Tracking world cases of breast implant-associated anaplastic large cell lymphoma (ALCL) is currently limited to patient registries at a few academic centers, dependent upon patient referral and case ...reports in the literature. The purpose of this study was to review and compare federal database adverse event reports of breast implant-associated ALCL encompassing the major breast implant markets worldwide.
Federal implantable device regulatory bodies were contacted and database queries were performed for 40 countries. Demographics, device characteristics, pathology, treatment modalities, and outcomes were assessed when available.
For the countries queried, 363 unique cases were reported for breast implant-associated ALCL. Search terms "anaplastic" and "ALCL" were queried of the U.S. Manufacturer and User Facility Device Experience (MAUDE) database and yielded 258 unique cases as of September 2015, of which only 130 had pathologic markers performed. Implant surface was textured significantly more than smooth (50 percent versus 4.2 percent; p = 0.0001). Treatment, when reported (n = 136), included explantation n = 125 (91.9 percent), chemotherapy n = 42 (30.8 percent), radiation therapy n = 25 (18.4 percent), and/or stem cell transplant n = 9 (6.6 percent), and five deaths were reported.
Federal reporting of breast implant-associated ALCL has limitations in providing clinical history, treatment, and oncologic follow-up. Worldwide and country-specific total and textured implant sales data are needed to determine critical incidence and prevalence analysis. International multi-institutional collaborations and centralized tissue consortiums working in concert with federal authorities are necessary to acquire accurate complete data on breast implant-associated ALCL.
Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and ...chemotherapy. Many patients with large (>5 cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow. Here we describe the development of a synergistic combination treatment strategy that may be applicable in both soft tissue sarcomas as well as sarcomas of bone that takes advantage of targeting the cell cycle. We show that Rb-positive cell lines treated with the CDK4/6 inhibitor palbociclib reversibly arrest in the G
phase of the cell cycle, and upon drug removal cells progress through the cell cycle as expected within 6-24 hours. Using a long-term high-throughput assay that allows us to examine drugs in different sequences or concurrently, we found that palbociclib-induced cell-cycle arrest poises Rb-positive sarcoma cells (SK-LMS1 and HT-1080) to be more sensitive to agents that work preferentially in S-G
phase such as doxorubicin and Wee1 kinase inhibitors (AZD1775). The synergy between palbociclib and AZD1775 was also validated
using SK-LMS1 xenografts as well as Rb-positive patient-derived xenografts (PDX) developed from leiomyosarcoma patients. This work provides the necessary preclinical data in support of a clinical trial utilizing this treatment strategy.
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Purpose
To inform bra design by analyzing 3D surface images of breast cancer patients who underwent autologous breast reconstruction.
Methods
We computed bra design measurements on 3D surface images ...of patients who underwent unilateral and bilateral autologous breast reconstruction. Breast measurements and right-left symmetry between preoperative baseline and postoperative time points were compared using either paired Student
t
-test or Wilcoxon signed-rank test, depending on the data’s distribution. Regression analysis determined associations between measurements and patient characteristics such as age. Postoperative measurements and symmetry differences were also compared between autologous and implant-based breast reconstruction.
Results
Among participants who underwent bilateral autologous breast reconstruction, the reconstructed breasts were smaller and positioned higher on the chest wall than their native breasts. For patients who underwent unilateral reconstruction, similar postoperative changes were observed in the contralateral breast due to symmetry procedures. Overall, for participants whose baseline breast measurements showed substantial asymmetry, unilateral reconstruction decreased right-left asymmetry whereas bilateral reconstruction amplified right-left asymmetry. Preoperative baseline breast measurements, age, and BMI were statistically significantly associated with most postoperative breast measurements for participants who underwent bilateral autologous reconstruction. Compared to implant-based reconstruction, autologous reconstruction resulted in fewer changes in breast shape and symmetry that are pertinent to bra fit.
Conclusion
Preoperative baseline breast measurements, age, and BMI can impact bra designs for breast cancer survivors who undergo autologous reconstruction due to size, shape, and symmetry changes. Bra needs of people who undergo autologous reconstruction differ from those who undergo implant-based reconstruction.
Background
Positive sentinel lymph node (SLN) findings in ductal carcinoma in situ (DCIS) range from 1 to 22 % but have unknown biologic significance. This study sought to identify predictors of ...positive SLNs and to assess their clinical significance for patients with an initial diagnosis of DCIS.
Methods
The study identified 1234 patients with an initial diagnosis of DCIS who underwent SLN dissection (SLND) at our institution from 1997 through 2011. Positive SLN findings were categorized as isolated tumor cells (ITCs) (≤0.2 mm), micrometastases (>0.2–2 mm), or macrometastases (>2 mm). Predictors of positive SLNs were analyzed, and survival outcomes were examined.
Results
Positive SLN findings were identified in 132 patients (10.7 %): 66 patients with ITCs (5.4 %), 36 patients with micrometastases (2.9 %), and 30 patients with macrometastases (2.4 %). Upstaging to microinvasive (
n
= 68, 5.5 %) or invasive (
n
= 259, 21.0 %) cancer occurred for 327 patients (26.5 %). Factors predicting positive SLNs included diagnosis by excisional biopsy (odds ratio OR 1.90;
P
= 0.007), papillary histology (OR 1.77;
P
= 0.006), DCIS larger than 2 cm (OR 1.55;
P
= 0.030), more than three interventions before SLND (4 interventions: OR 2.04;
P
= 0.022; ≥5 interventions: OR 3.87;
P
< 0.001), and occult invasion (microinvasive: OR 3.44;
P
= 0.001; invasive: OR 6.21;
P
< 0.001). The median follow-up period was 61.7 months. Patients who had pure DCIS with and without positive SLNs had equivalent survival rates (100.0 vs 99.7 %;
P
= 0.679). Patients with occult invasion and positive SLNs had the worst survival rate (91.7 %;
P
< 0.001).
Conclusions
Occult invasion and more than three total interventions were the strongest predictors of positive SLN findings in patients with an initial diagnosis of DCIS. This supports the theory of benign mechanical transport of breast epithelial cells. Except for patients at high risk for invasive disease, routine use of SLND in DCIS is not warranted.
Clinical predictors of pathological complete response have not reliably identified patients for whom an organ-sparing approach following neoadjuvant chemoradiation be undertaken for esophageal cancer ...patients. We sought to identify high-risk predictors of residual carcinoma that may preclude patients from a selective surgical approach.
Patients treated with neoadjuvant chemoradiation followed by esophagectomy for esophageal adenocarcinoma were identified.
Correlation between clinical and pathologic complete responses were examined. Regression models and recursive partitioning were utilized to identify features associated with residual carcinoma. External validation of these high-risk factors was performed on a data set from an independent institution.
A total of 326 patients were identified, in whom clinical complete response was noted in 104/326 (32%). Pathologic complete response was noted in only 33/104 (32%) of these clinical complete responders. Multivariable analysis identified that the presence of stricture ( P =0.011), positive biopsy ( P =0.010), and signet ring cell histology ( P =0.019) were associated with residual cancer. Recursive partitioning corroborated a 94% probability of residual disease, or greater, for each of these features. The positive predictive value was >90% for these characteristics. A SUV max >5.4 at the esophageal primary in the absence of esophagitis was also a high-risk factor for residual carcinoma. External validation confirmed these high-risk factors to be implicated in the finding of residual carcinoma.
Clinical parameters of response are poor predictors of complete pathologic response leading to challenges in selecting candidates for active surveillance. However, we characterize several high-risk features for residual carcinoma which indicate that esophagectomy should not be delayed.
Interleukin 24 (IL-24) is a tumor-suppressing protein, which inhibits angiogenesis and induces cancer cell-specific apoptosis. We have shown that IL-24 regulates apoptosis through phosphorylated ...eukaryotic initiation factor 2 alpha (eIF2α) during endoplasmic reticulum (ER) stress in cancer. Although multiple stresses converge on eIF2α phosphorylation, the cellular outcome is not always the same. In particular, ER stress-induced apoptosis is primarily regulated through the extent of eIF2α phosphorylation and activating transcription factor 4 (ATF4) action. Our studies show for the first time that cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation is required for IL-24-induced cell death in a variety of breast cancer cell lines and this event increases ATF4 activity. We demonstrate an undocumented role for PKA in regulating IL-24-induced cell death, whereby PKA stimulates phosphorylation of p38 mitogen-activated protein kinase and upregulates extrinsic apoptotic factors of the Fas/FasL signaling pathway and death receptor 4 expression. We also demonstrate that phosphorylation and nuclear import of tumor suppressor TP53 occurs downstream of IL-24-mediated PKA activation. These discoveries provide the first mechanistic insights into the function of PKA as a key regulator of the extrinsic pathway, ER stress, and TP53 activation triggered by IL-24.
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