Bachelor of Arts, Yale University (2003)
Doctor of Medicine, University of Michigan Ann Arbor (2010)
The role of surveillance studies in limited-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been well defined. We sought to evaluate the use of imaging (computed tomography [CT] and positron emission tomography [PET]-CT) scans and lactate dehydrogenase (LDH) in surveillance of patients with stage I to II DLBCL.A retrospective analysis was performed of patients who received definitive treatment between 2000 and 2013.One hundred sixty-two consecutive patients with stage I to II DLBCL were treated with chemotherapy +/- rituximab, radiation, or combined modality therapy. The 5-year rates of overall survival (OS) and freedom from progression (FFP) were 81.2% and 80.8%, respectively. Of the 162 patients, 124 (77%) were followed up with at least 1 surveillance PET scan beyond end-of-treatment scans; of those, 94 of 124 (76%) achieved a complete metabolic response on PET scan after completion of chemotherapy, and this was associated with superior FFP (P=.01, HR=0.3) and OS (P=.01, HR 0.3). Eighteen patients experienced relapse after initial response to therapy. Nine relapses were initially suspected by surveillance imaging studies (8 PET, 1 CT), and 9 were suspected clinically (5 by patient-reported symptoms and 4 by symptoms and physical examination). No relapses were detected by surveillance LDH. The median duration from initiation of treatment to relapse was 14.3 months among patients with relapses suspected by imaging, and 59.8 months among patients with relapses suspected clinically (P=.077). There was no significant difference in OS from date of first therapy or OS after relapse between patients whose relapse was suspected by imaging versus clinically. Thirteen of 18 patients underwent successful salvage therapy after relapse.A complete response on PET scan immediately after initial chemotherapy is associated with superior FFP and OS in stage I to II DLBCL. The use of PET scans as posttreatment surveillance is not associated with a survival advantage. LDH is not a sensitive marker for relapse. Our results argue for limiting the use of posttreatment surveillance in patients with limited-stage DLBCL.
View details for DOI 10.1016/j.ijrobp.2015.01.039
View details for PubMedID 25863757
Radiation therapy and immunotherapy are both well-established treatments for malignant disease. Radiotherapy has long been utilized for purposes of providing local tumor control, and the recent success with novel immunomodulatory agents has brought immunotherapy into the forefront of clinical practice for the treatment of many tumor types. Although radiotherapy has traditionally been thought to mediate tumor regression through direct cytotoxic effects, it is now known that radiation also alters the local tumor microenvironment with effects on both the local and systemic anti-tumor immune response. There is growing evidence that the rational integration of the immunomodulatory effects of radiotherapy with the expanding armamentarium of clinically approved immunotherapeutics can yield potent anti-tumor responses exceeding the benefit of either therapy alone. Here we summarize current approaches to the combination of immunotherapy with radiation therapy.
View details for DOI 10.1053/j.seminoncol.2014.09.019
View details for PubMedID 25499631
To evaluate survival and neurocognitive outcomes in pediatric acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement treated according to an institutional protocol with stem cell transplantation (SCT) and a component of craniospinal irradiation (CSI) in addition to total-body irradiation (TBI) as preparative regimen.Forty-one pediatric ALL patients underwent SCT with TBI and received additional cranial irradiation or CSI because of CNS leukemic involvement. Prospective neurocognitive testing was performed before and after SCT in a subset of patients. Cox regression models were used to determine associations of patient and disease characteristics and treatment methods with outcomes.All patients received a cranial radiation boost; median total cranial dose was 24 Gy. Eighteen patients (44%) received a spinal boost; median total spinal dose for these patients was 18 Gy. Five-year disease-free survival (DFS) for all patients was 67%. Those receiving CSI had a trend toward superior DFS compared with those receiving a cranial boost alone (hazard ratio 3.23, P=.14). Patients with isolated CNS disease before SCT had a trend toward superior DFS (hazard ratio 3.64, P=.11, 5-year DFS 74%) compared with those with combined CNS and bone marrow disease (5-year DFS 59%). Neurocognitive testing revealed a mean post-SCT overall intelligence quotient of 103.7 at 4.4 years. Relative deficiencies in processing speed and/or working memory were noted in 6 of 16 tested patients (38%). Pre- and post-SCT neurocognitive testing revealed no significant change in intelligence quotient (mean increase +4.7 points). At a mean of 12.5 years after transplant, 11 of 13 long-term survivors (85%) had completed at least some coursework at a 2- or 4-year college.The addition of CSI to TBI before SCT in pediatric ALL with CNS involvement is effective and well-tolerated. Craniospinal irradiation plus TBI is worthy of further protocol investigation in children with CNS leukemia.
View details for DOI 10.1016/j.ijrobp.2014.01.056
View details for Web of Science ID 000334590500011
View details for PubMedID 24725690
Limited treatment options exist for isolated local recurrence of pancreatic ductal adenocarcinoma (PDA) following surgical resection accompanied by neoadjuvant or adjuvant chemoradiation therapy (CRT). While select patients are eligible for re-resection, recurrent lesions are often unresectable. Stereotactic body radiation therapy (SBRT) represents a possible minimally invasive treatment option for these patients, although published data in this setting are currently lacking. This study examines the safety, efficacy, and palliative capacity of re-irradiation with SBRT for isolated local PDA recurrence. All patients undergoing SBRT at two academic centers from 2008-2012 were retrospectively reviewed to identify those who received re-irradiation with SBRT for isolated local recurrence or progression of PDA after previous conventionally fractionated CRT. Information regarding demographics, clinicopathologic characteristics, therapies received, survival, symptom palliation, and toxicity was obtained from patient charts. Kaplan-Meier statistics were used to analyze survival and the log-rank test was used to compare survival among patient subgroups. Eighteen patients were identified. Fifteen had previously undergone resection with neoadjuvant or adjuvant CRT, while 3 received definitive CRT for locally advanced disease. Median CRT dose was 50.4 Gy [interquartile range (IQR), 45.0-50.4 Gy] in 28 fractions. All patients subsequently received gemcitabine-based maintenance chemotherapy, but developed isolated local disease recurrence or progression without evidence of distant metastasis. Locally recurrent or progressive disease was treated with SBRT to a median dose of 25.0 Gy (range, 20.0-27.0 Gy) in 5 fractions. Median survival from SBRT was 8.8 months (95% CI, 1.2-16.4 months). Despite having similar clinicopathologic disease characteristics, patients who experienced local progression greater than vs. less than 9 months after surgery/definitive CRT demonstrated superior median survival (11.3 vs. 3.4 months; P=0.019) and progression-free survival (10.6 vs. 3.2 months; P=0.030) after SBRT. Rates of freedom from local progression at 6 and 12 months after SBRT were 78% (14 of 18 patients) and 62% (5 of 8 patients), respectively. Effective symptom palliation was achieved in 4 of 7 patients (57%) who reported symptoms of abdominal or back pain prior to SBRT. Five patients (28%) experienced grade 2 acute toxicity; none experienced grade ≥3 acute toxicity. One patient (6%) experienced grade 3 late toxicity in the form of small bowel obstruction. In conclusion, re-irradiation with hypofractionated SBRT in this salvage scenario appears to be a safe and reasonable option for palliation of isolated local PDA recurrence or progression following previous conventional CRT. Patients with a progression-free interval of greater than 9 months prior to isolated local recurrence or progression may be most suitable for re-irradiation with SBRT, as they appear to have a better prognosis with survival that is long enough for local control to be of potential benefit.
View details for DOI 10.3978/j.issn.2078-6891.2013.044
View details for PubMedID 24294505
Primary squamous cell carcinoma (SCCA) of the vagina is a rare malignancy with limited data to guide treatment. We evaluated prognostic factors and outcomes for patients with primary vaginal SCCA treated with definitive radiation therapy at a single institution.A retrospective analysis was performed on patients treated for primary vaginal SCCA from 1959 to 2011.Ninety-one patients with primary vaginal SCCA were treated with definitive radiation therapy. Thirty-eight patients had FIGO stage I, 28 stage II, 13 stage III, and 12 stage IV disease. The mean total dose was 70.1Gy. Two-year overall survival (OS), locoregional control rate (LRC), and distant metastasis-free survival by stage were, respectively: stage I: 96.2%, 80.6%, 87.5%; stage II: 92.3%, 64.7%, 84.6%; stage III: 66.6%, 44.4%, 50.0%; and stage IV: 25.0%, 14.3%, 25.0%. Treatment with total dose over 70Gy was associated with improved OS (p=0.0956) and LRC (p=0.055). There was a significant difference in median dose received by patients who developed grade 3/4 toxicity compared to those who did not (82.9Gy versus 70.0Gy, p=0.0019). None of the 10 patients treated with IMRT experienced locoregional recurrence or grade 3/4 toxicity. Tumor size larger than 4cm was associated with worse OS (p=0.0034) and LRC (p=0.006).Our analysis suggests that the optimal dose for definitive treatment of SCCA of the vagina lies between 70 and 80Gy. Treatment with IMRT may allow for dose escalation with reduced toxicity and excellent LRC. Tumor size over 4cm is associated with inferior outcomes and may require additional treatment modalities.
View details for DOI 10.1016/j.ygyno.2013.08.012
View details for Web of Science ID 000326427900019
Angiosarcomas are aggressive tumors of vascular endothelial origin, occurring sporadically or in association with prior radiotherapy. We compared clinicopathologic and biologic features of sporadic angiosarcomas (SA) and radiation-associated angiosarcomas (RAA). Methods. From a University of Michigan institutional database, 37 SA and 11 RAA were identified. Tissue microarrays were stained for p53, Ki-67, and hTERT. DNA was evaluated for TP53 and ATM mutations. Results. Mean latency between radiotherapy and diagnosis of RAA was 11.9 years: 6.7 years for breast RAA versus 20.9 years for nonbreast RAA (P = 0.148). Survival after diagnosis did not significantly differ between SA and RAA (P = 0.590). Patients with nonbreast RAA had shorter overall survival than patients with breast RAA (P = 0.03). The majority of SA (86.5%) and RAA (77.8%) were classified as high-grade sarcomas (P = 0.609). RAA were more likely to have well-defined vasoformative areas (55.6% versus 27%, P = 0.127). Most breast SA were parenchymal in origin (80%), while most breast RAA were cutaneous in origin (80%). TMA analysis showed p53 overexpression in 25.7% of SA and 0% RAA, high Ki-67 in 35.3% of SA and 44.4% RAA, and hTERT expression in 100% of SA and RAA. TP53 mutations were detected in 13.5% of SA and 11.1% RAA. ATM mutations were not detected in either SA or RAA. Conclusions. SA and RAA are similar in histology, immunohistochemical markers, and DNA mutation profiles and share similar prognosis. Breast RAA have a shorter latency period compared to nonbreast RAA and a significantly longer survival.
View details for DOI 10.1155/2013/798403
View details for PubMedID 24082817
Melanoma is a relatively immunogenic tumor, in which infiltration of melanoma cells by T lymphocytes is associated with a better clinical prognosis. We hypothesized that radiation-induced cell death may provide additional stimulation of an anti-tumor immune response in the setting of anti-CTLA-4 treatment.In a pilot melanoma patient, we prospectively tested this hypothesis. We treated the patient with two cycles of ipilimumab, followed by stereotactic ablative radiotherapy to two of seven hepatic metastases, and two additional cycles of ipilimumab.Subsequent positron emission tomography-computed tomography scan indicated that all metastases, including unirradiated liver lesions and an unirradiated axillary lesion, had completely resolved, consistent with a complete response by RECIST.The use of radiotherapy in combination with targeted immunotherapy as a noninvasive in vivo tumor vaccine strategy appears to be a promising method of enhancing the induction of systemic immune responses and anti-tumor effect.
View details for DOI 10.1593/tlo.12280
View details for Web of Science ID 000313359800002
View details for PubMedID 23323154
The epidermal growth factor receptor (EGFR) has been targeted for inhibition using tyrosine kinase inhibitors and monoclonal antibodies, with improvement in outcome in subsets of patients with head and neck, lung, and colorectal carcinomas. We have previously found that EGFR stability plays a key role in cell survival after chemotherapy and radiotherapy. Heat shock protein 90 (HSP90) is known to stabilize mutant EGFR and ErbB2, but its role in cancers with wild-type (WT) WT-EGFR is unclear. In this report, we demonstrate that fully mature, membrane-bound WT-EGFR interacts with HSP90 independent of ErbB2. Further, the HSP90 inhibitors geldanamycin (GA) and AT13387 cause a decrease in WT-EGFR in cultured head and neck cancer cells. This decrease results from a significantly reduced half-life of WT-EGFR. WT-EGFR was also lost in head and neck xenograft specimens after treatment with AT13387 under conditions that inhibited tumor growth and prolonged survival of the mice. Our findings demonstrate that WT-EGFR is a client protein of HSP90 and that their interaction is critical for maintaining both the stability of the receptor as well as the growth of EGFR-dependent cancers. Furthermore, these findings support the search for specific agents that disrupt HSP90's ability to act as an EGFR chaperone.
View details for DOI 10.1593/neo.12986
View details for Web of Science ID 000308490500001
View details for PubMedID 22952420
Cisplatin and its analogues are the most commonly used agents in the treatment of head and neck squamous cell carcinoma. In this study, we investigated a possible role of epidermal growth factor (EGF) receptor (EGFR) phosphorylation and degradation in cisplatin-induced cytotoxicity. Cisplatin treatment led to an increase in initial EGFR phosphorylation at Y1045, the binding site of ubiquitin ligase, Casitas B-lineage lymphoma (c-Cbl), followed by ubiquitination in the relatively cisplatin-sensitive cell lines. However, cisplatin-resistant cell lines underwent minimal EGFR phosphorylation at the Y1045 site and minimal ubiquitination. We found that EGFR degradation in response to cisplatin was highly correlated with cytotoxicity in seven head and neck cancer cell lines. Pretreatment with EGF enhanced cisplatin-induced EGFR degradation and cytotoxicity, whereas erlotinib pretreatment blocked EGFR phosphorylation, degradation, and cisplatin-induced cytotoxicity. Expression of a mutant Y1045F EGFR, which is relatively resistant to c-Cbl-mediated degradation, in Chinese hamster ovary cells and the UMSCC11B human head and neck cancer cell line protected EGFR from cisplatin-induced degradation and enhanced cell survival compared with wild-type (WT) EGFR. Transfection of WT c-Cbl enhanced EGFR degradation and cisplatin-induced cytotoxicity compared with control vector. These results show that cisplatin-induced EGFR phosphorylation and subsequent ubiquitination and degradation is an important determinant of cisplatin sensitivity. Our findings suggest that treatment with an EGFR inhibitor before cisplatin would be antagonistic, as EGFR inhibition would protect EGFR from cisplatin-mediated phosphorylation and subsequent ubiquitination and degradation, which may explain the negative results of several recent clinical trials. Furthermore, they suggest that EGFR degradation is worth exploring as an early biomarker of response and as a target to improve outcome.
View details for DOI 10.1158/0008-5472.CAN-09-4294
View details for Web of Science ID 000278486000031
View details for PubMedID 20215522
Epidermal growth factor receptor (EGFR) inhibitors are increasingly used in combination with radiotherapy in the treatment of various EGFR-overexpressing cancers. However, little is known about the effects of cell cycle status on EGFR inhibitor-mediated radiosensitization. Using EGFR-overexpressing A431 and UMSCC-1 cells in culture, we found that radiation activated the EGFR and extracellular signal-regulated kinase pathways in quiescent cells, leading to progression of cells from G(1) to S, but this activation and progression did not occur in proliferating cells. Inhibition of this activation blocked S-phase progression and protected quiescent cells from radiation-induced death. To determine if these effects were caused by EGFR expression, we transfected Chinese hamster ovary (CHO) cells, which lack EGFR expression, with EGFR expression vector. EGFR expressed in CHO cells also became activated in quiescent cells but not in proliferating cells after irradiation. Moreover, quiescent cells expressing EGFR underwent increased radiation-induced clonogenic death compared with both proliferating CHO cells expressing EGFR and quiescent wild-type CHO cells. Our data show that radiation-induced enhancement of cell death in quiescent cells involves activation of the EGFR and extracellular signal-regulated kinase pathways. Furthermore, they suggest that EGFR inhibitors may protect quiescent tumor cells, whereas radiosensitization of proliferating cells may be caused by downstream effects such as cell cycle redistribution. These findings emphasize the need for careful scheduling of treatment with the combination of EGFR inhibitors and radiation and suggest that EGFR inhibitors might best be given after radiation in order to optimize clinical outcome.
View details for DOI 10.1158/0008-5472.CAN-09-0466
View details for Web of Science ID 000267506400025
View details for PubMedID 19509222
Bowen's disease (BD), a form of squamous cell carcinoma in situ, can transform into invasive squamous cell carcinoma and should be treated aggressively. Although standard treatment for BD is electrodessication and curettage, radiotherapy (RT) can be used for those patients who are poor surgical candidates or when surgery could result in a poor cosmetic and functional outcome. Surgical treatment of BD of the digit can result in poor function and sometimes amputation. Here, we report our experience using a unique water bath technique to treat BD of the digit.This retrospective review evaluates the outcomes and toxicity of nine consecutive patients with BD of the digit treated with RT between 1999 and 2004. Fourteen digit lesions were immersed in a water bath and treated with photon irradiation. The median radiation dose delivered was 50Gy (range 25-66Gy) in 2.5Gy fractions (range 2-3Gy).The median age of the patients treated was 77 years (range 29-87 years). Three patients (33%) had more than one digit treated. With a median follow-up of 25 months (range 0.4-52 months), all 14 digit lesions are locally controlled. The majority of lesions demonstrated mild to moderate erythema, desquamation, or edema (grade 1-2) acutely following RT which resolved within one month of treatment. Two digits (14%) developed ulcers (grade 4) which healed following RT. The only long-term toxicity was decreased sensation and strength in one patient who had three circumferential lesions. This toxicity was limited and did not appear to influence the patient's daily activities (grade 2).These preliminary results demonstrate high rates of tumor control with minimal morbidity following definitive RT in the treatment of BD of the digit, and suggest that RT may be a viable treatment alternative to surgery for selected lesions. Through a multidisciplinary assessment, treatment of BD of the digit can be individualized to optimize patient care.
View details for DOI 10.1016/j.radonc.2008.05.025
View details for Web of Science ID 000260203800013
View details for PubMedID 18571754
Medication-taking behavior is influenced by many factors, as described by the Health Belief Model. Information on withdrawals of drugs from the market may be an example of negative external stimuli that might influence patients' decisions to persist with long-term drug therapy.To evaluate the association between the withdrawal of cerivastatin from the market and persistence in taking all other statins in patients who recently experienced acute coronary syndrome (ACS).Patients from a large ACS registry who responded to questions about medication use during a postdischarge telephone survey between November 2000 and February 2002 were categorized into 3 groups: pre- (November 1, 2000-April 30, 2001), peri- (May 1, 2001-August 31, 2001), and post- (September 1, 2001-February 28, 2002) cerivastatin withdrawal periods. Patients were considered persistent if, at the time of the survey, they continued to take study medication that had been prescribed at discharge. Persistence with angiotensin-converting enzyme inhibitors, aspirin, and beta-blockers was also assessed to determine whether changes in statin persistence were unique to the class or related to other medication issues that affected all classes. The Kruskal-Wallis test, with post hoc Mann-Whitney U test, was used to analyze the differences in persistence between the groups. All comparisons were considered statistically significant at p less than 0.05.There were no significant differences in patient characteristics between study groups. Persistence with statins decreased during the periwithdrawal period (88.4% pre vs 76.7% peri) and rebounded in the postwithdrawal period (90.8%; p = 0.007). There were no significant differences in persistence with the other drug classes.The temporary decline in statin persistence appeared to be associated with the withdrawal of cerivastatin, while persistence with the other study medications remained constant. Clinicians need to understand the potential effect of factors such as media attention surrounding a drug's withdrawal on patients' medication-taking behavior.
View details for DOI 10.1345/aph.1K575
View details for PubMedID 18523235