Aerobic exercise training combined with local strength exercise restores muscle blood flow and maximal aerobic capacity in long-term Hodgkin lymphoma survivors.

It is unclear whether muscle blood flow (MBF) is altered in long-term Hodgkin lymphoma (HL) survivors. We tested the hypothesis that 1) MBF response during mental stress (MS) is impaired in long-term HL survivors and 2) aerobic exercise training combined with local strength exercise (ET) restores MBF responses during MS in these survivors. Eighteen 5-year HL survivors and 10 aged-paired healthy subjects (HC) were studied. Twenty HL survivors were randomly divided into two groups: exercise-trained (HLT, n = 10) and untrained (HLUT, n = 10). Maximal aerobic capacity was evaluated by a cardiopulmonary exercise test and forearm blood flow (FBF) by venous occlusion plethysmography. MS was elicited by Stroop color and word test. ET was conducted for 4 mo, 3/wk for 60 min each session. The aerobic exercise intensity corresponded to anaerobic threshold up to 10% below the respiratory compensation point. The strength exercises consisted of two to three sets of chest press, pulley and squat exercises, 12-15 repetitions each exercise at 30-50% of the maximal voluntary contraction. Baseline was similar in HL survivors and HC, except peak oxygen consumption (peak V̇o2, P = 0.013) and FBF (P = 0.006) that were lower in the HL survivors. FBF responses during MS were lower in HL survivors (P < 0.001). ET increased peak V̇o2 (11.59 ± 3.07%, P = 0.002) and FBF at rest (33.74 ± 5.13%, P < 0.001) and during MS (24 ± 5.31%, P = 0.001). Further analysis showed correlation between the changes in peak V̇o2 and the changes in FBF during MS (r = 0.711, P = 0.001). In conclusion, long-term HL survivors have impaired MBF responses during MS. ET restores MBF responses during MS.NEW & NOTEWORTHY Long-term Hodgkin lymphoma (HL) survivors have impaired muscle blood flow responses during mental stress and decreased maximal aerobic capacity. Supervised aerobic exercise training combined with local strength exercises restores muscle blood flow responses during mental stress and maximal aerobic capacity in these survivors. These findings provide evidence of safety and effectiveness of exercise training in HL survivors. Moreover, they highlight the importance of exercise training in the treatment of this set of patients.

Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity.

We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.

Inpatient palliative chemotherapy is associated with high mortality and aggressive end-of-life care in patients with advanced solid tumors and poor performance status.

BACKGROUND: The benefit of palliative chemotherapy (PC) in patients with advanced solid tumors and poor performance status (ECOG-PS) has not been prospectively validated, which makes treatment decision challenging. We aimed to evaluate the overall survival, factors associated with early mortality, and adoption of additional procedures in hospitalized patients with advanced cancer and poor ECOG-PS treated with PC. METHODS: We analyzed a retrospective cohort of patients with advanced cancer treated with PC during hospitalization at an academic cancer center in Brazil from 2014 to 2016. Eligibility criteria included: ECOG-PS 3-4 and start of first-line PC; or ECOG-PS ≥ 2 and start of second or subsequent lines. Primary endpoint was 30-day survival from start of PC. Kaplan-Meier method was used for survival estimates and Cox regression for factors associated with 30-day mortality. RESULTS: Two hundred twenty-eight patients were eligible. 21.9, 66.7 and 11.4% of patients had ECOG-PS 2, 3 and 4, respectively. 49.6% had gastrointestinal tumors. Median follow-up was 49 days (range 1-507). 98.2% of patients had died, 32% during the index hospitalization. The 30-day and 60-day survival rates were 55.7 and 38.5%, respectively. 30% of patients were admitted to the intensive care unit. In a multivariable analysis, ECOG-PS 3/4 (HR 2.01; P = 0.016), hypercalcemia (HR 2.19; P = 0.005), and elevated bilirubin (HR 3.17; P <  0.001) were significantly associated with 30-day mortality. CONCLUSIONS: Patients with advanced cancer and poor ECOG-PS had short survival after treatment with inpatient PC. Inpatient PC was associated with aggressive end-of-life care. Prognostic markers such as ECOG-PS, hypercalcemia and elevated bilirubin can contribute to the decision-making process for these patients.

Chemotherapy acutely impairs neurovascular and hemodynamic responses in women with breast cancer.

The purpose of the present study was to test the hypothesis that doxorubicin (DX) and cyclophosphamide (CY) adjuvant chemotherapy (CHT) acutely impairs neurovascular and hemodynamic responses in women with breast cancer. Sixteen women (age: 47.0 ± 2.0 yr; body mass index: 24.2 ± 1.5 kg/m) with stage II-III breast cancer and indication for adjuvant CHT underwent two experimental sessions, saline (SL) and CHT. In the CHT session, DX (60 mg/m2) and CY (600 mg/m2) were administered over 45 min. In the SL session, a matching SL volume was infused in 45 min. Muscle sympathetic nerve activity (MSNA) from peroneal nerve (microneurography), calf blood flow (CBF; plethysmography) and calf vascular conductance (CVC), heart rate (HR; electrocardiography), and beat-to-beat blood pressure (BP; finger plethysmography) were measured at rest before, during, and after each session. Venous blood samples (5 ml) were collected before and after both sessions for assessment of circulating endothelial microparticles (EMPs; flow cytometry), a surrogate marker for endothelial damage. MSNA and BP responses were increased (P < 0.001), whereas CBF and CVC responses were decreased (P < 0.001), during and after CHT session when compared with SL session. Interestingly, the vascular alterations were also observed at the molecular level through an increased EMP response to CHT (P = 0.03, CHT vs. SL session). No difference in HR response was observed (P > 0.05). Adjuvant CHT with DX and CY in patients treated for breast cancer increases sympathetic nerve activity and circulating EMP levels and, in addition, reduces muscle vascular conductance and elevates systemic BP. These responses may be early signs of CHT-induced cardiovascular alterations and may represent potential targets for preventive interventions. NEW & NOTEWORTHY It is known that chemotherapy regimens increase the risk of cardiovascular events in patients treated for cancer. Here, we identified that a single cycle of adjuvant chemotherapy with doxorubicin and cyclophosphamide in women treated for breast cancer dramatically increases sympathetic nerve activity and circulating endothelial microparticle levels, reduces the muscle vascular conductance, and elevates systemic blood pressure.

Local Consolidation Therapy (LCT) After First Line Tyrosine Kinase Inhibitor (TKI) for Patients With EGFR Mutant Metastatic Non-small-cell Lung Cancer (NSCLC).

INTRODUCTION: Although most NSCLC patients with sensitizing epidermal growth factor receptor (EGFR) mutations have an impressive initial response, the vast majority has residual disease and develops acquired resistance after 9 to 14 months of EGFR tyrosine kinase (TKI) therapy. We recently reported a phase II trial showing that, for patients with molecularly unselected oligometastatic NSCLC who did not progress after first-line systemic therapy, local consolidation therapy (LCT) with surgery or radiation improved progression-free survival (PFS), compared with maintenance therapy alone. Herein, we report a retrospective analysis of LCT after TKI in patients with metastatic EGFR mutant NSCLC. PATIENTS AND METHODS: We identified patients with metastatic EGFR mutant NSCLC treated with TKI plus LCT or with TKI alone in the MD Anderson GEMINI (Genomic Marker-Guided Therapy Initiative) database and in our recently published LCT trial. PFS was compared between LCT plus TKI and TKI only treated patients using the log-rank test. RESULTS: We identified 129 patients with EGFR mutant NSCLC who were treated with first-line TKI and 12 that were treated with TKI followed by LCT. Among the 12 patients treated with TKI plus LCT, 8 patients had oligometastatic disease (defined as ≤ 3 metastases), and 4 patients had > 3 metastases. LCT regimens were hypofractionated radiotherapy or stereotactic ablative body radiotherapy for 11 patients and surgery for 1 patient. TKI followed by LCT resulted in a significantly longer PFS (36 months) compared with TKI alone (PFS, 14 months; log-rank P = .0024). CONCLUSIONS: Our data suggests that first-line TKI plus LCT is a promising therapeutic strategy for patients with EGFR mutant NSCLC that merits further investigation.

Perioperative chemotherapy with and without high-dose methotrexate in adult osteosarcoma.

Treatment of adult osteosarcoma (AOS) includes perioperative chemotherapy and surgery. Standard chemotherapy consists of cisplatin (CP) and doxorubicin (DOX). Although considered the standard of care for pediatric patients, high-dose methotrexate (HDM) remains controversial in adults. We aimed to evaluate the role of HDM in AOS treated with curative intent. This study included patients with AOS who received perioperative chemotherapy with DOX and CP (group 1; N=16) and DOX, CP, and HDM (group 2; N=10). The primary endpoint was grade 3 or superior toxicities. The secondary endpoints included overall survival (OS) and disease-free survival. Despite lower average age (35.0±12.1 vs. 18.9±2.1 years), group 2 presented more grade 3-4 thrombocytopenia (0 vs 50%) and mucositis (0 vs 40%), whereas group 1 presented more grade 3-4 neutropenia (43.75 vs 40%). No grade 3-4 renal toxicities occurred. Two grade 5 toxicities occurred in group 2, both after the first HDM cycle. Disease-free survival (4.38±0.61 vs. 2.3±0.54 years, P=0.228) and OS (4.70±0.56 vs 2.52±0.57 years, P=0.107) were not statistically different, but presented a trend toward better outcomes in group 1. The 4-year OS was 65.6 and 32.8% for groups 1 and 2, respectively. In conclusion, HDM was associated with greater severe and lethal toxicity when added to CP and DOX in AOS. Also, it does not seem to impact on treatment efficacy. These data do not support the use of HDM for the perioperative treatment of AOS.

Management of Para-aortic Lymph Node Disease in Patients With Cervical Cancer: What Is the Best Approach?

Cervical cancer remains a prevalent and deadly disease in low-income countries, especially among young and otherwise healthy women. Multimodality treatment has led to a significant improvement in outcomes for patients with locally advanced disease, and this is mainly because of the incorporation of platinum-based chemoradiotherapy in current treatment protocols. However, locally advanced tumors are associated with a greater risk for para-aortic lymph node (PALN) involvement, which is an important adverse prognostic factor. Most staging techniques have low accuracy for detection of disease in this area, which could lead to understaging and undertreatment. Meanwhile, patients with PALN disease are underrepresented in trials addressing the treatment of advanced cervical cancer and a few studies have been directed at this population. The aim of this review is to analyze the current data regarding staging and treatment of cervical cancer with PALN disease to determine which strategy is best when managing these patients.

Sorafenib for the Treatment of Progressive Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis.

BACKGROUND: Treatment of advanced medullary thyroid carcinoma (MTC) was recently improved with the approval of vandetanib and cabozantinib. However, there is still a need to explore sequential therapy with more than one tyrosine kinase inhibitor (TKI) and to explore alternative therapies when vandetanib and cabozantinib are not available. This study reports the authors' experience with sorafenib as a treatment for advanced MTC. METHODS: This is a retrospective longitudinal study of 13 patients with progressive metastatic MTC treated with sorafenib 400 mg twice daily between December 2011 and January 2015. The primary endpoints were to evaluate response and progression-free survival (PFS) in patients treated with sorafenib outside a clinical trial. The secondary endpoint was an assessment of the toxicity profile. One patient was excluded because of a serious allergic skin rash one week after starting sorafenib. RESULTS: The analysis included 12 patients with metastatic MTC (median age 48 years), 10 with sporadic and 2 with hereditary disease. The median duration of treatment was 11 months, and the median follow-up was 15.5 months. At data cutoff, 2/12 (16%) patients were still on treatment for 16 and 34 months. According to Response Evaluation Criteria in Solid Tumors analysis, 10 (83.3%) patients showed stable disease, and two (16.6%) had progression of disease; no partial response was observed. The median PFS was nine months. However, three patients with extensive and rapidly progressive disease died within three months of sorafenib treatment. The median PFS excluding these three patients was 12 months. Adverse events (AE) occurred in nine (75%) patients. The main AEs were skin toxicity, weight loss, and fatigue. Five (41.6%) patients needed dose reduction, and one patient discontinued treatment because of toxicity. CONCLUSIONS: Treatment with sorafenib in progressive metastatic MTC is well tolerated and resulted in disease control and durable clinical benefit in 75% of patients. Sorafenib treatment could be considered when vandetanib and cabozantinib are not available or after failing these drugs.

Definitive chemoradiotherapy for advanced cervical cancer: should it be different in the elderly?

BACKGROUND: Cervical cancer (CC) is the second most common cancer in Brazilian women, and approximately 10% of cases occur in elderly patients (pts). In this age group, disease is usually diagnosed in more advanced stages and oncological therapies are usually less intensive, due to comorbidities and impaired performance status. METHODS: Retrospective analysis of pts ≥65 years old with CC admitted at a Brazilian University Cancer Center from August 2008 to February 2012. We performed a descriptive analysis of baseline performance status (PS), disease stage (FIGO), histology, body mass index (BMI), treatment received and overall survival, using the Kaplan-Meier method. RESULTS: 900 medical records were analyzed and 75 pts (8%) fulfilled the inclusion criteria. Median age was 73.4 years old (±5.5 years). Squamous cell carcinoma (SCC) was the most common histology (71 pts, 94.7%). 67 (89.3%) had PS 0 or 1 and 52 pts (69.3%) were eutrophic (BMI 18.5-25 kg/m(2)). At presentation, disease staging consisted of 18 pts (24%) stage I, 35 pts (46.7%) stage II, 8 pts (10.7%) stage III, 12 pts (16%) stage IVa and 2 pts (2.7%) stage IVb. 24 pts (32%) underwent surgery (hysterectomy, adnexectomy, pelvic and paraaortic lymphadenectomy). Adjuvant treatment with radiotherapy (RT) was performed in 13 pts (total dose of external RT in pelvis ranged from 39.6 to 45 Gy, parametrial boost ranged from 14 to 20 Gy and 4 inserts from 7 to 7.5 Gy of brachytherapy); 8 of them received concomitant platinum-based chemotherapy (CT). 30 pts underwent definitive CRT, 17 definitive RT, 1 palliative CT and 3 best supportive care. In the CRT group, 18 pts received cisplatin (CDDP 40 mg/m(2)/w/6w) and 12 carboplatin (AUC 2/w/6w). During definitive CRT, treatment was discontinued in 39% of pts who received CDDP and 25% of pts who received carboplatin, all due to treatment toxicities. CDDP was associated with more nefrotoxicity (5 pts, 28%) than carboplatin (1 pt, 8.3%). The CDDP group also presented more radiodermatitis and stroke. However, myelosuppression and diarrhea were similar in both groups. After a 26.1-month follow-up, median OS was not reached. CONCLUSIONS: Despite advanced age, more than 60% of pts underwent complete CRT treatment. Thus, age should not be the only factor to guide therapeutic decisions in CC. Carboplatin was better tolerated than CDDP in CRT group, but prospective trials are necessary to evaluate the best treatment option in this population.

Immature uterine teratoma associated with uterine inversion.

Teratomas are the most commonly diagnosed germ cell tumors and occur primarily in testes and ovaries. Platinum-based therapy followed by surgical resection of the residual lesion is generally the recommended treatment. In contrast, immature uterine teratomas are rare, with few cases reported in the literature. Moreover, there is no standard treatment for these tumors. Non-puerperal uterine inversion is also rare in women younger than 45 years of age, and neoplastic lesions are responsible for this condition. Here, we report a case of an immature uterine teratoma associated with uterine inversion. The patient underwent surgery followed by adjuvant chemotherapy and continues to be monitored.