cancer. •Lipid relaxation times can be acquired rapidly in a clinically relevant manner using a single-voxel technique, termed MRSF. •Relaxation times of T1 at 1.3 ppm, 4.1 ppm, and 5.22 ppm, as well as of T2 at 5.31 ppm, were significantly different between measurements within breast cancer and the normal fibroglandular tissue.

Ultrafast DCE-MRI for discriminating pregnancy-associated breast cancer lesions from lactation related background parenchymal enhancement.

OBJECTIVE: To investigate the utility of ultrafast dynamic-contrast-enhanced (DCE) MRI in visualization and quantitative characterization of pregnancy-associated breast cancer (PABC) and its differentiation from background-parenchymal-enhancement (BPE) among lactating patients. MATERIALS AND METHODS: Twenty-nine lactating participants, including 10 PABC patients and 19 healthy controls, were scanned on 3-T MRI using a conventional DCE protocol interleaved with a golden-angle radial sparse parallel (GRASP) ultrafast sequence for the initial phase. The timing of the visualization of PABC lesions was compared to lactational BPE. Contrast-noise ratio (CNR) was compared between the ultrafast and conventional DCE sequences. The differences in each group's ultrafast-derived kinetic parameters including maximal slope (MS), time to enhancement (TTE), and area under the curve (AUC) were statistically examined using the Mann-Whitney test and receiver operator characteristic (ROC) curve analysis. RESULTS: On ultrafast MRI, breast cancer lesions enhanced earlier than BPE (p < 0.0001), enabling breast cancer visualization freed from lactation BPE. A higher CNR was found for ultrafast acquisitions vs. conventional DCE (p < 0.05). Significant differences in AUC, MS, and TTE values were found between the tumor and BPE (p < 0.05), with ROC-derived AUC of 0.86 ± 0.06, 0.82 ± 0.07, and 0.68 ± 0.08, respectively. The BPE grades of the lactating PABC patients were reduced as compared with the healthy lactating controls (p < 0.005). CONCLUSION: Ultrafast DCE MRI allows BPE-free visualization of lesions, improved tumor conspicuity, and kinetic quantification of breast cancer during lactation. Implementation of this method may assist in the utilization of breast MRI for lactating patients. CLINICAL RELEVANCE: The ultrafast sequence appears to be superior to conventional DCE MRI in the challenging evaluation of the lactating breast. Thus, supporting its possible utilization in the setting of high-risk screening during lactation and the diagnostic workup of PABC. KEY POINTS: • Differences in the enhancement slope of cancer relative to BPE allowed the optimal visualization of PABC lesions on mid-acquisitions of ultrafast DCE, in which the tumor enhanced prior to the background parenchyma. • The conspicuity of PABC lesions on top of the lactation-related BPE was increased using an ultrafast sequence as compared with conventional DCE MRI. • Ultrafast-derived maps provided further characterization and parametric contrast between PABC lesions and lactation-related BPE.

Neoadjuvant therapy with doxorubicin-cyclophosphamide followed by weekly paclitaxel in early breast cancer: a retrospective analysis of 200 consecutive patients treated in a single center with a median follow-up of 9.5 years.

PURPOSE: We analyzed outcomes of doxorubicin-cyclophosphamide (AC) followed by weekly paclitaxel as neoadjuvant chemotherapy (NAC) for breast cancer (BC), in an everyday practice with long-term follow-up of patients. METHODS: All patients (n = 200) who received the AC-paclitaxel combination as NAC for BC at the Soroka University Medical Center from 2003 to 2012 were included in this retrospective cohort study. AC was administered on an every 3-week schedule (standard dose) until May, 2007 (n = 99); and subsequently every 2-week dose dense (dd) (n = 101). Clinical pathologic features, treatment course, and outcome information were recorded. Complete pathologic response (pCR) was analyzed according to BC subtype, dose regimen, and stage. RESULTS: Median age was 49 years; 55.5% and 44.5% of patients were clinically stage 2 and 3, respectively. Standard dose patients had more T3 tumors. Subtypes were human epidermal growth factor receptor-2 (HER2)-positive 32.5% (of whom 82% received trastuzumab), hormone receptor-positive/HER2-negative 53%, and triple negative 14.5%. Breast-conserving surgery (BCS) was performed in 48.5% of patients; only 9.5% were deemed suitable for BCS prior to NAC. Toxicity was acceptable. The overall pCR rate was 26.0% and was significantly higher in the dd group and HER2-positive patients. With a median follow-up of 9.51 years median event-free survival (EFS) and overall survival (OS) are 10.85 years and 12.61 years, respectively. Patients achieving pCR had significantly longer EFS and OS. CONCLUSION: NAC for BC with AC-paclitaxel can be safely administered in the "real-world' setting with high efficacy. Current efforts are aimed at increasing rates of pCR and identifying patients who may benefit from additional therapy or conversely, de-escalated treatment.

Diffusivity in breast malignancies analyzed for b > 1000 s/mm2 at 1 mm in-plane resolutions: Insight from Gaussian and non-Gaussian behaviors.

Diffusion-weighted imaging (DWI) can improve breast cancer characterizations, but often suffers from low image quality -particularly at informative b > 1000 s/mm2 values. The aim of this study was to evaluate multishot approaches characterizing Gaussian and non-Gaussian diffusivities in breast cancer. This was a prospective study, in which 15 subjects, including 13 patients with biopsy-confirmed breast cancers, were enrolled. DWI was acquired at 3 T using echo planar imaging (EPI) with and without zoomed excitations, readout-segmented EPI (RESOLVE), and spatiotemporal encoding (SPEN); dynamic contrast-enhanced (DCE) data were collected using three-dimensional gradient-echo T1 weighting; anatomies were evaluated with T2 -weighted two-dimensional turbo spin-echo. Congruence between malignancies delineated by DCE was assessed against high-resolution DWI scans with b-values in the 0-1800 s/mm2 range, as well as against apparent diffusion coefficient (ADC) and kurtosis maps. Data were evaluated by independent magnetic resonance scientists with 3-20 years of experience, and radiologists with 6 and 20 years of experience in breast MRI. Malignancies were assessed from ADC and kurtosis maps, using paired t tests after confirming that these values had a Gaussian distribution. Agreements between DWI and DCE datasets were also evaluated using Sorensen-Dice similarity coefficients. Cancerous and normal tissues were clearly separable by ADCs: by SPEN their average values were (1.03 ± 0.17) × 10-3 and (1.69 ± 0.19) × 10-3  mm2 /s (p < 0.0001); by RESOLVE these values were (1.16 ± 0.16) × 10-3 and (1.52 ± 0.14) × 10-3 (p = 0.00026). Kurtosis also distinguished lesions (K = 0.64 ± 0.15) from normal tissues (K = 0.45 ± 0.05), but only when measured by SPEN (p = 0.0008). The best statistical agreement with DCE-highlighted regions arose for SPEN-based DWIs recorded with b = 1800 s/mm2 (Sorensen-Dice coefficient = 0.67); DWI data recorded with b = 850 and 1200 s/mm2 , led to lower coefficients. Both ADC and kurtosis maps highlighted the breast malignancies, with ADCs providing a more significant separation. The most promising alternative for contrast-free delineations of the cancerous lesions arose from b = 1800 s/mm2 DWI. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 3.

[Plasma DNA measurement as a biomarker of cancer].

BACKGROUND: Carcinoembryonic antigen (CEA) and CA 15-3 serve as biomarkers in the two prevalent cancers of the colon and breast, respectively. However, their sensitivity for screening is tow. Circulating DNA has been suggested as a potential marker. We developed a fluorometric method which enables an easy, fast and reliable DNA measurement. This manuscript presents the results of our experiments to evaluate the significance of DNA measurements in breast and colon patients. METHODS: Patients who had been diagnosed with early stages of colon or breast cancer were recruited into a prospective study. Blood samples were withdrawn for the determination of CEA, CA 15-3 (according to the type of cancer) and circulating DNA concentrations prior to any therapeutic intervention. Control DNA Levels were determined in blood samples of healthy volunteers. RESULTS: Mean circulating DNA in patients with colon cancer was higher than in control subjects [798+409 ng/ml vs. 308 +/- 256 ng/ml, p<0.0001. High DNA concentrations were identified in 40% of colon patients compared with 28% with increased CEA levels. Mean DNA levels among breast cancer patients was higher than the control group [1060 +/- 670.9 ng/mt vs. 376.2 +/- 244.1 ng/ml, p=0.0001]. High DNA concentrations were identified in 53% of breast cancer patients compared with 9% with increased CA 15-3 levels. CONCLUSION: A novel simple, rapid, cheap and reliable fluoroscopic method was used to determine circulating DNA levels in the blood of breast and colon cancer patients. Increased DNA concentrations were found in the blood of early cancer patients. This method demonstrates a better sensitivity compared with the traditional markers.

Application of Intraoperative Radiotherapy in Early-Stage Breast Cancer Patients in a Clinical Setting.

Background: Intraoperative radiation therapy (IORT) has gained popularity in recent years as an alternative to external beam whole breast radiation therapy (WBRT) for early-stage breast cancer. Here, we report 43-month recurrence and survival outcomes in a multiethnic cohort treated with IORT in a clinical context. Method: Two hundred and eleven patients with low-risk features were treated with IORT for early-stage breast cancer from 2014 to 2021. Selection criteria were based on Group Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) guidelines: preferably unifocal intraductal carcinoma (IDC), aged > 50, tumor size ≤ 2.0 cm, and without lymph node involvement. All patients received 20 Gy of radiation dose during the lumpectomy. Information on patient and tumor characteristics was collected. Results: The mean age of this cohort was 67.5 years; 95.2% of patients are Jewish, and the rest are Bedouins (4.7%). Most tumors were intraductal carcinoma (97.2%) and stage 1 (94.8%). The mean follow-up time was 43.4 months. Bedouins had larger tumor sizes (mean 1.21 vs. 1.13 cm) and were younger at diagnosis than Jewish patients (mean 65.4 vs. 67.6 years), although the differences are not significant. The overall recurrence rate was 1.4%. One case of local recurrence (0.5%) and two cases of metastasis (0.9%) were observed during the study period. One patient died from metastasis. Conclusion: Our findings suggest that IORT in selected low-risk patients can achieve an excellent prognosis with low rates of recurrence and metastasis.

Relaxation-Diffusion T2-ADC Correlations in Breast Cancer Patients: A Spatiotemporally Encoded 3T MRI Assessment.

Quantitative correlations between T2 and ADC values were explored on cancerous breast lesions using spatiotemporally encoded (SPEN) MRI. To this end, T2 maps of patients were measured at more than one b-value, and ADC maps at several echo time values were recorded. SPEN delivered quality, artifact-free, TE-weighted DW images, from which T2-ADC correlations could be obtained despite the signal losses brought about by diffusion and relaxation. Data confirmed known aspects of breast cancer lesions, including their reduced ADC values vs. healthy tissue. Data also revealed an anticorrelation between the T2 and ADC values, when comparing regions with healthy and diseased tissues. This is contrary to expectations based on simple water restriction considerations. It is also contrary to what has been observed in a majority of porous materials and tissues. Differences between the healthy tissue of the lesion-affected breast and healthy tissue in the contralateral breast were also noticed. The potential significance of these trends is discussed, as is the potential of combining T2- and ADC-weightings to achieve an enhanced endogenous MRI contrast about the location of breast cancer lesions.

Cell-free DNA concentration in patients with clinical or mammographic suspicion of breast cancer.

Mammography has a crucial role in the detection of breast cancer (BC), yet it is not limitation-free. We hypothesized that the combination of mammography and cell-free DNA (cfDNA) levels may better discriminate patients with cancer. This prospective study included 259 participants suspected with BC before biopsy. Blood samples were taken before biopsy and from some patients during and at the end of treatment. cfDNA blood levels were measured using our simple fluorescent assay. The primary outcome was the pathologic diagnosis of BC, and the secondary aims were to correlate cfDNA to severity, response to treatments, and outcome. Median cfDNA blood levels were similar in patients with positive and negative biopsy: 577 vs. 564 ng/ml (p = 0.98). A significant decrease in cfDNA blood level was noted after the following treatments: surgery, surgery and radiation, neo-adjuvant chemotherapy and surgery, and at the end of all treatments. To conclude, the cfDNA level could not be used in suspected patients to discriminate BC. Reduction of tumor burden by surgery and chemotherapy is associated with reduction of cfDNA levels. In a minority of patients, an increase in post-treatment cfDNA blood level may indicate the presence of a residual tumor and higher risk. Further outcome assessment for a longer period is suggested.

Can intensive care physicians safely perform percutaneous dilational tracheostomy? An analysis of 207 cases.

BACKGROUND: Percutaneous tracheostomy has largely replaced surgical tracheostomy in the intensive care unit setting. Although it seems logical that surgeons continue to do tracheostomies, anesthesiologists and intensive care specialists are familiar with airway control and guide wire techniques and could replace surgeons in the performance of PDT. OBJECTIVES: To assess the safety and effectiveness of bedside PDT in the ICU. METHODS: We conducted a retrospective chart review of 207 patients in the ICU who underwent PDT by an intensive care physician. RESULTS: Subcutaneous emphysema without pneumothorax occurred in one patient. Four patients underwent surgical revision following PDT. Early bleeding (during the first 48 hours following the procedure) was the indication in two patients and late bleeding, on the 10th post-PDT day, in one. In one case PDT was converted to surgical tracheostomy due to inadvertent early decannulation. There was one death directly related to the procedure, due to an unrecognized paratracheal insertion of the tracheostomy tube followed by mechanical ventilation, which led to bilateral pneumothorax, pneumomediastinum and cardio-circulatory collapse. No infectious complications were seen at the stoma site or surrounding tissues. CONCLUSIONS: PDT by intensive care physicians appears to be safe and should be included in the curriculum of intensive care residency.

The effect of hypertonic (3%) saline with and without furosemide on plasma osmolality, sodium concentration, and brain water content after closed head trauma in rats.

Adding furosemide (F) to mannitol causes a greater decrease of brain volume, intracranial pressure, and brain water content (BW) as compared with mannitol alone. We examined whether adding F to hypertonic saline (HS) causes less increase of BW early after closed head trauma (CHT) as compared with HS alone. With institutional approval, 125 rats underwent sham surgery or CHT and then immediately received no treatment, HS (1.2 g/kg, 3% solution), or HS + F (2 mg/kg). In groups 1-10 (n = 8/group), the percent BW content was determined at 30, 60, or 120 minutes. In groups 11-14 (n = 8/group), physiologic values were determined at 0, 30, 60, and 120 minutes. At 120 minutes, the increase of BW caused by CHT (sham = 78.9 +/- 0.6% and CHT = 81.5 +/- 2.2%, mean +/- SD) was prevented by HS + F (78.0 +/- 0.8%) but not by HS (80.7 +/- 2.2%). Both HS and HS + F similarly increased plasma osmolality and sodium concentration. Post-CHT hypotension and acidosis (30 and 60 minutes) and decrease of hemoglobin concentration (120 minutes) were less with HS + F than with HS. We conclude that adding F to HS decreases BW without causing more increase of osmolality and Na than that caused by HS alone.

Measurement of circulating cell-free DNA levels by a simple fluorescent test in patients with breast cancer.

OBJECTIVES: To evaluate circulating cell-free DNA (CFD) measured by a simple fluorescent assay as a biomarker of breast cancer. METHODS: We enrolled 38 patients with breast cancer before surgery, two patients with noncancerous breast lesions, nine patients after surgery, 16 healthy participants, and 29 control women admitted to the hospital emergency ward and released without hospitalization. CFD levels were measured by a direct fluorescence assay. RESULTS: Presurgery patients with cancer had elevated CFD levels (1,010 ± 642 ng/mL), which were higher than those measured in the healthy control group (395 ± 248 ng/mL, P < .001), the noncancer breast lesion group (386 ± 40 ng/mL), the nonhospitalized control group (492 ± 193 ng/mL, P < .001), and the postsurgery cancer group (398 ± 162 ng/mL, P < .01). The area under the receiver operating characteristic curve of the presurgery vs healthy patient group was 0.83. CFD levels correlated with tumor size (P = .03, ρ = 0.36), nodal involvement (P = .0003, ρ = 0.56), and TNM stage (P = .0002, ρ = 0.56). All patients with axillary node involvement had a CFD value greater than 600 ng/mL. CONCLUSIONS: CFD measured using a simple fluorometric assay has shown good correlation to stage and enhanced sensitivity to locally advanced disease. A large prospective study is warranted to evaluate if inclusion of this method as a decisive marker before mammography is advantageous.