TN Patients Research Articles

Diffusion tensor imaging for assessment of microstructural changes associate with treatment outcome at one-year after radiofrequency Rhizotomy in trigeminal neuralgia

BackgroundTrigeminal neuralgia (TN) is characterized by facial pain that may be sudden, intense, and recurrent. Neurosurgical interventions, such as radiofrequency rhizotomy, can relieve TN pain, but their mechanisms and effects are unknown. The aim of the present study was to investigate the microstructural tissue changes of the trigeminal nerve (TGN) in patients with TN after they underwent radiofrequency rhizotomy.MethodsThirty-seven patients with TN were recruited, and diffusion tensor imaging was obtained before and two weeks after radiofrequency rhizotomy. By manually selecting the cisternal segment of the TGN, we measured the volume of the TGN, fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD). The TGN volume and mean value of the DTI metrics of the post-rhizotomy lesion side were compared with those of the normal side and those of the pre-rhizotomy lesion side, and they were correlated to the post-rhizotomy visual analogue scale (VAS) pain scores after a one-year follow-up.ResultsThe alterations before and after rhizotomy showed a significantly increased TGN volume and FA, and a decreased ADC, AD, and RD. The post-rhizotomy lesion side showed a significantly decreased TGN volume, FA, and AD compared with the normal side; however, no significant difference in the ADC and RD were found between the groups. The TGN volume was significantly higher in the non-responders than in the responders (P = 0.016).ConclusionOur results may reflect that the effects of radiofrequency rhizotomy in TN patients include axonal damage with perineural edema and that prolonged swelling associated with recurrence might be predicted by MRI images. Further studies are necessary to understand how DTI metrics can quantitatively represent the pathophysiology of TN and to examine the application of DTI in the treatment of TN.

Favourable prognosis of trigeminal neuralgia when enrolled in a multidisciplinary management program - a two-year prospective real-life study

BackgroundPrognosis of medically treated trigeminal neuralgia patients is assumed to be poor, but the evidence is lacking. Thus, prospective real-life studies of medical management of trigeminal neuralgia are warranted.MethodsThis was an observational study. Patients were consecutively enrolled in a structured management program at a specialist centre for facial pain. Optimisation of medical treatment, physiotherapy, psychotherapy, and advice from trained nurses, were parts of the program. Medically intractable patients were referred for neurosurgery. Data-collection was prospective using standardised schemes and patient surveys. The aim was to describe the two-year outcome of medical treatment at the specialist centre. The primary outcome was a 50% reduction in the overall burden of pain according to a Numerical Rating Scale (NRS) after two years.ResultsA total of 186 primary TN patients were enrolled in the program of which 103 patients remained medically managed and completed the two-year follow-up. Fifty patients were treated surgically within the first two years of follow-up. Half of the medically managed patients (53 (51%)), had more than a 50% reduction in the overall burden of pain over the two-year period. The overall burden of pain on NRS decreased from mean 5.34 to 3.00, p < 0.01. There was no significant association between primary outcome and sex, depression and/or anxiety, concomitant persistent pain, or neurovascular contact with morphological changes of the trigeminal nerve.ConclusionsPatients with trigeminal neuralgia improve over a two-year period when enrolled in a structured medical management program. Optimisation of drug treatment, continuous advice and education and support by the multidisciplinary team, referral of the medically intractable patients for surgery or the natural history of the disease, can be some of the reasons for the improvement. The favourable prognosis provides hope and optimism for medically managed TN patients.Trial registrationCurrent study was observational, and patients were offered standard clinical care and laboratory workups according to current American Academy of Neurology and European Federation of Neurological Societies treatment guidelines. The study has been registered at ClincalTrials.gov. ID: NCT03838393.

A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients

BackgroundPathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature.MethodsEpigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K array) from Illumina. The epigenetic silencing of those methylated genes in the discovery cohort were validated by bisulfite pyrosequencing (PyroMark Q96 System version 2.0.6, Qiagen) and qRT-PCR in an independent cohort of TN patients and in TN cell lines.ResultsTwenty-four and 30 patients were included in the discovery and validation cohorts, respectively. In the discovery cohort, nine genes were differentially methylated: six presented higher methylation in non-responder patients (LOC641519, LEF1, HOXA5, EVC2, TLX3, CDKL2) and three greater methylation in responder patients (FERD3L, CHL1, and TRIP10). After validation, a two-gene (FER3L and TRIP10) epigenetic score predicted RCB = 0 with an area under the ROC curve (AUC) = 0.905 (95% CI = 0.805–1.000). Patients with a positive epigenetic two-gene score showed 78.6% RCB = 0 versus only 10.7% RCB = 0 if signature were negative.ConclusionsThese results suggest that pCR in TNBC could be accurately predicted with an epigenetic signature of FERD3L and TRIP10 genes. Further prospective validation of these findings is warranted.

Abstract P3-13-02: Breast conserving therapy after neoadjuvant systemic therapy in patients with T3 breast cancer is feasible

Abstract Background An important advantage of neoadjuvant systemic therapy (NST) in breast cancer patients is down-sizing of the primary tumor. However, many patients with T3 tumors are treated with mastectomy regardless of response to NST. In this study, we evaluated predictive characteristics for positive margins and local control in T3 breast cancer patients who underwent breast-conserving therapy (BCT) after NST. Methods This single institution study included all clinical T3 breast cancer patients (determined by contrast-enhanced magnetic resonance imaging [MRI]) who underwent breast conserving surgery (BCS) after NST between 2000-2015. Clinical T3 was defined as a breast tumor &amp;gt;50mm on MRI pre-NST. Patient, tumor and treatment characteristics were recorded, as well as response on MRI and final pathology. The local recurrence probability was estimated with the Kaplan-Meier method. Predictive characteristics for positive margins in patients undergoing BCS were analyzed using Fishers exact test. Results In total, 115 T3 patients were identified. Patient, tumor and MRI findings are presenting in the table. Median tumor size was 60 mm on MRI pre-NST (range 51-120 mm) and 4 mm after NST (range 0-58 mm). Overall pathologic complete response was 19%: 5% in HR+/HER2- patients, 32% in HR-/HER2+ patients and 40% in TN patients. After initial BCS, 73 patients had negative margins (63.5%), 18 focally positive margins (15.7%) and 24 more than focally positive margins (20.9%). Patients with HR+/HER2- tumors (52%) were more likely to have positive margins than patients with HR-/HER2+ and TN tumors (21% and 19%, p=0.002). In addition, positive margins rate was higher in patients with lobular carcinoma compared to patients with ductal carcinoma (57 vs 32%, p=0.031). Presence of non-mass enhancement on pre-NST MRI was predictive for positive margins (52% in patients with and 25% in patients without non-mass enhancement, p=0.003). Of patient with positive margins, 15 underwent radiotherapy with boost, 6 underwent re-excision and 21 underwent mastectomy. Finally, 94/115 patients were treated with BCT (82%). Of these patients, two had a local recurrence after a median follow-up of 6.5 years (6-year local recurrence probability 2.6% (95%-CI 0-7%). Conclusion In this series, BCT after NST was successful in 82% of patients with T3 breast cancer and local control in this group was excellent. The positive margin rate after BCS was higher in patients with HR+ tumors, lobular carcinoma and tumors with non-mass enhancement on MRI pre-NST. BCT should always be considered in T3 cancers after NST. CharacteristicTotal (n=115)Positive margins (focally+ &amp;gt;focally), n=42(%)p-valueHistology 0.031Ductal9229(32) Lobular2313(57) Subtype 0.002HR+/HER2-6132(52) HER2+347(21) TN203(15) MRI morphology of mass pre-NST 0.948Unifocal288(29) Multifocal4012(33) Multicentric134(31) Only non-mass enhancement34 MRI non-mass enhancement before NST 0.003Absent6516(25) Present5026(52) MRI response after NST 0.952rCR5218(35) non-rCR6221(38) Missing1 Citation Format: van der Noordaa ME, Vrancken Peeters M-JM, Ioan I, Loo CE, van Urk J, van Werkhoven E, Voorthuis R, Wiersma T, Groen E, Rutgers ET, van Duijnhoven FH. Breast conserving therapy after neoadjuvant systemic therapy in patients with T3 breast cancer is feasible [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-13-02.

Abstract P1-14-02: A phase 2 study of low dose metronomic eribulin in metastatic breast cancer

Abstract Background: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor approved by FDA in treatment of metastatic breast cancer (MBC) based on improvements in overall survival in the pivotal EMBRACE trial. Eribulin is approved at 1.4mg/m2 administered D1,8 of q21d cycle. However, this dose and schedule may have significant myelosuppression and peripheral neuropathy requiring dose reductions and treatment delays for some patients. We hypothesized that a low dose metronomic schedule will allow responding patients to remain on treatment, resulting in longer TTP (time to progression) and decreased incidence of toxicities and treatment-related discontinuations. Methods: A multi-site prospective open-label phase II trial of metronomic dosing of eribulin in patients with MBC has completed accrual of 60 patients, outcomes will be updated at presentation. Patients whose disease had progressed following 1-6 prior regimens with prior exposure to a taxane, ECOG performance status of 0 – 2, measurable disease per RECIST 1.1, with normal marrow and organ function were eligible. Eribulin was administered at 0.9mg/m2 weekly for 3 out of 4 weeks. For patients with HER2 positive disease, concurrent trastuzumab administration was allowed. Concurrent denosumab or bisphosphonates were allowed for patients with bone disease. Results: 60 patients were enrolled, average age 58 (range 34-83). Majority were postmenopausal Caucasian females, but the study included African American, Hispanic, native American, male patients. The majority of tumors were ER+, infiltrating ductal, but the study included 13 HER2+, and 12 TN tumors, with 5 ILC, and 5 mixed ILC/IDC. Nearly half of the enrolled patients had clinical benefit from the regimen, remaining on therapy for 6 months or longer, with stable disease or response; 50% had progression PD at 3 months 32% had stable disease and 18% had a partial or complete response (1, long term). Overall Survival, OS, for the entire group of heavily pre-treated patients was 1.2 years, with TN and HER2 positive patients faring better than ER+ in this small study. One HER2+ patient remains in long-term remission, off chemotherapy. The regimen was extremely well tolerated. The majority of the patients experienced grade 0 or 1 toxicity for alopecia (48/60) and peripheral neuropathy (7 with grade 2 neuropathy, 5 pre-existing, 2 with grade 3 neuropathy). There were few dose reductions (n=15), thrombocytopenia (11 grade 1 only), or use of G-CSF (14). Conclusions: Metronomic weekly low dose eribulin appears to be an active and tolerable regimen with less myelosuppression, alopecia and peripheral neuropathy than is seen with approved dose, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen. Outcomes will be updated at presentation. Citation Format: Chalasani P, Liu AJ, Khanjian JA, Peha M, Buening BJ, Gadi VK, Specht JM, Salazar L, Linden HM. A phase 2 study of low dose metronomic eribulin in metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-14-02.

Imetelstat Is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels

Imetelstat Is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels

Surgical treatment of trigeminal neuralgia with no neurovascular compression: A retrospective study and literature review

The objective of the current study is to summarize the experiences of 360-degree circumferential arachnoid dissection for TN in patients without NVC. Clinical data from 19 TN patients without NVC who underwent 360-degree circumferential arachnoid dissection were retrospectively analyzed. All patients underwent preoperative examinations of three-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA) and three-dimensional nuclear magnetic resonance of constructive interference in steady state (3D-CISS) to identify the neurovascular structures around the trigeminal nerve. Surgical outcomes were evaluated based on the Barrow Neurological Institute (BNI) Pain Intensity Scale, and severity of pain was determined using the visual analogue scale (VAS) score. Preoperative imaging showed that no patients had NVC compression. The preoperative BNI pain score was IV among 9 patients and V among other 10 patients. The preoperative VAS score was 7.89 ± 0.658. After the operation, pain disappeared in all 19 patients, and transient facial numbness occurred in 3 patients. During follow-up, pain in 2 of 19 patients (10.5%) recurred at postoperative 20 and 23 months. This study demonstrated that 360-degree circumferential arachnoid dissection is an alternative treatment for trigeminal neuralgia in patients with no neurovascular compression, especially when a thickened arachnoid, angulation, or torsion of the trigeminal nerve root was found during the operation. However, further study is needed to compare the outcomes of different surgical strategies and prove the efficacy of 360-degree circumferential arachnoid dissection in cases without neurovascular compression (NVC).

Dosimetric Comparison of 6 MV Flattening Filter Free and 6 MV Stereotactic Radiosurgery Beam Using 4 mm Conical Collimator for Trigeminal Neuralgia Radiosurgery

Background: The purpose of our study was to compare the dosimetric advantages of Flattening filter free (FFF) beams for trigeminal neuralgia patients using 4 mm conical collimators over previously treated patients with 6 MV SRS beam. Materials and Methods: A retrospective study was conducted for 5 TN patients who had been previously treated at our institution using frame-based, LINAC-based stereotactic radiosurgery (SRS) on Novalis Tx using 6 MV SRS beam were replanned on 6X FFF beams on Edge Linear accelerator with same beam angles and dose constraints using 4 mm conical collimator. The total number of monitor units along with the beam on time was compared for both Edge and Novalis Tx by redelivering the plans in QA mode of LINAC to compare the delivery efficiency. Plan quality was evaluated by homogeneity index (HI) and Paddick gradient index (GI) for each plan. We also analyzed the doses to brainstem and organ at risks (OARs). Results and Discussion: A 28% beam-on time reduction was achieved using 6X FFF when compared with 6X SRS beam of Novalis Tx. A sharp dose fall off with gradient index value of 3.4 ± 0.27 for 4 mm Varian conical collimator while 4.17 ± 0.20 with BrainLab cone. Among the 5 patients treated with a 4 mm cone, average maximum brainstem dose was 10.24 Gy for Edge using 6X FFF and 14.28 Gy for Novalis Tx using 6X SRS beam. Conclusion: The use of FFF beams improves delivery efficiency and conical collimator reduces dose to OAR’s for TN radiosurgery. Further investigation is warranted with larger sample patient data.

Diagnostic Efficacy of Serum 1,3-β-D-glucan for Invasive Fungal Infection: An Update Meta-Analysis Based on 37 Case Or Cohort Studies.

ObjectiveThe aim of this study was to investigate the diagnostic performance of serum 1,3-β-D-gluan as biomarker for invasive fungal infection through meta-analysis.MethodsThe electronic databases of Medline, Cochrane, Embase, Web of Science, OVID and CNKI were systematic searched to identified the case-control or Cohort studies relevant to diagnostic efficacy of serum 1,3-β-D-glucan for invasive fungal infection. The data of true positive (tp), false positive (fp), false negative (fn) and true negative (tn) patients number were extracted from each of the original included studies. The diagnostic sensitivity, specificity and systematic receiver operating characteristic (SROC) curve were calculated and pooled through random or fixed effect method. The publication bias was evaluated by the Deek’s funnel plot.ResultsThirty-seven relevant studies were fulfilled the inclusion criteria and included in our present meta-analysis. The combined sensitivity, specificity, positive likely hood ratio (+lr), negative likely hood ratio (-lr) and diagnostic odds ratio(dor) for 1,3-β-D-glucan in diagnosis of invasive fungal infectionwere 0.83 (95%CI:0.38-0.61), 0.81 (95%CI:0.80-0.82), 5.13 (95%CI:3.98-6.62), 0.23 (95%CI:0.18-0.30), and 29.68 (95%CI:18.94-46.52) respectively. The pooled area under the ROC curve (AUC) was 0.91.The Deek’s funnel plot asymmetry test showed there was no publication bias for 1,3-β-D-glucan in diagnosis of invasive fungal infection of the included 37 studies.ConclusionSerum 1,3-β-D-glucan assay was a promising biomarker for invasive fungal infection diagnosis.

Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide

AbstractLenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutated gene was SF3B1 (15%), followed by NOTCH1 (14%) and TP53 (14%), with R/R patients having significantly more TP53 mutations than did TN patients. Among all lenalidomide-treated patients, del(17p) (P ≤ .001), del(11q) (P = .032), and complex karyotype (P = .022), along with mutations in TP53 (P ≤ .001), KRAS (P = .034), and DDX3X (P ≤ .001), were associated with worse overall response (OR). R/R patients with SF3B1 and MGA mutations had significantly worse OR (P = .025 and .035, respectively). TN and R/R patients with del(17p) and TP53 mutations had worse overall survival (OS) and progression-free survival (PFS). In R/R patients, complex karyotype and SF3B1 mutations were associated with worse OS and PFS; DDX3X mutations were associated with worse PFS only. Weibull regression multivariate analysis revealed that TP53 aberrations (del(17p), TP53 mutation, or both), along with complex karyotype and SF3B1 mutations, were associated with worse OS in the R/R cohort. Taken together, cancer gene mutations in CLL contribute to the already comprehensive risk stratification and add to prognosis and response to treatment. The related trials were registered at www.clinicaltrials.gov as #NCT00267059, #NCT00535873, #NCT00759603, #NCT01446133, and #NCT01002755.

Abstract PD6-14: Analysis of DNA repair deficiency biomarkers as predictors of response to the PD1 inhibitor pembrolizumab: Results from the neoadjuvant I-SPY 2 trial for stage II-III high-risk breast cancer

Abstract Background: Pembrolizumab (P), an anti-PD-1 immune checkpoint inhibitor, has been approved for treatment of microsatellite instability-high and mismatch repair deficient cancers. In I-SPY 2, patients were randomized to receive standard chemotherapy alone or in combination with an experimental agent. P was one of the experimental agents evaluated in HER2- patients in I-SPY 2 and graduated in the TN, HR+HER2-, and HER2- signatures. We hypothesize that a combination of two signatures predicting response to veliparib/carboplatin therapy in I-SPY 2 [MammaPrint High2 (MP2)/PARPi7-high] and reflecting DNA damage repair deficiency, may also predict response to P. In addition, we also tested 9 gene expression signatures reflecting different aspects of DNA damage and repair: FA, MMR, BER, HR, TLS, NER, NHEJ, DR, and DNA damage sensing (DDS) pathways. Methods: Data from 249 patients (P: 69 and controls: 180) were available. Pre-treatment biopsies were assayed using Agilent gene expression arrays. All I-SPY 2 qualifying biomarker analyses follow a pre-specified analysis plan. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of P response if it associates with response in the P arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p&amp;lt;0.05). This analysis is also performed adjusting for HR status as a covariate, and within receptor subsets, sample size permitting. For successful biomarkers, we use Bayesian modeling to estimate the pCR rates of 'predicted sensitive' patients in each arm. Our statistics are descriptive rather than inferential and do not adjust for multiplicities of other biomarkers outside this study. Results: MP2 status associates with pCR in P (OR=7.7; p=0.00021), but also to a lesser extent in the control arm (OR=2.4:p=0.045), with an OR ratio of 3.3 which trends toward significance, even after adjusting for HR status (LR p=0.083). A majority of TN patients are MP2; and TN/MP2 patients have an estimated pCR rate of 67% in P (vs. 23% in control). Although only ~30% of HR+HER2- patients were MP2, their estimated pCR rate in P is 61%, compared to 29% in unselected HR+/HER2- patients. PARPi7 predicted response in the P arm only in the HR+HER2- group (LR p= 0.025), but not in the population as a whole or the TN subtype. Combining MP2 and PARPi7 into MP2/PARPi7-high did not improve performance over MP2 as a single biomarker. Of the 9 DDR pathway signatures tested, both BER and DDS associate with pCR in P, but only DDS (which includes ATM, ATR, CHEK1-2) associates with pCR in the P arm (LR p=0.00029), and not the control arm (LR p=0.53), with a significant interaction with treatment (LR p=0.0064) that retains significance in a model adjusting for HR status. When dichotomized to optimize the biomarker x treatment interaction, the estimated pCR rate is 75% in P vs 18% in control, in the DDS+ subset. Conclusion: In this small study, MP2 status and a DNA damage sensing pathway but not the PARPi7 or other repair pathways show promise as predictive biomarkers for immune checkpoint inhibition therapy in breast cancer. Citation Format: Yau C, Wolf D, Brown-Swigart L, Hirst G, Sanil A, Singhrao R, I-SPY 2 TRIAL Investigators, Asare S, DeMichele A, Berry D, Esserman L, van 't Veer L, Nanda R, Liu M, Yee D. Analysis of DNA repair deficiency biomarkers as predictors of response to the PD1 inhibitor pembrolizumab: Results from the neoadjuvant I-SPY 2 trial for stage II-III high-risk breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-14.

Risk Analyses Factor of Infant Mortality Caused by Tetanus Neonatorum in East Java

Tetanus neonatorum is an infection in infants ( &lt; 28 days), caused by bacteria Clostridium tetani that enter the body through the wound. Tetanus neonatorum is one of the leading causes of neonatal mortality in the world. The case of tetanus neonatorum is present in 14 provinces in Indonesia, East Java has the second highest case of tetanus neonatorum. Factors affecting infant mortality among others include maternal immunization status, parity, delay admission of TN patients, and umbilical cord care. The purpose of this study was to analyze the relationship between maternal immunization status, parity, delay admission of TN patients, and umbilical cord care with mortality of tetanus neonatorum. This study uses cross sectional design using 59 respondents obtained from T2 report to Dinas Kesehatan Provinsi Jawa Timur in 2014-2016. The result of the research by using chi-square test and α= 0,05 obtained TT immunization of pregnant women (p = 0.257), parity (p = 0.034; PR= 0.39; 95% CI 0.16-0.98), delay admission of TN patients (p = 0.061), and umbilical cord care (p = 0.007; PR = 2.31; 95% CI 1.29-4.15). The conclusion of this study is there are no relationships between maternal immunization status and delay admission with mortality of tetanus neonatorum and a significant relationships between parity and umbilical cord care with mortality of tetanus neonatorum in East Java in 2014-2016. To reduce the risk factors of infant mortality, it is necessary to socialize TT immunization to pregnant women, planning of pregnancy, clean delivery and umbilical cord care.Keywords: risk factors, delay admission, mortality of tetanus neonatorum, parity, and umbilical cord care, maternal immunization

O1-10-1 - Feasibility study of Dose-dense AC or EC followed by PTX for Japanese breast cancer patients

The feasibility study of Dose-Dense chemotherapy for operable Japanese breast cancer patients(SBP 09) Dose-dense(D-D) chemotherapy for operable breast cancer revealed significant survival benefit compared to the standard chemotherapy. In western countries, it has become a standard of care. Whereas in Japan, owing to the unapproval of G-CSF primary prophylactic administration, Dose-dense chemotherapy has not been defined for a long time in spite of its efficacy. Although in recent years, the number of reports regarding D-D therapy is slightly increasing in this country, prospective feasibility study is still uncommon. To verify of the feasibility of D-D chemotherapy, we conducted a multicenter phaseII study. We enrolled patients aged under 70years, with HER2 negative and operable node-positive primary breast cancer from 10centers. The primary end point was pCR rate, and the secondary end points were safety(FN rate, completion rate),overall response rate, toxicity profile and RDI. Neoadjuvant chemotherapy with D-D AC or EC followed by PTX was administrated to eligible patients every 2weeks with Pegfilgrastim support. 50 patients were scheduled to be enrolled. 41/50 patients have been enrolled to this point. In analysis of 14/41 patients, median age was 48years(34-66), Histological subtypes were 57% Triple negative, 21% Luminal A Like, 21% LuminalB like. Clinical stageII and III were 64%, 36% respectively, and of them, StageIIIC was included at 21%. pCR rate showed 25% and, all were TN patients. Overall response rate was 100%, Grade3 or worse adverse events occurred in 33% of the patients (febrile neutropenia, pneumonia and so on). 20% of the patients were converted from q2w PTX to wPTX because of Grade3 adverse event. At the present, 80% accrual enrollment has been achieved. We plan to report the result of 50 patients full analysis.

S65 Neurophysiological data favoring a central mechanism of trigeminal neuralgia

Current opinion is that TN is caused by a proximal compression of the trigeminal nerve root by a ectasic blood vessel leading to mechanical twist of nerve fibers and secondary demyelination. These changes lower the excitability threshold of affected fibers and promote inappropriate ephaptic propagation towards adjacent fibers. Not all patients have a nerve vessel conflict and 25% of people without any clinical signs of TN did show a nerve vessel contact. Possible involvement of central factors, suggesting a central facilitation and resulting hyperexcitability of the trigeminal system sustained by peripheral as well as central mechanisms were discussed. Sensitisation of second order wide dynamic range (WDR) neurons was discussed as additional pathophysiological mechanism. Since these WDR neurons receive convergent information from tactile (A-beta) and nociceptive (A-delta and C) fibers, their sensitisation could facilitate nociceptive input while promoting the perception of pain in response to tactile stimuli (i.e., allodynia). Central facilitation was demonstrated in TN patients with additional constant dull background pain besides their typical TN attacks using pain-related evoked potentials (PREP) and nociceptive blink reflex (nBR) [4]. Borsook et al. (2007) reported increased fMRI activation of a single TN patient in the primary somatosensory cortex, insula, anterior cingulate, and thalamus to further support cortical involvement [28]. Structural changes of the cortical grey matter was also reported to further support a central origin of the disease.

Abstract 3359: TET1 mediated hypomethylation activates oncogenic signaling pathways in triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is a subtype of breast cancer that occurs in 15-20% of patients, and is defined by tumors that do not overexpress the estrogen, progesterone and HER2 receptors. This aggressive subtype has a significantly worse overall survival compared to non-TNBC and importantly, these patients lack options for targeted therapy. To identify novel subtype-specific therapeutic targets, we must first understand the biological underpinnings of the disease. DNA methylation is a hallmark of cancer, as it can regulate gene expression of both tumor suppressor genes and oncogenes. We have found that TN tumors have widespread genome-wide hypomethylation when compared to other breast cancer subtypes and normal breast controls. TET1 is a DNA demethylase that converts 5-methyl cytosine into 5-hydroxymethyl cytosine, which can be further oxidized into un-methylated cytosine. To determine if TET1 could possibly play a role in TNBC hypomethylation, we analyzed genome-wide DNA methylation, DNA mutation and RNA-seq datasets from the TCGA breast cancer cohort. We identified a subset of TN patients that upregulate TET1 and display DNA hypomethylation. To identify the hypomethylated TET1 target genes, we computed Spearman correlations between TET1 expression and methylation % for 450,000 sites (450K array) across 67 TNBC patients. Filtering for sites with r&amp;lt;-0.3 revealed 42,559 sites negatively correlated with TET1 expression. Cluster analysis of the sites that lose methylation compared to normal breast (12,807 CpG sites) revealed two distinct clusters. Cluster 1 (42% of TNBC cases) were TET1 high and hypomethylated, while cluster 2 (58%) looked more like normal breast controls. Gene set enrichment analysis of the hypomethylated genes revealed Hippo Signaling, Pathways in Cancer and PI3K-Akt Signaling as significantly enriched, with p&amp;lt;0.001. In addition, only 4% of patients in cluster 1 have mutations/genomic alterations in the PI3K pathway, compared to 29% of cluster 2 patients, p=0.01. Most strikingly, analysis of phosphorylated EIF4EBP1 RPPA proteomic data revealed TET1 high patients have increased PI3K pathway activity, even though they lack mutations in the pathway, p=0.02. We hypothesize that the PI3K hyper-activation, in part, can be explained by TET1 upregulation and target gene demethylation. In TET1 knock out MDA-MB-231 cells, we observed a reduction in phosphorylated 4E-BP1, suggesting loss of PI3K activity is concomitant with loss of TET1 as well as decreased cellular proliferation (p&amp;lt;0.01). Furthermore, breast cancer cell lines with high TET1 (but not low TET1) are sensitive to drugs targeting the PI3K/ERK pathway (XMD8-85, AZ628, TGX221). In addition to explaining and predicting PI3K inhibitor sensitivity in breast cancer, our studies may establish TET1 as a TNBC specific oncogene that could serve as a novel druggable target for therapeutic intervention. Citation Format: Charly Ryan Good, Andrew Kelly, Jozef Madzo, Jaroslav Jelinek, Jean-Pierre Issa. TET1 mediated hypomethylation activates oncogenic signaling pathways in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3359. doi:10.1158/1538-7445.AM2017-3359

Abstract P1-12-06: Factors related to the prognosis of breast cancer patients after the development of brain metastases

Abstract Background: Brain metastases (BM) are a serious relatively common complication of breast cancer (BC). We evaluated prognostic factors for survival after diagnosis of BM from BC in a contemporary cohort of pts. Methods:Pts diagnosed with BM from BC between 1999 and march 2016 and treated at the Istituto Oncologico Veneto of Padua were evaluated. Overall survival (OS) was defined as time from BM diagnosis to death or last follow-up. Pts were classified in 4 categories according to the breast cancer-specific Graded Prognostic Assessment (GPA) index according to validated criteria (Sperduto et al, 2012), based on age, Karnofsky Performance Status (KPS) and BC phenotype. Cox proportional models were used to calculate HR and 95% CI. Results: 199 pts were identified. Median age at BM diagnosis was 56 yrs (range 28-84). Tumor phenotype distribution was as follows: triple negative (TN, 20.1%), hormone receptor (HR)-HER2+ (16.8%), HR+HER2+ (24.0%) and HR+HER2- (39.1%). Median time to BM diagnosis was 48.9 months (range 0-327), with significant differences according to tumor phenotype (median 27.3, 31.8, 46.1 and 55.2 months in TN, HR-HER2+, HR+HER2+, HR+HER2-, respectively, p=0.009). With respect to OS, no significant difference was observed across tumor phenotypes, with TN patients experiencing the worse outcome (median: 4.7, 7.7, 11.0 and 6.2 months in TN, HR-HER2+, HR+HER2+, HR+HER2-, p=0.187). The breast-specific GPA index, which combines tumor phenotype with patient-related features, was significantly associated with OS (Table). The number of local treatment received (radiotherapy, either whole brain or stereotactic, or neurosurgery) and the administration of systemic treatment after BM diagnosis were significantly associated with better OS (Table). Patients in the less favorable GPA category (GPA index &amp;lt;1) were less likely to receive systemic treatment after BM diagnosis compared to other GPA categories (43% vs 71%, p=0.009); no association between GPA category and local treatment was observed. Patients undergoing increased lines of local treatments where more likely to receive systemic therapy (chi2 square test p&amp;lt;0.001). To avoid bias we performed two separate multivariate analyses including: i) GPA category and number of local treatments; ii) GPA category (patients with GPA index &amp;lt;1 excluded) and systemic treatment. GPA maintained a significant prognostic value in both models (p=0.002 and p=0.038, respectively). Both local and systemic treatments added independent prognostication beyond GPA (Table). Prognostic factorsMedian OS, months (95%CI)HR (95%CI), univariatep, univariateHR (95%CI), corrected for GPAGPA category 3.5-418.8 (15.2-22.5)ref -2.5-38.8 (3.8-13.8)1.40 (0.80-2.43) -1.5-25.5 (3.5-7.5)1.76 (1.00-3.10) -0-1.02.7 (1.2-4.3)2.67 (1.35-5.28)0.019-Number of local tretaments received 03.0 (1.8-7.5)ref ref18.0 (5.8-10.3)0.53 (0.38-0.74) 0.54 (0.38-0.78)221.3 (15.2-27.3)0.36 (0.20-0.65) 0.49 (0.26-0.93)335.5 (33.5-37.6)0.12 (0.04-0.38)&amp;lt;0.0010.08 (0.02-0.33)Systemic treatment yes13.1 (8.7-17.4) no2.6 (1.3-3.8)0.42 (0.30-0.58)&amp;lt;0.0010.46 (0.31-0.68) Conclusions: Patient-related features, tumor phenotype and multimodal treatments all independently contribute to modulate the prognosis of pts with BM from BC. Citation Format: Griguolo G, Dieci MV, Giarratano T, Giorgi CA, Orvieto E, Ghiotto C, Falci C, Mioranza E, Tasca G, Milite N, Miglietta F, Conte P, Guarneri V. Factors related to the prognosis of breast cancer patients after the development of brain metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-06.

Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

BACKGROUNDVenetoclax(VEN), a once daily oral inhibitor of BCL2, has demonstrated high response rates and acceptable toxicity in patients with relapsed or refractory (R/R) CLL both as a single agent and in combination with the anti-CD20 monoclonal antibodies rituximab and obinutuzumab (formerly GA-101, G), where minimal residual disease (MRD) negative responses have been observed in the majority of patients. Ibrutinib (IBR), a once daily oral inhibitor of the Brutontyrosine kinase, likewise induces remissions in the majority of treated patients, but complete response (CR) is uncommon even after prolonged administration. Early genetic studies have demonstrated that BCL2 over-expression rescues BTK deficient XID murine B-cells from spontaneous apoptosis (J Immunol 1996), so we hypothesized that combination therapy would more efficiently achieve deep response endpoints. We report phase 1b results of a single-institution phase 1b/2 study of G, IBR, and VEN to characterize the safety and preliminary efficacy of the combination.METHODSPatients with CLL relapsed after or refractory to ≥1 prior therapy and who required treatment were eligible. Enrolled patients had ECOG ≤1 and preserved end-organ function, including creatinine clearance ≥50 mL/min/m2. Patients with chronic viral hepatitis infection, uncontrolled autoimmunecytopenia, active Richter transformation, and known cysteine-481 BTK mutation or clinical disease progression during treatment with a cysteine-481-binding BTK inhibitor were excluded. G, IBR, and VEN were started sequentially over the first 3 of fourteen 28-day cycles as detailed in the table. To establish the safety of VEN in combination with OBIN and IBR, VEN dose was escalated in 3 x 3 cohorts (100, 200, 400 mg) to a maximum planned dose of 400 mg daily. Dose limiting toxicity (DLT) was defined during the third cycle. Risk assessment for VEN dose ramp-up was conducted according to US prescribing information. Adverse events were assessed and graded using CTCAE v4.03. Response assessment according to IWCLL 2008 criteria, including bone marrow biopsy with 4-colorimmunophenotyping of marrow and peripheral blood (PB) for MRD, occurs after cycles 8 and 14.RESULTSTwelve R/R patients have been treated in the phase 1b portion of the trial. Median age was 57 years (range: 42-70) and median prior therapies was 1 (range: 1-7). Baseline genetic risk features includedunmutatedIGHV in 11 (92%),del(17p) in 1 (8%), del(11q) in 8 (67%), and complex abnormal karyotype in 5 (42%) patients. Tumor lysis (TLS) risk was low in 1 (8%), medium in 7 (58%), and high in 4 (33%) patients at study entry. In general, observed toxicities for the combination were consistent with those reported for the single agents. DLTs were not observed at any VEN dose level, establishing VEN 400 mg daily as safe in combination with standard doses of G and IBR. The most common grade ≥3 adverse events (regardless of attribution) were neutropenia (50%), lymphopenia (33%),hypertension(25%), and fatigue (17%). Grade 1/2 adverse events occurring in over half the patients included bruising (all grade 1, 83%), infusion related reaction (75%), hypertension (67%), headache (67%), hyperuricemia (all grade 1, 75%), hypocalcemia (75%), and diarrhea (all grade 1, 67%), AST and/or ALT elevation (58%), and rash (50%). No cases of either clinical or laboratory TLS were observed. All patients remain on therapy and 6 have reached response assessment after completing 8 cycles of therapy. All 6 have achieved objective response: 5 PR, including 1 MRD-negative in PB (VEN 100) and 1 MRD-negative in both PB and marrow (VEN 100), and 1 CR with MRD-negative PB and marrow (VEN 200).CONCLUSIONSG, IBR, and VEN can be safely administered in combination at doses standard for the treatment of CLL. DLTs were not observed, establishing VEN 400 mg as the recommended phase 2 dose in combination with G and IBR. Adverse events were manageable and largely consistent with those reported in the single agent phase 2 studies. Objective responses, including MRD-negative responses, have been observed among all R/R patients from the first dose cohorts. Accrual continues to parallel phase 2 cohorts of R/R (n=25) and TN (n=25) patients. Updated phase 1b toxicity and response data will be presented. [Display omitted] DisclosuresJones:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Pharmacyclics: Consultancy; Novartis Oncology: Consultancy; Innate Pharma: Research Funding.

Beyond breast specific-Graded Prognostic Assessment in patients with brain metastases from breast cancer: treatment impact on outcome.

Brain metastases are a serious relatively common complication of breast cancer. We evaluated prognostic factors for survival after diagnosis of brain metastases from breast cancer in a contemporary cohort of patients. Patients diagnosed with breast cancer brain metastases at our institution between 1999 and March 2016 were evaluated. Overall survival was defined as time from brain metastasis diagnosis to death or last follow-up. Patients were classified according to the Breast cancer-specific Graded Prognostic Assessment (BS-GPA), based on age, Karnofsky performance score and breast cancer phenotype. 181 patients were identified. Tumor phenotype distribution was as follows: triple negative (TN, 18.8%), hormone receptor (HR)-HER2+ (16.6%), HR+HER2+ (23.2%) and HR+HER2- (30.9%), not available (10.5%). Median overall survival from brain metastasis diagnosis was 7.7 mos (95% CI 5.4-10.0 mos). Although TN patients experienced the worse outcome, no significant difference was observed across tumor phenotypes (median 5.1, 7.7, 11.0 and 8.6 months in TN, HR-HER2+, HR+HER2+, HR+HER2-, p = 0.081). The BS-GPA index was significantly associated with overall survival (median 18.8, 8.8, 6.2 and 3.6 months, respectively, for BS-GPA categories 3.5-4, 2.5-3, 1.5-2 and 0-1, p = 0.014). Increased number of local treatments for brain metastasis (radiotherapy or neurosurgery) or the administration of systemic therapy after brain metastasis diagnosis were also significant predictors of better overall survival (p < 0.001) and, when evaluated in multivariate analysis with BS-GPA, both added independent prognostication beyond BS-GPA. Patient-related features, tumor phenotype and multimodal treatments all independently contribute to modulate prognosis of patients diagnosed with breast cancer brain metastases.

Alternation of regional homogeneity in trigeminal neuralgia after percutaneous radiofrequency thermocoagulation

We used resting-state fMRI to investigate regional homogeneity (ReHo) changes in patients with TN before and after PRT procedure, and to speculate about its possible mechanisms.Thirty-one TN patients underwent the PRT procedure had MRI scans just before and 6 months after surgery. The anatomical and resting-state functional images were all acquired. Patients’ visual analog scales (VAS) scores, facial numbness, and disease duration were also recorded. Voxel-wise ReHo analysis was performed to detect the altered regional clusters after surgery. The correlations between the mean ReHo values of each significant cluster and clinical variables were examined.Compared with presurgical condition, patients after the PRT procedure showed a significant ReHo value increases in the right fusiform gyrus (FG) and bilateral anterior cingulate cortex (ACC), but decreases in the left inferior parietal lobule (IPL), right calcarine, right middle temporal gyrus (MTG), left postcentral gyrus (PoCG), and left insula. We demonstrated a positive correlation between ReHo in the left PoCG and VAS scores, a negative correlation between pre-surgical ReHo in the right MTG and VAS changes (ΔVAS).Alterations of ReHo post-surgical were found in several regions, which are related to sensory, affective, and emotional processes. The MTG may be a specific area that is associated with analgesic efficiency of PRT procedure.

Abstract 859: Gene and pathway differences between MammaPrint High1/High2 risk classes: results from the I-SPY 2 TRIAL in breast cancer

Abstract BACKGROUND: Further stratification of the 70-gene MammaPrint(TM) prognostic signature into ‘high’ and ‘ultra-high’ risk groups may help predict chemo-sensitivity. In I-SPY 2, patients were classified as MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2), using a threshold predefined by the median cut-point of I-SPY 1 participants who fit the eligibility criteria for I-SPY 2. MP1/2 classification was added to HR and HER2 to define the subtypes used in the I-SPY 2 adaptive randomization engine. The first two experimental agents/combinations to graduate from I-SPY 2 were veliparib/carboplatin (V/C) in the TN subset, and neratinib (N) in the HR-HER2+ subset. MP2 was found to be a sensitivity marker for V/C but not N, whereas MP1 class appears associated with resistance to N within the HER2- subset. Despite these associations with response, it remains unclear whether MP1/MP2 classification represents differences in tumor biology. Here, we present exploratory analysis to elucidate the pathway differences between the MP classes. METHODS: 263 patients (V/C: 71, N: 115, and controls: 77) with pre-treatment Agilent 44K microarrays and MP1/2 class assessments were considered in this analysis. To identify signature genes associated with MP1 vs. MP2 class, we (1) apply a Wilcoxon rank sum test and (2) fit a logistic model. P-values are corrected for multiple comparisons using the Benjamini-Hochberg (BH) method, with a significance threshold of BH p&amp;lt;0.05 from both tests. We then perform pathway enrichment analysis using DAVID. In addition, we perform multivariate analysis adjusting for receptor subtype. Our study is exploratory and does not adjust for multiplicities of other biomarkers in the trial but outside this study. RESULTS: 63% (165/263) of patients are MP1 class and 37% (98/263) MP2. MP1/2 class is associated with receptor subtype (Fisher's exact test: p&amp;lt;2E-16), where 71% of TN patients are MP2 and 96% of HR+HER2+ patients are MP1. Of the 70 signature genes, 86% (60/70) differ in expression between MP1 and MP2, with 70% (42/60) expressed at a higher level in MP2, including CDCA7, MELK and CENPA. In a whole transcriptome analysis, 10,500 genes (of ∼30,000) appear differentially expressed. Following adjustment for HR and HER2 status, 4368 genes are significantly differentially expressed between MP1 and MP2. By DAVID enrichment analysis, the biggest pathway-level differences are found in cell cycle, proliferation, and DNA repair, with the MP2 set showing higher expression. CONCLUSION: MP2 class appears associated with higher expression of cell cycle &amp; DNA repair genes. Association between MP2 class and response to V/C suggests that higher cell cycle activity may contribute to V/C sensitivity. Citation Format: Denise M. Wolf, Christina Yau, Lamorna Brown-Swigart, Gillian Hirst, Meredith Buxton, Melissa Paoloni, I-SPY 2 TRIAL Investigators, Olufunmilayo Olopade, Angela De Michele, Fraser Symmans, Hope Rugo, Don Berry, Laura Esserman, Laura van ‘t Veer. Gene and pathway differences between MammaPrint High1/High2 risk classes: results from the I-SPY 2 TRIAL in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 859.