Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy: A Secondary Analysis of the TAILORx Randomized Clinical Trial.

Importance: A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit. Objective: To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone. Design, Setting, and Participants: In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019. Interventions: The adjuvant chemotherapy regimen was selected by the treating physician. Main Outcomes and Measures: Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]). Results: Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%). Conclusions and Relevance: The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. Trial Registration: ClinicalTrials.gov identifier: NCT00310180.

An experimental model of hemothorax autotransfusion: impact on coagulation.

BACKGROUND: Traumatic hemothorax (HTX) has been demonstrated to predictably contain low fibrinogen, low hematocrit, and low platelet counts. When analyzed on its own, shed HTX demonstrates coagulopathy. However, when mixed with normal pooled plasma (NPP) at physiologically relevant dilutions, HTX demonstrates accelerated coagulation. We hypothesize that when HTX is mixed with a patient's own plasma, the mixture will demonstrate hypercoagulability. The accelerated coagulation of this mixture would have important implications for the autotransfusion of HTX as a method of resuscitating a trauma patient. METHODS: Adult trauma patients from whom greater than 140 mL of HTX was evacuated within 1 hour of tube thoracostomy were included. HTX was sampled at 1 hour after evacuation, and a portion of the sample was centrifuged and stored as frozen plasma for later analysis. The remainder of the sample was analyzed (coagulation, hematology, electrolytes), and values were compared with concurrent venous values extracted via chart review. A citrate tube containing the patient's venous blood was additionally spun down and frozen for subsequent mixing study analysis. Coagulation was further evaluated by mixing serial dilutions of the previously frozen HTX with NPP. Additionally, the previously frozen HTX was mixed in serial dilutions with the previously frozen sample of patient plasma (PTP). RESULTS: Subjects (10) were enrolled based on inclusion criteria and collection of a discarded venous sample. In HTX samples analyzed alone, no thrombus was formed in any coagulation test (activated partial thromboplastin time [aPTT] > 180). The median aPTT value of PTP alone was 25.5. In 1-hour specimens mixed at a clinically relevant dilution of 1:4, HTX mixed with NPP had a mediana PTT value of 26.0, whereas HTX mixed with PTP had a median aPTT value of 21.7. Thus, the mixture of HTX + PTP demonstrated a statistically significantly lower aPTT than the mixture of HTX + NPP (P = 0.01). Additionally, the mixture of HTX and PTP shows a statistically significantly lower aPTT value than PTP alone (P = 0.03), indicating a hypercoagulable state. CONCLUSIONS: HTX demonstrates coagulopathy when analyzed independently, but is hypercoagulable when mixed with NPP or PTP. Furthermore, mixing studies show a statistically significantly lower aPTT when HTX is mixed with PTP versus HTX mixed with NPP. Thus, autotransfusion of HTX would likely produce a hypercoagulable state in vivo, and should not be used in place of other blood products to resuscitate a trauma patient. The autotransfusion of HTX may, however, be of use in a resource-limited environment where other blood products are not available.

A small amount can make a difference: a prospective human study of the paradoxical coagulation characteristics of hemothorax.

BACKGROUND: The evacuated hemothorax has been poorly described because it varies with time, it has been found to be incoagulable, and its potential effect on the coagulation cascade during autotransfusion is largely unknown. METHODS: This is a prospective descriptive study of adult patients with traumatic chest injury necessitating tube thoracostomy. Pleural and venous samples were analyzed for coagulation, hematology, and electrolytes at 1 to 4 hours after drainage. Pleural samples were also analyzed for their effect on the coagulation cascade via mixing studies. RESULTS: Thirty-four subjects were enrolled with a traumatic hemothorax. The following measured coagulation factors were significantly depleted compared with venous blood: international normalized ratio (>9 vs 1.1) (P < .001) and activated partial thromboplastin time (aPTT) (>180 vs 24.5 seconds) (P < .001). Mixing studies showed a dose-dependent increase in coagulation dilutions through 1:8 (P < .05). CONCLUSIONS: An evacuated hemothorax does not vary in composition significantly with time and is incoagulable alone. Mixing studies with hemothorax plasma increased coagulation, raising safety concerns.

Autotransfusion of hemothorax blood in trauma patients: is it the same as fresh whole blood?

BACKGROUND: Autotransfusable shed blood has been poorly characterized in trauma and may have similarities to whole blood with additional benefits. METHODS: This was a prospective descriptive study of adult patients from whom ≥50 mL of blood was drained within the first 4 hours after chest tube placement. Pleural and venous blood samples were analyzed for coagulation, hematology, and electrolytes. RESULTS: Twenty-two subjects were enrolled in 9 months. The following measured coagulation factors of hemothorax were significantly depleted compared with venous blood: international normalized ratio (>9 in contrast to 1.1, P < .001), activated partial thromboplastin time (>180 in contrast to 28.5 seconds, P < .001), and fibrinogen (<50 in contrast to 288 mg/dL, P < .001). The mean hematocrit (26.4 in contrast to 33.9), (P = .003), hemoglobin (9.3 in contrast to 11.8 g/dL, P = .004), and platelet count (53 in contrast to 174 K/µL, P < .001) of hemothorax were significantly lower than venous blood. A hemothorax volume of 726 mL was calculated to be equivalent to 1 U of red blood cells. CONCLUSIONS: Hemothorax blood contains significantly decreased coagulation factors and has lower hemoglobin when compared with venous blood.

Development of iron-containing multiwalled carbon nanotubes for MR-guided laser-induced thermotherapy.

AIMS: To test iron-containing multiwalled carbon nanotubes (MWCNTs) as bifunctional nanomaterials for imaging and thermal ablation of tumors. MATERIALS & METHODS: MWCNTs entrapping iron were synthesized by chemical vapor deposition. The T2-weighted contrast enhancement properties of MWCNTs containing increasing amounts of iron were determined in vitro. Suspensions of these particles were injected into tumor-bearing mice and tracked longitudinally over 7 days by MRI. Heat-generating abilities of these nanomaterials following exposure to near infrared (NIR) laser irradiation was determined in vitro and in vivo. RESULTS: The magnetic resonance contrast properties of carbon nanotubes were directly related to their iron content. Iron-containing nanotubes were functional T2-weighted contrast agents in vitro and could be imaged in vivo long-term following injection. Iron content of nanotubes did not affect their ability to generate thermoablative temperatures following exposure to NIR and significant tumor regression was observed in mice treated with MWCNTs and NIR laser irradiation. CONCLUSION: These data demonstrate that iron-containing MWCNTs are functional T2-weighted contrast agents and efficient mediators of tumor-specific thermal ablation in vivo.

Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer.

Mutations in the alpha catalytic subunit of phosphoinositol-3-kinase (PIK3CA) occur in approximately 30% of ER positive breast cancers. We therefore sought to determine the impact of PIK3CA mutation on response to neoadjuvant endocrine therapy. Exons 9 (helical domain) and 20 (kinase domain-KD) mutations in PIK3CA were determined samples from four neoadjuvant endocrine therapy trials.Interactions with clinical, pathological, and biomarker response parameters were examined. A weak negative interaction between PIK3CA mutation status and clinical response to neoadjuvant endocrine treatment was detected(N = 235 P < or = 0.05), but not with treatment-induced changes in Ki67-based proliferation index (N = 418). Despite these findings, PIK3CA KD mutation was a favorable prognostic factor for relapse-free survival (RFS log-rank P = 0.02) in the P024 trial (N = 153). The favorable prognostic effect was maintained in a multivariable analysis(N = 125) that included the preoperative endocrine prognostic index, an approach to predicting RFS based on post neoadjuvant endocrine therapy pathological stage, ER, and Ki67 levels (HR for no PIK3CA KD mutation, 14, CI 1.9-105 P = 0.01). PIK3CA mutation status did not strongly interact with neoadjuvant endocrine therapy responsiveness in estrogen receptor-positive breast cancer. Nonetheless, as with other recent studies, a favorable interaction between PIK3CA KD mutation and prognosis was detected. The mechanism for the favorable prognostic impact of PIK3CA mutation status therefore remains unexplained.

The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment.

PURPOSE: We hypothesized that administration of the angiotensin type 1 (AT1) receptor antagonist, L-158,809, to young adult male rats would prevent or ameliorate fractionated whole-brain irradiation (WBI)-induced cognitive impairment. MATERIALS AND METHODS: Groups of 80 young adult male Fischer 344 x Brown Norway (F344xBN) rats, 12-14 weeks old, received either: (1) fractionated WBI; 40 Gy of gamma rays in 4 weeks, 2 fractions/week, (2) sham-irradiation; (3) WBI plus L-158,809 (20 mg/L drinking water) starting 3 days prior, during, and for 14, 28, or 54 weeks postirradiation; and (4) sham-irradiation plus L-158,809 for 14, 28, or 54 weeks postirradiation. An additional group of rats (n = 20) received L-158,809 before, during, and for 5 weeks postirradiation, after which they received normal drinking water up to 28 weeks postirradiation. RESULTS: Administration of L-158,809 before, during, and for 28 or 54 weeks after fractionated WBI prevented or ameliorated the radiation-induced cognitive impairment observed 26 and 52 weeks postirradiation. Moreover, giving L-158,809 before, during, and for only 5 weeks postirradiation ameliorated the significant cognitive impairment observed 26 weeks postirradiation. These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks postirradiation, respectively. CONCLUSIONS: Administering L-158,809 before, during, and after fractionated WBI can prevent or ameliorate the chronic, progressive, cognitive impairment observed in rats at 26 and 52 weeks postirradiation. These findings offer the promise of improving the quality of life for brain tumor patients.

Iodine-131 metaiodobenzylguanidine treatment for metastatic carcinoid. Results in 98 patients.

BACKGROUND: Iodine-131 metaiodobenzylguanidine (131I-MIBG) is useful for imaging carcinoid tumors and recently has been applied to the palliative treatment of metastatic carcinoid in small studies. The authors now report their results on the therapeutic utility of high-dose 131I-MIBG treatment in a large group of patients with metastatic carcinoid tumors. METHODS: The authors performed a retrospective review of 98 patients with metastatic carcinoid who were treated at their institution with 131I-MIBG over a 15-year period. Endpoints examined included the World Health Organization criteria for treatment response: symptoms, hormone (5-hydroxyindoleacetic acid [5-HIAA]) production, and clinical tumor response. RESULTS: Patients received a median dose of 401 +/- 202 millicuries (mCi) 131I-MIBG. The median survival after treatment was 2.3 years. Patients who experienced a symptomatic response had improved survival (5.76 years vs. 2.09 years; P < 0.01). For the 56 patients who had 5-HIAA levels monitored, the mean urine 5-HIAA levels decreased significantly after 131I-MIBG treatment (126 +/- 122 ng/mL vs. 91 +/- 125 ng/mL; P < 0.01); however, the patients with reduced 5-HIAA levels did not experience improved survival (4.11 years vs. 3.42 years; P = 0.2). Patients who received an initial 131I-MIBG dose > 400 mCi lived longer than patients who received < 400 mCi (4.69 years vs. 1.86 years; P = 0.05). Radiographic tumor response did not predict survival. Toxicity included pancytopenia, thrombocytopenia, nausea, and emesis. CONCLUSIONS: The current data support 131I-MIBG treatment in select patients with metastatic carcinoid who progress despite optimal medical management. Improved survival was predicted best by symptomatic response to 131I-MIBG treatment, but not by hormone or radiographic response.

Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma.

INTRODUCTION: Iodine 131-meta-iodobenzylguanidine ((131)I-MIBG) has been applied to the palliative treatment of metastatic pheochromocytoma in small studies. We report our institutional experience for the treatment of metastatic pheochromocytoma and paraganglioma. METHODS: We performed a retrospective review of 33 patients with metastatic pheochromocytoma (n=22) and paraganglioma (n=11) treated at our institution with (131)I-MIBG over a 10-year period. RESULTS: Patients received a mean dose of 388+/-131 mCi (131)I-MIBG. Median survival after treatment was 4.7 years. Most patients experienced a symptomatic response leading to an improved survival (4.7 years vs 1.8 years, P<.01). Patients with a measurable hormone response demonstrated an increased survival in comparison to those with no response (4.7 years vs 2.6 years, P=.01). Patients who received a high dose (>500 mCi) as their initial therapy also had improved survival (3.8 years vs 2.8 years, P=.02). CONCLUSION: These data support (131)I-MIBG treatment for select patients with metastatic pheochromocytoma. In our experience, prolonged survival was best predicted by symptomatic and hormone response to (131)I-MIBG treatment. An initial dose of 500 mCi may be optimal. The benefit of (131)I-MIBG treatment for metastatic pheochromocytoma must also be weighed against its side effects.