Median Time To Failure Research Articles

Treatment of hydrocephalus following fetal repair of myelomeningocele: comparing endoscopic third ventriculostomy with choroid plexus cauterization to ventricular shunting.

The aim of this study was to compare clinical and craniometric outcomes of patients treated for hydrocephalus following fetal myelomeningocele repair (fMMR) via a ventriculoperitoneal shunt (VPS) or endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC). This was a retrospective cohort study of children who were treated for hydrocephalus following fMMR via VPS or ETV with or without CPC (ETV ± CPC) at Vanderbilt between 2012 and 2021. The primary outcomes were treatment failure and time to failure (TTF). Secondary outcomes included changes in hydrocephalus metrics (fronto-occipital horn ratio [FOHR] and head circumference measurements) and healthcare resource utilization (number of hospital admissions, clinic visits, and neuroimaging findings). Among 88 patients who underwent fMMR, 37 (42%) required permanent CSF diversion, of whom 19 received treatment at the authors' institution. Twelve patients underwent ETV ± CPC, and 7 underwent VPS placement at a median corrected age of 23 weeks versus 1 week (p = 0.002). The preoperative median head circumference percentiles and z-scores for patients in the ETV ± CPC cohort were similar to those of the VPS cohort (percentiles: 98.5 vs 94.0, p = 0.064; z-scores: 2.32 vs 1.60, p = 0.111). There was no difference in preoperative median FOHR measurements between the two cohorts (0.57 vs 0.59, p = 0.53). At 6 months postoperatively, the median head circumference percentile and z-score for the ETV ± CPC cohort remained similar between the two cohorts (percentiles: 98.0 vs 67.5, p = 0.315; z-scores: 2.12 vs 0.52, p = 0.307). There was no difference in the change in FOHR (-0.06 vs -0.09, p = 0.37) and change in head circumference percentile (-1.33 vs -28.6, p = 0.058) between the cohorts 6 months after the index CSF diversion procedure. One patient in the ETV ± CPC cohort experienced a seizure and a nonoperative subdural hemorrhage postoperatively; no other complications were observed. Six of the 7 patients in the VPS cohort required shunt revision with a median TTF of 9.8 months while 2 of the 12 ETV ± CPC patients required a repeat ETV at a median of 17.5 months (86% vs 17%, p = 0.013). The median number of hydrocephalus-related hospital readmissions was significantly lower in the ETV ± CPC cohort than in the VPS cohort (0 vs 1, p = 0.006). The ETV ± CPC cohort had fewer CT scans (0 vs 2, p = 0.004) and radiographs (0 vs 2, p < 0.001) than the VPS cohort. In a single-center cohort, hydrocephalic fMMR patients treated via ETV ± CPC remained shunt free, while a majority of patients receiving an upfront shunt required revision. This is the first study comparing ETV ± CPC with VPS in the fMMR hydrocephalus population. While larger, multicenter studies are needed, these results suggest that ETV/CPC may be a preferred means of CSF diversion following fMMR.

Efficacy and safety of bevacizumab-containing therapy for refractory advanced breast cancer: a retrospective study.

Advanced breast cancer (ABC) is difficult to treat due to the primary and acquired resistance, which is the main cause of rescue treatment failure. Thus, developing a new rescue treatment strategy for clinicians is a challenge. This study retrospectively collected the medical information of patients with refractory ABC who were treated with bevacizumab at our department to analyze the efficacy and safety of bevacizumab-containing therapy as a new treatment method for refractory ABC. The complete medical information of patients receiving bevacizumab treatment from November 2017 to November 2020 was collected, and patients' general medical history and disease characteristics were analyzed. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to failure (TTF), overall survival (OS), and safety were also analyzed using SPSS 20.0 statistical software. The data of 68 women with refractory ABC who received bevacizumab-containing therapy were collected. The last follow-up examinations were performed on March 31, 2021. The ORR was 41.2% and the DCR was 88.2%. The median PFS, TTF, and OS were 6.0 months [95% confidence interval (CI): 3.4-8.6 months], 4.0 months (95% CI: 3.2-4.8 months), and 26.6 months (95% CI: 10.2-43.0 months), respectively. Treatment was discontinued in 2 patients due to chemo-related adverse reactions. The main adverse events related to bevacizumab were hypertension (7.4%) and bleeding (2 cases, 2.9%), both of which were grade 1. No specific adverse events causing the discontinuation of bevacizumab treatment were observed in the other patients. Among patients with refractory ABC, bevacizumab-containing therapy is feasible and safe, and can be used as a new treatment strategy. However, the question of who can benefit the most from bevacizumab-containing therapy requires further exploration.

Life-Extending Benefit of Chip Sealing for Pavement Preservation

Chip seals are effective pavement preservation treatments that are usually applied to address non-fatigue cracking, weathering, and raveling, to seal the surface, to delay oxidation, and, finally, to improve skid resistance. This study used field performance data of test sections from the Pavement Preservation Group Study being conducted by the National Center for Asphalt Technology and the Minnesota DOT’s Road Research Facility. Data from test sections located in a low-traffic-volume road with a hot, wet, no-freeze climate collected over a period of 7 years were used to evaluate the effect of several chip seal treatments. Treatments range from single layer to multilayer systems, and include different construction techniques such as rejuvenating scrub seal and fiber membrane. Also, a section was crack sealed before the application of a single layer chip seal to assess the benefits. A semi-parametric survival analysis was performed to determine the differences in median time to failure (MTTF) for different chip seal sections versus a controlled section—representing a “do-nothing” scenario. The results showed that the MTTF for a single layer chip seal ranges from 6.8 to 9.1 years depending on the pretreatment condition. Crack sealing before chip seal could extend the MTTF by an additional 1–3 years, depending on initial conditions. Double and triple layer chip seals extend the MTTF beyond 10 years. Finally, the scrub seal provided the highest benefits, with survival rates close to 100% after 10 years of performance.

Life-Extending Benefit of Crack Sealing for Pavement Preservation

Crack sealing and filling is used as a pavement preservation treatment to prevent water infiltration and loss of load-carrying capacity, hence extending the life of the pavement. This study used field performance data of test sections from the Pavement Preservation Group (PG) Study being conducted in part by the National Center for Asphalt Technology (NCAT). Data from test sections located in a low traffic volume road with a hot, wet, no-freeze climate collected over a period of more than 6 years were used to evaluate the effect of crack sealing and filling, either as a stand-alone treatment or in combination with other surface treatments. A semi-parametric survival analysis was performed to determine the difference in median time to failure (MTTF) for sections with and without crack sealing. The results showed that when used as a stand-alone treatment on a pavement in “good” condition, the life-extending benefit from crack sealing/filling could not be calculated for the selected analysis period because the MTTF would not be reached within 10 years. The estimated benefit for pavements in “fair” and “poor” condition ranged from 1.1 to 7.3 years, depending on pretreatment condition and travel lane. If used in combination with a chip seal, the additional life-extending benefit for a pavement in “good” condition is approximately 2 years, and is slightly decreased to approximately 1.5 years if the pavement is in “fair” to “poor” category. Test sections continue to be monitored as part of a broader long-term study.

Palbociclib in clinical use for metastatic breast cancer at a single institution

Abstract Background The PALOMA2/3 trials demonstrated prominent efficacy of combination therapy of palbociclib (PAL) and endocrine therapy (ET) compared with monotherapy. PAL was approved for metastatic breast cancer in Japan in 2017. We evaluated the efficacy and safety in practice after approval of PAL in Japan. Methods We retrospectively reviewed patients who newly received PAL at Aichi Cancer Center after Dec 2017. The patients were classified by treatment-line and assessed as follows; clinical benefit rate (CBR) defined as the rate of clinical PR, CR and long SD (more than 6 months) based on physician’s judgment, time to failure (TTF) defined as the duration time of PAL, prior ET response, and adverse events (AEs). TTFs were figured with swimmer’s plot by treatment-line, PAL doses (125, 100, 75mg/day). Results Between Dec 2017 and Oct 2018, 64 patients were eligible. Median age was 62.5 (37-82). Forty-one patients (64%) had visceral metastasis. PAL was administered for 1st to 3rd line (early-line group) in 52% (n = 33), and for more than 4th line (late-line group) in 48% (n = 31). Combination ETs were aromatase inhibitors (n = 27, 42%), fulvestrant (n = 35, 55%), and tamoxifen (n = 2, 3%). Prior ET was sensitive in 59% (n = 33). The dose reduction was needed in 62% (100mg; n = 19, 75mg; n = 21). Twenty-eight patients (43.8%) were continuing PAL. Overall CBR was 38%. By treatment line, CBR was 51.6% in the early-line group, and 22.6% in the late-line group. Median TTF was 4.6 months (0.2-10.2). There were no significant differences of TTF by treatment-line, prior ET response, and PAL doses. The grade 3-4 hematological toxicity, such as neutropenia and anemia, were observed in 83% (n = 53). Stomatitis, nausea, and fatigue were common, but most of them were grade 1-2. No patients discontinued PAL due to AEs. Conclusions In the clinical setting, PAL was given in many late line-patients who were not eligible for the PALOMA2/3 trials. Its efficacy was not sufficient, although it was feasible.

Heterogeneity of first-line palliative systemic treatment in synchronous metastatic esophagogastric cancer patients: A real-world evidence study.

The optimal first‐line palliative systemic treatment strategy for metastatic esophagogastric cancer is not well defined. The aim of our study was to explore real‐world use of first‐line systemic treatment in esophagogastric cancer and assess the effect of treatment strategy on overall survival (OS), time to failure (TTF) of first‐line treatment and toxicity. We selected synchronous metastatic esophagogastric cancer patients treated with systemic therapy (2010–2016) from the nationwide Netherlands Cancer Registry (n = 2,204). Systemic treatment strategies were divided into monotherapy, doublet and triplet chemotherapy, and trastuzumab‐containing regimens. Data on OS were available for all patients, on TTF for patients diagnosed from 2010 to 2015 (n = 1,700), and on toxicity for patients diagnosed from 2010 to 2014 (n = 1,221). OS and TTF were analyzed using multivariable Cox regression, with adjustment for relevant tumor and patient characteristics. Up to 45 different systemic treatment regimens were found to be administered, with a median TTF of 4.6 and OS of 7.5 months. Most patients (45%) were treated with doublet chemotherapy; 34% received triplets, 10% monotherapy and 10% a trastuzumab‐containing regimen. The highest median OS was found in patients receiving a trastuzumab‐containing regimen (11.9 months). Triplet chemotherapy showed equal survival rates compared to doublets (OS: HR 0.92, 95%CI 0.83–1.02; TTF: HR 0.92, 95%CI 0.82–1.04) but significantly more grade 3–5 toxicity than doublets (33% vs. 21%, respectively). In conclusion, heterogeneity of first‐line palliative systemic treatment in metastatic esophagogastric cancer patients is striking. Based on our data, doublet chemotherapy is the preferred treatment strategy because of similar survival and less toxicity compared to triplets.

Ag–Pd–Cu alloy reflector to improve the opto-electrical performance and electromigration resistance of near ultraviolet GaN-based light-emitting diode

We investigated the opto-electrical and electromigration properties of near ultraviolet light emitting diodes (UV-LEDs) fabricated with Ag–Pd–Cu (APC) and Ag only reflectors. It was shown that unlike Ag only sample, the APC sample revealed a smooth surface with hillocks when annealed at 600 °C. The 600 °C-annealed APC sample gave a reflectance of 84.2% at 400 nm, whereas the Ag sample had 69.0%. Both the samples exhibited ohmic behavior when annealed. The specific contact resistivity of the Ag and APC contacts annealed at 500 °C were estimated to be 2.59 × 10−4 and 1.85 × 10−4 Ωcm2, respectively. The X-ray photoemission spectroscopy Ga 2p core level results showed that for the annealed APC sample, the Ga 2p core level was shifted towards the lower binding-energies by 0.67 eV as compared to that of the as-deposited sample. Both UV-LEDs with the 500 °C-annealed Ag and APC reflectors gave the same forward voltage of 3.23 V at 20 mA. The UV-LED with the annealed APC reflector yielded 9.07% higher output at 100 mA than that with the annealed Ag reflector. The APC sample exhibited a longer median-time-to-failure (MTF) by a factor of 1.4 than the Ag sample. The activation energy for the electromigration of these samples was measured to be 0.58–0.7 eV. Electron back scatter diffraction (EBSD) and inverse pole figure (IPF) images revealed that the Ag sample was more <111>-textured than the APC sample. Based on the scanning electron microscopy, EBSD and IPF results, the better thermal and electromigration properties of the APC sample are described and discussed.

Abstract P4-22-24: A retrospective study about re-biopsy at disease progression on T-DM1

Abstract Background: T-DM1 is an antibody-drug conjugate, which consists of trastuzumab, DM1, and linker. It has been established as standard of care for human epidermal receptor (HER) 2-positive metastatic breast cancer (MBC). At the first step, trastuzumab has to combine with extracellular domain of HER2. Then T-DM1 is delivered into HER2-positive cancer cells, and DM1 is released. After that, antitumor activity of DM1 can be exerted. In this way, T-DM1 works on HER2-positive cancer cells with high specificity. This retrospective study is aimed to examine whether HER2 status at disease progression on T-DM1 is related to efficacy of T-DM1. Patients: We identified 23 patients who started treatment with T-DM1 between February 2014 and March 2016 at our department. The data cut-off date was April 30, 2016. Methods: We retrospectively reviewed the medical records of these 23 patients and investigated the following items: patient characteristics, time to failure (TTF), objective response, and results of re-biopsy. TTF were analyzed by the Kaplan–Meier method. The definition of HER2-positive was immunohistochemistry 3+, or FISH &amp;gt;2.2. Results: There were 23 patients who started administration of T-DM1 for MBC at our department in this period. All patients had HER2-positive MBC which was diagnosed as HER2 positive by examination of samples from primary tumor. At the time of data cut-off, five patients had continued T-DM1 therapy, and 18 patients had finished it due to disease progression in 15 patients and adverse events in three patients. Re-biopsy was conducted to 13 (87%) of 15 patients who experienced disease progression during TDM-1 therapy. Samples of re-biopsy were acquired from the site that showed progression during T-DM-1 therapy. Re-biopsy revealed that HER2 status had changed to negative in six (46%) patients (Negative group), and had remained positive in seven (54%) patients (Positive group). Patient characteristics are shown in table. Median TTF was 65.5 days (95% CI: 34-NA) in Negative group, 126 days (95%CI: 70-140) in Positive group, and 196 days (95%CI: 93-594) in all patients. Proportion of progressive disease (PD) was 83% (five in six patients) in Negative group, 43% (three in seven patients) in Positive group, and 39% (nine of 23 patients) in all patients. Patient characteristics All patients (23)Negative group (6)Positive group (7)Age at start T-DM1 (year) Median (rang)61 (38-80)63 (48-71)58 (38-78)ECOG PS 0-121 (91%)6 (100%)7 (100%)2-32 (9%)--ER and/or PgR positive13 (57%)5 (83%)4 (57%)ER and PgR negative10 (43%)1 (17%)3 (43%)Number of prior chemotherapy regimens for MBC Median (rang)2 (1-9)2 (1-9)2 (1-5)Prior Lapatinib10 (43%)2 (33%)4 (57%) Conclusions: In 46% of patients who received re-biopsy, HER2 status changed to negative. There was a trend that TTF was shorter and PD rate was higher in Negative group than in Positive group. We demonstrated that some of patients who experienced PD during T-DM1 therapy had HER2-negative MBC, and in these patients efficacy of T-DM1 was likely to be insufficient. In such a case that disease progression occurs in a few months of T-DM1 therapy, we have to consider whether its HER2 status remains positive or changes to negative. Citation Format: Yoshinami T, Hasegawa A, Fujisawa F, Kittaka N, Ishitobi M, Sugimoto N, Nakayama T, Toshinari Y, Tamaki Y, Imamura F. A retrospective study about re-biopsy at disease progression on T-DM1 [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 P4-22-24.

Phase II trial of S-1 plus leucovorin in patients with advanced gastric cancer and clinical prediction by S-1 pharmacogenetic pathway

BackgroundThe first one-arm phase II trial aimed to evaluate and predict efficacy and safety of S-1 plus oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach.Patients and methodsA total of 39 patients orally took S-1 at conventional dose and LV simultaneously at a dose of 25 mg twice daily for a week, within a 2-week cycle. The primary endpoint was overall response rate (ORR), while the secondary endpoints were progression-free survival (PFS), time to failure (TTF), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Peripheral blood was sampled prospectively for baseline expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics.ResultsThe ORR and DCR were 41.0 and 76.9%. The median PFS, TTF, and OS were 4.13, 3.70, and 11.40 months. Grade 3–4 AEs occurred in only 13 patients, and grade 4 AEs occurred in only 1 of them. High OPRT/TS and peritoneal metastasis (vs. liver metastasis) independently predicted responding. High OPRT/DPD independently predicted grade 3–4 AEs. High AUC0–24h of 5-FU and metastatic/recurrent sites ≤2 (vs. >3) independently predicted prolonged PFS. Low baseline plasmic DPD independently predicted prolonged OS.ConclusionsTwo-week, oral S-1/LV regimen demonstrated promising efficacy and safety as first-line chemotherapy for AGC.ClinicalTrials.gov identifierNCT02090153

A Phase II Study of the Combination of Lenalidomide and Rituximab in Patients with Treatment-NaïVe and Relapsed Chronic Lymphocytic Leukemia

Introduction. The combination of Lenalidomide (Len) and rituximab has been investigated in patients (pts) with treatment-naive (TN) and relapsed (R) CLL with an overall response rate (ORR) ranging between 66% and 85%. Fludarabine refractoriness and a median daily Len dose Methods. Pts were eligible for this study if they had treatment indications per IWCLL 2008 criteria, WHO PS ≤2 and adequate hepatic and renal function. Len was started on day 9 of cycle 1 at 10 mg orally and administered daily indefinitely. Rituximab, 375 mg/m2, was administered every 28 days for 12 cycles. Response was assessed at month 3, 6 and every 6 months thereafter. Pts in this study returned to our center at time of response assessment and were allowed to receive R infusion at their oncologist9s office. The primary end point of this study was ORR. Results. One-hundred-twenty pts (61 TN and 59 R) were enrolled between 1/2012 and 11/2014; 83 (69%) pts received their R infusion locally. Baseline pts characteristics are shown in the Table. The median number of cycles administered was 16 [1-54] in TN and 20 [1-59] in R pts. Fifty-five TN and 53 R pts were evaluable for response. Twelve pts discontinued therapy before the first response assessment [toxicity (8), loss to follow-up (3), and death (1)]. ORR was 73% in TN and 64% in R pts, CR/CRi rate was 35% in TN and 28% in R pts. MRD eradication was achieved in 16% of TN and 2% of R pts. Median time to response was 11 [8-14] and 6 [5-7] months in TN and R pts. Median response duration (RD) has not been reached for TN pts and was 37 (29-45) months for R pts; 28% of TN and 62% of R pts have progressed. Characteristics predictive of higher ORR were: B2M ≤ 4 mg/L in TN pts (85% vs 55%, p=0.03); age 60 mL/min in R pts; on MVA, only B2M maintained its association (84% vs 46%; OR 5, 95% CI 1.1-10; p=0.03). FISH and IGHV status did not predict ORR. Characteristics associated with longer RD were age ≤ 65 years (p=0.009) and non-complex karyotype (p=0.05) in TN pts; on MVA, only age maintained its association (not reached vs 33 months; HR 5; 95% CI 1-25.6; p=0.05); Treatment-associated G 3-4 toxicities occurred in 28% of TN and 30% of R pts. Most common toxicities were: infections (10% of TN and 22% of R pts), thromboembolic complications (6%, both groups), skin rash (6% in TN pts only), and tumor flare reaction 6% (TN pts only). Forty-three (70%) TN and 50 (85%) R pts have discontinued treatment, median time to failure (TTF) was 22 [16-28] and 34 [25-43] months, respectively. Reasons for interruption were: progression in 13 (30%) TN and 25 (50%) R pts, toxicity in 25 (57%) TN and 20 (40%) R pts, pt/physician choice in 3 (7%) TN and 4 (8%) R pts, and other cancers in 2 (5%) TN and 1(2%) R pt. Factors predictive of a longer median TTF were eGFR ≥ 60 mL/min in TN pts (23 months vs 7 months, p=0.05) and early Rai stage in R pts (41 vs 36 months, p=0.04). At a median follow-up of 34 [1-53+] months, 4 (7%) TN and 14 (24%) R pts died, with a 4-year OS of 90% and 70%, respectively. Factors associated with shorter median OS were advanced Rai stage in TN pts (75% vs 100%, p=0.02), and > 2 prior treatments in R pts (on MVA; 50% vs 90% 4-years OS; HR 5.2; 95% CI 1.3-21; p=0.02). When comparing pts treated at our center to those receiving R infusion in the community, no significant differences in ORR, G3-4 toxicity rate or OS were observed. Conclusions. In our experience, the combination of Len and R is able to induce responses in 73% of TN and in 64% of R pts. Pts age IGHV status. Similar results in terms of efficacy and toxicity were observed in pts treated at our center or managed in close cooperation with local providers. With the expanding number of active treatment options for pts with CLL, the identification of clinical and biological factors predictive of response is becoming increasingly important. Disclosures Thompson: Pharmacyclics: Consultancy, Honoraria. Jain: Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Infinity: Research Funding; Genentech: Research Funding; Servier: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Incyte: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger: Pharmacyclics: Research Funding. Wierda: Gilead: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Novartis: Research Funding; Genentech: Research Funding. Kantarjian: Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Abstract P6-10-05: First-line chemotherapy versus first-line endocrine therapy in hormone receptor positive HER2 negative patients with metastatic breast cancer in China: Results of the study of breast cancer group of the Chinese Society of Clinical Oncology (CSCO)

Abstract Background: The primary objective for metastatic breast cancer is to prolong the patients survival. So the appropriate choice of the first-line therapy strategy is very important. For the HR-positive metastatic breast cancer, we haven't strong data to head-to-head compare the chemotherapy with endocrine therapy as the first-line treatment. Methods: Two hundreds patients with HR-positive metastatic breast cancer were enrolled at 47 cancer centers in China from 2009 to 2012. Investigators decided to give chemotherapy or endocrine therapy according to their clinical judgements. Chemotherapy and endocrine therapy regimens followed the NCCN guildline. All the patiens haven't take any treatment after relapse or metastasis. All the patients were estrogen- receptor positive and/or progesterone-receptor positive,HER2 negative. Chemotherapy or endocrine therapy was continued in the progressive disease(PD) or unacceptable toxicity. Primary endpoint was progression-free survival(PFS), second endpoints were time to failure(TTF), response rate. Results: According to the investigator judgements, one hundred patient took chemotherapy(CT arm), another one hundreds patients took endocrine therapy(ET arm). Pt characteristics were balanced between the two arms: median age 49y/50y, median disease-free survival(DFS) 40m/30m, visceral/non-visceral metastatic 52%/40%. There was more patients with ≥2 metastatic sites in CT arm than ET arm (50% vs 32%). Following up to Dec 2012, reasons for early treatment discontinuation were : PD 25 pts, toxicity 38 pts in CT arm, PD 82 pts, toxicity 2 pts in ET ram. The median PFS was 52 weeks(95% CI 23.2-80.8 weeks) and 48 weeks(95% CI 38.9-57.0 weeks) for CT arm and ET arm(P = 0.589),respectively. The median TTF was 20 weeks and 48 weeks for CT arm and ET arm,respectively(P = 0.025). Response rate was 63% and 22% for CT arm and ET arm,respectively(P&amp;lt;0.001). But clinical benefit rate(CR+PR+SD≥6months) was 67% and 69% for CT arm and ET arm,respectively(P = 0.333). Subgroup analysis showed TTF were 48 weeks in ET arm and 15 weeks in CT arm(p = 0.038) for patients who had more than 2 years DFS. TTF results also indicated significant difference in single metastatic site pts and non-visceral metastatic pts between two arms. ET arm was superior to CT arm. Conclusions: Our results indicate first-line chemotherapy has higher response rate than first-line endocrine therapy for HR-positive meatstatic breast cancer, but chemotherapy has shorter maintaining therapy time. First-line endocrine therapy was more suitable than first-line chemotherapy for pts with DFS≥2y, single metastatic site and non-visceral metastatic. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-10-05.

Reliability Analysis of Small-Delay Defects Due to Via Narrowing in Signal Paths

The number of open defects in vias has increased with the introduction of the copper process, smaller geometries, and via counts in the order of billions for modern integrated circuits. The authors investigate reliability risks by estimating the Median Time to Failure (MTF) as a function of the void size in vias placed. The number of open defects in vias has increased with the introduction of the copper process, smaller geometries, and via counts in the order of billions for modern integrated circuits. The authors investigate reliability risks by estimating the Median Time to Failure (MTF) as a function of the void size in vias placed on signal paths.

Efficacy and safety of cladribine: Subcutaneous versus intravenous administration in hairy cell leukemia.

7013 Background: Hairy cell leukemia (HCL) is rare B-cell lymphoproliferative disorder. Its treatment has evolved from splenectomy with time to failure (TTF) of 19 months to Cladribine that increased complete remission (CR) rate to 90%, with only small percentage of patients relapsing at 30 months. Cladribine (CDA) is originally administered intravenously as continuous infusion for 7 days; Subsequently, it was administered subcutaneously. This study aims at comparing efficacy and toxicity of Subcutaneous (SC) versus Intravenous (IV) administration of CDA in treatment of HCL. Methods: This retrospective study included HCL patients presented to National Cancer Institute and Nasser Institute, Cairo, Egypt, during period 2004-2010. Included patients received CDA as 1st or 2nd line with minimum follow up of 12 months. All files were reviewed for baseline clinical &amp; laboratory parameters, route of administration, response, adverse events and survival. Results: This study included 49 eligible patients, 41 patients received CDA as 1st line treatment, while 8 patients as 2nd line. Eighteen patients were treated by continuous IV infusion whereas 31 patients by SC injections. Both groups were comparable regarding baseline clinical and laboratory parameters with no statistically significant difference. At median follow up period of 33.5 months, complete remission rate was 94% in IV group versus 97% in SC group (p=0.691); median TTF for IV group was 52.9 months while that for SC group was not reached (p=0.035). The median time to achieve CR in both arms was similar. By analyzing different factors affecting TTF using multivariate analysis, route of administration proved to be the only statistically significant factor (P=0.006). Regarding adverse events, there was no difference between both groups in hematological toxicities. IV route was associated with a significant higher incidence of mucositis (p=0.02) and viral infections (p=0.01). Hepatotoxicity and neurotoxicity were higher in SC group but difference was not statistically significant. Conclusions: SC administration of cladribine is an alternative route to IV in treatment of HCL with similar response rate, longer time to treatment failure and better tolerability.

Electromigration-Induced Plastic Deformation in Cu Interconnects: Effects on Current Density Exponent, n, and Implications for EM Reliability Assessment

While Black’s equation for electromigration (EM) in interconnects with n = 1 is rigorously based on the principles of electrotransport, n > 1 is more commonly observed empirically. This deviation is usually attributed to Joule heating. An alternative explanation is suggested by the recent discovery of EM plasticity. To examine this possibility, we have retested samples that had been previously subjected to a predamaging phase of high temperature and current densities to determine whether the loss of median time to failure (MTF) is retained. We find that the predamaged samples exhibit MTFs that are permanently reduced, which is a characteristic of EM plasticity.

Ten‐year follow‐up after intense chemoimmunotherapy with Rituximab‐HyperCVAD alternating with Rituximab‐high dose methotrexate/cytarabine (R‐MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma

Mantle cell lymphoma (MCL) has a poor overall survival after treatment with conventional chemotherapy. Intense chemoimmunotherapy without consolidation stem cell transplantation is a potential therapeutic option. We report on a prospective Phase II study with rituximab in combination with fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R-Hyper-CVAD) alternating with rituximab in combination with high-dose methotrexate-cytarabine (R-MA) in untreated patients with diffuse and nodular MCL and their blastoid variants. Ninety-seven patients were treated, of whom 97% responded and 87% achieved a complete remission. At 10 years of follow up (median 8 years), the median overall survival (OS) for all patients had not been reached and the median time to failure (TTF) for all patients was 4.6 years, without a plateau in the curves. For the group of patients aged 65 years or younger, the median OS had not been reached and the median TTF was 5.9 years. Multivariate analysis revealed pre-treatment serum levels of beta(2) microglobulin, International Prognostic Index (IPI) score and mantle cell IPI (MIPI) score, as predictive of both OS and TTF. We conclude that intense chemoimmunotherapy without stem cell transplantation is effective for untreated aggressive MCL.

Pegylated liposomal doxorubicin (PLD) treatment for recurrent epithelial ovarian cancer (rEOC): Implications of BRCA mutations.

5043 Background: Does BRCA status affect outcome of rEOC patients treated with PLD? Tumors deficient in homologous recombination (HR) DNA repair are sensitive to platinums. Recurrences likely reflect acquired platinum resistance, perhaps from recovering BRCA function (as suggested in preclinical studies). We now investigate whether sensitivity to PLD and other DNA damaging agents is retained in BRCA mutation carriers (BRCA+) with rEOC. Methods: We retrospectively analyzed rEOC patients treated with PLD as second- or third-line from 1998 to 2009 in 4 institutions (Israel, Italy, NY):155 rEOC patients have been evaluated of which 38 (24.5%) are BRCA+ and 117 (75.5%) non-hereditary consisting of 35 (22.5%) who tested negative and 82 (53%) untested, (excluding 10 patients with a family history in a first-degree relative). Results: Median age is 59 (31-83) years; 44 (28%) patients have a platinum free interval (PFI) of < 6 months and 111 (72 %) of > 6 months; 104 (67%) received PLD as second-line and 55 (33%) as third-line. PLD with a platinum was used in 90 (58%) and PLD alone in 65 (42%). BRCA+ vs. non-hereditary comparisons show: response rate 68.4% vs. 49%; median TTF (time to failure) 11.4 (CI 95% 5.9-18.1) vs. 9.4 (CI 95% 7.7-11.9) m; OS (overall survival) 56.8 (CI 95% 32.5-87.9) vs. 22.6 (CI 95% 16.0-34.1) m this last comparison (p = 0.005). Cox survival models showed OS to be associated with BRCA status when adjusting for age and PFI (p = 0.02; hazard ratio, BRCA- vs. BRCA+ = 3.5); PFI was significantly associated with overall survival (p = 0.04). BRCA+are being further analyzed for role of subsequent platinums and other drugs. Conclusions: BRCA mutation carriers rEOC have improved outcome, suggesting persistent defects in HR, accounting for responses to other DNA damaging agents even after acquired platinum resistance. The potential role for PARP inhibitors after chemotherapy induced-remission is reinforced by these findings. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Yissum-Hadasit Doxil Royalties

Quantitative analysis on median-time-to-fail of copper interconnect with lose object defects

In the paper， influence of lose object defects on electromigration median-time-to-failure （MTF） for six-layer copper interconnect is investigated. The temperature model with defects for each interconnection layer and MTF model for defects in different interconnection layers are presented respectively. So， the defect influence on electromigration MTF of copper interconnect can be calculated quantitatively， and the method to increase MTF is also presented. The bigger the ratio of interconnect width to the effective interconnect width at the defects， the shorter the MTF， and higher temperature at defects can also shorten the MTF. When the parameters of interconnect wire vary greatly between different layers， the MTF is affected by the ratios and the temperature， and decreases rapidly. Based on the physical model， the temperature and the MTF of copper interconnect can be calculated accurately， which can guide IC design and manufacture effectively.

Acceleration factors for THB induced degradation of AlGaAs/InGaAs pHEMT devices

PHEMT devices initially showing high failure rates during Temperature Humidity Bias (THB) reliability testing were investigated further using a number of temperature and humidity conditions. Ambient temperature was varied from 85 °C to 110 °C, humidity from 65% RH (Relative Humidity) to 85% RH. Failure rates were fit to a Peck acceleration model using the method of maximum likelihood. Median time to failure (MTTF) estimates were calculated at anticipated field service conditions using the experimentally determined model parameters. The MTTF is predicted to be typically less than a year for the die variant studied. Countermeasures outside the scope of this investigation have been implemented to effectively eliminate this issue allowing RFMD to supply products with suitable reliability.

Maintenance rituximab (MR) compared to observation (OBS) after R-CHOP or CHOP in older patients (pts) with diffuse large B-cell lymphoma (DLBCL): An Intergroup E4494/C9793 update

8011 Background: Maintenance therapy is generally not used in treatment of DLBCL. However, older pts are a unique group in which to study this approach, due to poorer outcome. Methods: As part of intergroup trial E4494/C9793, 415 pts &gt;= 60 years (yr) of age with DLBCL who responded to induction therapy with CHOP or R-CHOP were randomized to MR (rituximab, 375 mg/m2 weekly {wk} X 4 every 6 months for 2 yr) starting 4 wk after the last chemotherapy (n=207) or observation (OBS, n=208) in a prospective 2 × 2 randomized trial design (J Clin Oncol 2006;24:3121). Impact of MR on failure-free survival (FFS) was the primary objective, and impact on time to failure (TTF) and overall survival (OS) were secondary objectives. All p-values are two-sided. Results: Results are presented for 352 centrally reviewed evaluable pts, with a median follow-up after maintenance randomization of 5.5 yr. All results were similar for the intent-to-treat population. Baseline characteristics and response to induction therapy are balanced among the CHOP/R-CHOP pts. At 6 yr, FFS was 46% for those pt who received MR and 36% for the OBS cohort (p=0.005, hazard rate {HR} 0.64); 6-yr OS was 62% for MR and 64% for OBS (p=0.83, HR 0.96). Outcome was also examined in the four treatment subgroups. The 6-yr FFS were: CHOP+MR 44%, CHOP+OBS 35%, R-CHOP+MR 47%, and R- CHOP+OBS 40%. No differences in 6-yr OS were observed according to maintenance randomization following CHOP (57% MR vs 55% OBS) or R-CHOP (67% MR and 72% OBS). Median TTF after maintenance randomization following CHOP+MR was 5.2 yr vs 1.6 yr for CHOP-OBS (p=0.0004), and following R-CHOP+MR was 5.6 yr vs 5.4 yr with R-CHOP-OBS (p=0.50). Proportionately more of the treatment failures occurred within 2 yr after CHOP+OBS (85%) compared to CHOP+MR (61%), p=0.01. In contrast, the proportion of failures within 2 yr was similar for R- CHOP+OBS (47%) and R-CHOP+MR (53%), p=NS. Conclusions: MR after CHOP, but not after R-CHOP, significantly prolongs TTF, but fails to prolong OS, possibly due to a delayed pattern of relapse and/or the efficacy of rituximab in the salvage setting. As 6-yr FFS declined to &lt;50% among R-CHOP responders, with or without MR, there is a need for more effective treatment strategies in older DLBCL pts. No significant financial relationships to disclose.

CoWP as a Drift Barrier for Cu Ions Studied by Electric Measurements

Electrical characteristics of self-aligned cobalt–tungsten–phosphide (CoWP) as a copper (Cu) drift barrier for advanced Cu interconnects were investigated using blanket metal-insulator-metal (MIM) structures. The time-dependent dielectric breakdown measurements of the MIM structure under the bias-temperature stress tests demonstrated that the median time-to-failure (MTF) of chemical-vapor-deposited improves by more than 20 times by forming a 10 nm thick CoWP. The improved MTF is comparable to that measured with the reversed-bias stress in which no Cu-ion drift occurs. It is concluded that Cu-ion drift is suppressed by a thick CoWP barrier.