DIBH reduces right coronary artery and lung radiation dose in right breast cancer loco-regional radiotherapy.

To determine whether deep inspiratory breath-hold (DIBH) reduces dose to organs-at-risk (OAR), in particular the right coronary artery (RCA), in women with breast cancer requiring right-sided post-mastectomy radiotherapy (PMRT) including internal mammary chain (+IMC) radiotherapy (RT). Fourteen consecutive women requiring right-sided PMRT + IMC were retrospectively identified. Nodal delineation was in accordance with European Society for Radiology and Oncology (ESTRO) guidelines and tangential chest wall fields marked. Patients were planned with Anisotropic Analytical Algorithm using free-breathing (FB) and DIBH datasets. Dose was calculated using Acuros External Beam algorithm. FB and DIBH dose comparisons were analyzed for heart, RCA and right lung, as were chest wall and IMC planning target volumes (PTVs). DIBH vs FB resulted in median decreases of: the RCA mean dose by 0.6Gray (Gy) (interquartile range (IQR) 0.1, 1.9) (p = 0.002), RCA max dose by 1.8Gy (IQR 0.8, 6.1) (p = 0.002), and V5Gy by 2.9% (IQR 0.0, 37.2) (p = 0.016). RCA data indicated no statistically significant dosimetric reduction ≥10Gy. A median reduction of 1.7Gy (c -0.0, 7.1) (p = 0.019) in maximum heart dose was recorded with DIBH vs FB; no significant difference was observed in other heart and left anterior descending coronary artery parameters. The median reduction in right lung mean dose was 2.8Gy for DIBH vs FB plans (IQR 1.6, 3.6) (p = 0.001); significant median reductions of V5Gy, V20Gy, and V30Gy were all achieved with DIBH. Chest wall PTV coverage did not significantly differ between DIBH and FB plans; IMC dosimetric coverage improved with use of DIBH (V47.5Gy, V45Gy, V42Gy). DIBH reduced OAR dose in right-sided PMRT + IMC patients. A novel finding was that DIBH decreased RCA dose. Heart and right lung dose were also decreased with DIBH, whilst optimally dosed PTVs were maintained.

Rhombencephalitis in Pregnancy-A Challenging Case of Probable Listeria Infection.

Rhombencephalitis refers to inflammation of the brainstem and cerebellum, and can be caused by infections, autoimmune disorders or paraneoplastic syndromes. The most common infective cause is the bacterium Listeria monocytogenes. Listeria monocytogenes is the predominant species to cause human listeriosis, and is commonly due to the ingestion of contaminated foods. Symptoms include a mild gastroenteritis, fever (often with extreme temperature variations), headache, and myalgia. In more severe cases, invasive disease may lead to bacteraemia and neurolisteriosis. Pregnant women are more susceptible to listeriosis, which is believed to be due to pregnancy-related immune modulation. Maternal-neonatal infection with adverse pregnancy outcomes include neonatal listeriosis, spontaneous miscarriage and intrauterine fetal demise. Diagnosis may be challenging due to initial nonspecific symptoms and low sensitivity and specificity of confirmatory diagnostic laboratory tests. Here, we describe a case of rhombencephalitis in pregnancy, attributed to Listeria, and review the clinical features, diagnosis and multidisciplinary management. Lastly, we describe the immunological response to Listeria monocytogenes and show in vitro pro-inflammatory effects of Listeria monocytogenes on peripheral blood mononuclear cells and placental explants.

Feasibility of arm-draining lymph node-sparing radiotherapy of breast cancer: A pilot planning study.

INTRODUCTION: Lymphoedema following axillary radiotherapy for breast cancer causes significant morbidity. Our goal was to evaluate the feasibility of sparing the lymph node that drains the arm's lymphatics (ARM node) while achieving standard dose constraints for whole breast and comprehensive lymph node irradiation. METHODS: Six patients underwent lymphoscintigraphy and SPECT CT to identify the breast sentinel node (SN) and ARM node. The ARM node was contoured on the SPECT CT and deformably registered to the radiotherapy treatment planning CT. Radiotherapy plans (50 Gy in 25 fractions) with VMAT technique were generated, with the aim to spare the ARM node (Mean dose <25 Gy) and achieve adequate coverage to the remaining axilla. The plan required the breast SN site (clip + 10 mm surrounding the clip) to achieve D98% > 47.5 Gy, and axillary nodal CTV excluding ARM node to achieve D90% > 45 Gy. RESULTS: In one patient, the ARM node was within the volume of breast SN site and sparing was not possible. For the remaining 5 patients, an ARM node-sparing plan could be successfully generated; the mean dose to the ARM node ranged from 11.2 to 23.1 Gy (median 13.8 Gy). In these 5 subjects, D90% > 45 Gy of axillary nodal CTV (range, 44.9-48.5 Gy, median 46.2 Gy) and D98% > 47.5 Gy of breast SN site were achieved. CONCLUSION: In this planning study, ARM node-sparing VMAT of the breast and lymph nodes was feasible, while maintaining adequate dosimetric coverage. However, in some individuals, localization of the ARM node in close proximity to breast SN site precluded the generation of an ARM node-sparing treatment plan.

Verification using in vivo optically stimulated luminescent dosimetry of the predicted skin surface dose in patients receiving postmastectomy radiotherapy.

The purpose of this study was to evaluate whether dose to the skin surface underneath bolus, was accurately predicted by a 3D treatment planning system (TPS) in patients receiving 50 Gy/25# postmastectomy radiotherapy (PMRT) using optically stimulated luminescent dosimetry (OSLD) for verification. In vivo dosimetry using OSLDs was performed in 20 consecutive patients receiving PMRT. An array of 9 OSLDs were applied to the chest wall or neobreast in a grid arrangement. Dosimetry data were recorded on 3 separate treatment fractions, averaged, and extrapolated to 25 fractions. On the 3D TPS, the predicted dose was calculated using the departmental planning algorithm at points corresponding to the OSLDs. The mean within patient difference between the planned and measured dose at each of the 9 points was calculated and Bland-Altman limits of agreement used to quantify the extent of agreement. Paired t-tests were used to test for evidence of systematic bias at each point. The coefficient of variation of the 3 OSLD readings per patient at each of the 9 points was low for 8 points (≤4.4%) demonstrating comparable dose received per fraction at these points. The mean ratio between the in vivo measured extrapolated OSLD (IVME OSLD) dose and the planned TPS dose ranged between 0.97 and 0.99 across all points (standard deviation range 0.05 to 0.08). The mean within patient difference between the IVME OSLD and planned TPS was <1 Gy at 7 of the 9 points and the t-test for evidence of systematic bias was significant (p = 0.03) at only 1 of the 9 points. Our commercially available 3D TPS closely predicted PMRT skin surface dose underneath bolus as verified by OSLDs. At all sites, the average ratio of delivered to predicted dose was >0.97 but <1. This practical and feasible OSLD assessment of only 3 of 25 fractions facilitates quality assurance of a TPS in predicting skin surface dose under bolus.

Location of arm draining lymph node in relation to breast cancer radiotherapy field and target volume.

BACKGROUND: Lymphoedema of the arm following axillary surgery or radiotherapy remains a significant side effect affecting some women after breast cancer treatment. Axillary reverse mapping (ARM) is a technique used to identify the lymph node draining the arm (ARM node). Our study aim was to examine the location of the ARM nodes in relation to target volumes and treatment fields for breast cancer radiotherapy. MATERIALS AND METHODS: Eighteen breast cancer patients underwent lymphoscintigraphy of contralateral arm (left 10, right 8) and SPECT CT scan on a research study. Patient position for the SPECT CT scan approximated the position used for radiotherapy. Using MIM software™, the ARM node for each subject was contoured on the SPECT CT and verified by a nuclear medicine physician. The CT component of the SPECT CT was then transferred to ECLIPSE™ radiotherapy planning software, and the contralateral breast and axilla were contoured on this CT scan according to the ESTRO contouring guideline. Two radiotherapy plans were generated for each subject using standard tangential IMRT technique at a dose of 50 Gy in 25 fractions, one treating contralateral breast alone, the other treating contralateral breast and contralateral axilla level 1-4. The ARM node was considered "within the radiotherapy field" if the mean dose received by the ARM node was more than 50% of the prescribed dose: i.e., 25 Gy. RESULTS: One right-sided subject had 2 ARM nodes, all others had 1 ARM node. All ARM nodes (left 10, right 9) were located within level 1 of the axilla. For the subject with 2 ARM nodes, the node that received a higher dose was used for the analysis. The mean dose received by the ARM node in the whole breast radiotherapy plans ranged from 0.8 to 45.5 Gy, with a median of 10.9 Gy. The mean dose received by the ARM node in the whole breast and axilla plans ranged from 43.4 to 52.5 Gy, with a median of 49.3 Gy. In the whole breast radiotherapy plans, only 5 out of 18 ARM nodes were found to be "within radiotherapy field", and only 2 ARM nodes received more than 40 Gy. In the breast and axilla plans, all 18 ARM nodes were "within radiotherapy field" and all received more than 40 Gy. To better visualise the locations of ARM nodes, all left sided ARM nodes were then mapped onto a CT set from one of the left-sided subjects, and all the right sided ARM nodes mapped onto one of the right-sided subjects, and digitally reconstructed radiograph (DRR) for radiotherapy fields were produced. CONCLUSIONS: Our study demonstrates that the vast majority of ARM nodes (72%) are outside the tangential whole breast radiotherapy fields. In our study, all the ARM nodes were within the axillary radiotherapy fields covering level 1-4 axillary volumes according to the ESTRO contouring guideline, and complete shielding of the humeral head according to the EORTC consensus did not lead to sparing of the ARM nodes. A prospective study is needed to examine the oncological safety of ARM node-sparing axillary radiotherapy and its potential to reduce the risk of arm lymphoedema.

Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine.

PURPOSE: The activity and safety of eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, were evaluated in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, taxane, and capecitabine. PATIENTS AND METHODS: Eligible patients in this single-arm, open-label phase II study received eribulin mesylate (1.4 mg/m(2)) administered as a 2- to 5-minute intravenous infusion on days 1 and 8 of a 21-day cycle. The primary end point was objective response rate (ORR) assessed by independent review. RESULTS: Of 299 enrolled patients who had received a median of four prior chemotherapy regimens, 291 received eribulin (for a median of four cycles). Of these, 269 patients met key inclusion criteria for the primary efficacy analysis. The primary end point of ORR by independent review was 9.3% (95% CI, 6.1% to 13.4%; all partial responses [PRs]), the stable disease (SD) rate was 46.5%, and clinical benefit rate (complete response + PR + SD > or = 6 months) was 17.1%. The investigator-reported ORR was 14.1% (95% CI, 10.2% to 18.9%). Median duration of response was 4.1 months, and progression-free survival was 2.6 months. Median overall survival was 10.4 months. The most common treatment-related grade 3 or 4 toxicities were neutropenia (54%; febrile neutropenia, 5.5%), leukopenia (14%), and asthenia/fatigue (10%; no grade 4); grade 3 neuropathy occurred in 6.9% of patients (no grade 4). CONCLUSION: Eribulin demonstrated antitumor activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine, with a manageable tolerability profile.

Phase I study of eribulin mesylate administered once every 21 days in patients with advanced solid tumors.

PURPOSE: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of eribulin mesylate (E7389), a halichondrin B analogue, administered every 21 days in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Eribulin mesylate was given as a 1-hour infusion every 21 days at doses of 0.25, 0.5, 1, 2, 2.8, and 4 mg/m(2). The MTD was identified using an accelerated titration design. The pharmacokinetics of eribulin were evaluated in the plasma and urine with the first dose. RESULTS: Twenty-one patients were enrolled. At 4 mg/m(2), three patients experienced a DLT of febrile neutropenia on day 7. The dose level was reduced to 2.8 mg/m(2) where two of three patients experienced dose-limiting febrile neutropenia. Six additional patients were enrolled at 2 mg/m(2) (seven patients in total received this dose) and one of these patients experienced a neutropenic DLT. The MTD of eribulin mesylate was therefore 2 mg/m(2). Nonhematologic toxicities included alopecia, fatigue, anorexia, and nausea. Pharmacokinetic analysis showed linear kinetics for eribulin over the dose range studied and a terminal half-life of 2 days. The plasma-concentration-time profile exhibited a rapid distribution phase followed by a slow elimination phase. Drug clearance was nonrenal. One patient with non-small cell lung cancer achieved an unconfirmed partial response and 12 patients had stable disease. CONCLUSIONS: Eribulin mesylate administered as a 1-hour infusion every 21 days has a manageable toxicity profile at 2 mg/m(2), with further dose escalation limited by neutropenia.

Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

PURPOSE: Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC). METHODS: MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate. RESULTS: Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%. CONCLUSION: Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.