Publications by authors named "Margaret M Kozak"

33 Publications

Prospective randomized trial of email and/or telephone reminders to enhance vaginal dilator compliance in patients undergoing brachytherapy for gynecologic malignancies.

Brachytherapy 2021 Jul-Aug;20(4):788-795. Epub 2021 Apr 15.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford. Electronic address:

Purpose: To evaluate whether email survey +/- telephone reminder versus no intervention would facilitate compliance with vaginal dilator use in women undergoing brachytherapy for gynecologic malignancies and to assess changes in vaginal canal (VC) length between the groups.

Methods And Materials: A 72 patients were enrolled onto a three-arm single-institution randomized prospective clinical trial and stratified by whether they received external beam radiation treatment in addition to brachytherapy and by total radiation dose to the VC. Patients were subsequently randomized to one of three groups: email survey alone, email survey + telephone reminder, or no intervention. Change in VC length over time was measured for each patient.

Results: The median follow-up time was 17.3 months. There were no differences in patient-reported compliance between the 3 groups. Vaginal dilator compliance fell over the course of the study period and was 33% at 24 months. Baseline VC length and radiation dose were found to be the most important predictors of VC shortening over time. When accounting for baseline length, radiation dose, and follow-up time, type of intervention did not impact changes in VC length from baseline (p = 0.20).

Conclusions: Our study is the first to show the importance of baseline VC length as it relates to VC shortening following brachytherapy for gynecologic cancers and highlights the difficulties in improving VC compliance among this patient population. Further study is required to improve the incidence of late effects in this group.
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http://dx.doi.org/10.1016/j.brachy.2021.03.010DOI Listing
October 2021

Locoregional and Distant Outcomes in Women With cT1-3N1 Breast Cancer Treated With Neoadjuvant Chemotherapy With or Without Adjuvant Radiotherapy.

Clin Breast Cancer 2021 08 26;21(4):373-382. Epub 2021 Feb 26.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford CA. Electronic address:

Background: We evaluated the impact of postmastectomy radiotherapy (PMRT) or supraclavicular radiation therapy (SCV RT) in women with cT1-3N1 breast cancer (BC) who became node negative (ypN0) after neoadjuvant chemotherapy (NAC).

Patients And Methods: We retrospectively reviewed 485 women treated with NAC for BC between 2005 and 2019. Radiation treatment fields were reviewed in detail. Pathologic complete response (pCR) was defined as ypT0/Tis ypN0. Patients who had residual nodal disease were defined as ypN+. Those who achieved complete response in the lymph nodes but not in the breast were defined as ypT+ypN0.

Results: After excluding patients with cT4 and cN0 disease at diagnosis, a total of 185 patients with cT1-3N1 BC were included. Patients were more likely to receive PMRT if they had ypN+ disease (P < .001) and/or lymphovascular invasion (P = .03). Patients who underwent lumpectomy were more likely to receive SCV RT if they did not achieve pCR (P = .04) and/or if they had ypN+ disease (P = .01). The 5-year rates of locoregional recurrence (LRR) were 15% for all patients, 14% for patients who attained ypT+ypN0, and 5% for patients who achieved pCR. Of ypT+ypN0 patients (n = 98), 53 received PMRT or SCV RT and 45 did not. For these patients, there were no differences in LRR based on whether a patient did or did not receive PMRT or SCV RT (P = .23).

Conclusion: Recommendations for or against PMRT or SCV RT after NAC vary based on final pathologic response. We await the results of ongoing randomized clinical trials to help guide clinical decision making in this context.
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http://dx.doi.org/10.1016/j.clbc.2021.02.008DOI Listing
August 2021

Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer.

Clin Cancer Res 2021 02 1;27(4):1069-1081. Epub 2020 Dec 1.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Purpose: Although abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress antitumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood.

Experimental Design: To generate spatially resolved tumor and immune cell data at single-cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, IFN regulatory factor 5, MRC1 (CD206)] in the PDAC tumor microenvironment. Spatial point pattern analyses were conducted to assess the degree of colocalization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes.

Results: In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, and differed by somatic genotype. High densities of CD15ARG1 immunosuppressive granulocytic cells and M2-polarized macrophages were associated with worse patient survival. Moreover, beyond cell density, closer proximity of M2-polarized macrophages to tumor cells was strongly associated with disease-free survival, revealing the clinical significance and biologic importance of immune cell localization within tumor areas.

Conclusions: A diverse set of myeloid cells are present within the PDAC tumor microenvironment and are distributed heterogeneously across patient tumors. Not only the densities but also the spatial locations of myeloid immune cells are associated with patient outcomes, highlighting the potential role of spatially resolved myeloid cell subtypes as quantitative biomarkers for PDAC prognosis and therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345232PMC
February 2021

Lymphopenia and clinical outcomes in patients with residual nodal disease after neoadjuvant chemotherapy for breast cancer.

Cancer Causes Control 2020 Nov 4;31(11):1021-1026. Epub 2020 Sep 4.

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.

Background: Patients with residual nodal disease after neoadjuvant chemotherapy for breast cancer have a poor prognosis. We wanted to evaluate whether lymphopenia after treatment for breast cancer impacted clinical outcomes.

Materials And Methods: We assessed 99 patients with node-positive disease after neoadjuvant chemotherapy. Absolute lymphocyte count was recorded 1 year after radiation. Dates of local, regional, and distant failure were recorded. Time to event outcomes were evaluated using Kaplan-Meier analysis. Multivariable analysis determined factors predictive for overall survival.

Results: Median follow-up was 44 months (range 3-150). Median age was 48 years (range 23-79). Twenty-six patients (26%) had lymphopenia 1 year after RT. Patients with lymphopenia had a greater incidence of regional (p = 0.03) and distant failure (p = 0.009) compared to those with normal lymphocyte counts and had a 6.05 greater risk of death (p = 0.0002).

Conclusions: In patients with residual nodal disease after neoadjuvant chemotherapy, lymphopenia after breast cancer treatment was associated with overall survival. The relationship between lymphopenia and breast cancer outcomes warrants further investigation.
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http://dx.doi.org/10.1007/s10552-020-01337-6DOI Listing
November 2020

Patterns of Failure in Women Who Have Residual Nodal Disease After Neoadjuvant Chemotherapy for Breast Cancer According to Extent of Lymph Node Surgery.

Clin Breast Cancer 2020 10 7;20(5):431-438. Epub 2020 May 7.

Department of Surgery, Stanford Cancer Institute, Stanford, CA.

Background: Optimal surgical management of limited axillary nodal disease following neoadjuvant chemotherapy (NAC) for breast cancer is evolving. Concerns exist with respect to leaving residual disease in the axilla when omitting axillary lymph node dissection (ALND) in this setting. We sought to determine whether extent of nodal surgery altered patterns of failure and patient outcomes.

Patients And Methods: We identified 70 patients with breast cancer who were confirmed cN0 after NAC yet had residual nodal disease (ypN1) on sentinel lymph node biopsy (SLNB). Twenty-eight patients underwent SLNB alone and 42 underwent SLNB+completion (c)ALND in a non-randomized fashion. Most (n = 65) patients underwent adjuvant regional nodal irradiation (RNI). Detailed patterns of failure data were obtained for each patient.

Results: The median follow-up was 43.5 months. There were 30 (43%) recurrences. Of these, 5 were isolated locoregional failures, and 24 were distant failures. There were no significant differences in local (P = .13), regional (P = .62), or distant (P = .47) failure between patients who underwent SLNB alone versus SLNB+cALND. Seventeen (24%) patients died. Overall survival was similar in both groups with median overall survival not reached for those who underwent SLNB and 109 months for those who underwent SLNB+cALND (P = .45).

Conclusions: There were no differences in patterns of recurrence among patients with 1 to 3 involved lymph nodes after NAC who underwent SLNB alone versus SLNB+cALND in the setting of RNI. We await the results of ongoing, prospective clinical trials to confirm the relative merits of RNI in lieu of cALND in these patients.
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http://dx.doi.org/10.1016/j.clbc.2020.04.008DOI Listing
October 2020

Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1586-1595. Epub 2020 May 28.

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes.

Methods: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors.

Results: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; = 0.032). -mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, < 0.001).

Conclusions: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC.

Impact: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415636PMC
August 2020

Stereotactic Body Radiation Therapy for Cholangiocarcinoma: Optimizing Locoregional Control With Elective Nodal Irradiation.

Adv Radiat Oncol 2020 Jan-Feb;5(1):77-84. Epub 2019 Aug 21.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford Medicine, Stanford, California.

Purpose: To review our institutional experience of treating cholangiocarcinoma using stereotactic body radiation therapy (SBRT).

Methods And Materials: A total of 40 patients with intrahepatic ( = 25) or perihilar ( = 15) cholangiocarcinoma treated with SBRT were retrospectively reviewed. SBRT was delivered in 1 to 5 fractions with median dose of 40 Gy. Competing risk analysis was used to estimate cumulative incidence of local in-field, local out-of-field, regional, and distant failure. Kaplan-Meier and log-rank tests were used to calculate overall survival (OS). Toxicity was scored using Common Terminology Criteria for Adverse Events, version 4.0.

Results: The median follow-up time was 18 months. The 1-year incidence of local in-field, local out-of-field, regional, and distant failure was 8%, 23%, 13%, and 22%, respectively. Median OS was 23 months and 1- and 2-year OS rates were 69% and 39%, respectively. Patients with perihilar tumors had a 1-year incidence of regional failure of 24% and worse OS ( = .013). Patients with regional failure were more likely to develop distant metastases, 32% versus 19% at 1 year ( = .11). Acute grade 3 + hepatobiliary toxicity developed in 15 patients (36%).

Conclusions: In this series of cholangiocarcinoma patients treated with definitive SBRT, patterns of failure reveal that regional failures are not insignificant, particularly for perihilar tumors. Elective nodal irradiation of regional lymphatics should be considered when using SBRT. A prospective study of elective nodal irradiation in patients with perihilar tumors would further clarify whether this approach improves outcomes without increasing hepatobiliary toxicity.
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http://dx.doi.org/10.1016/j.adro.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004929PMC
August 2019

Central Nervous System Relapse After Stem Cell Transplantation in Adolescents and Young Adults with Acute Lymphoblastic Leukemia: A Single-Institution Experience.

J Adolesc Young Adult Oncol 2020 04 20;9(2):166-171. Epub 2019 Nov 20.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California.

To evaluate outcomes and central nervous system (CNS) relapse in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL), who underwent total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (allo-SCT). A total of 136 AYA patients with ALL who received TBI before allo-SCT between 1998 and 2018 were reviewed. Twenty patients received cranial radiation in their initial treatment before conditioning for transplant and were excluded. Competing risk analysis was used to estimate the cumulative incidence of relapse. Kaplan-Meier and log-rank tests were used to calculate overall survival (OS) and to identify factors predictive of relapse. OS and time to relapse were calculated from date of allo-SCT. One hundred sixteen patients were included in the analysis. Median age was 27 years and median follow-up time was 42 months. Twenty-six patients suffered a disease relapse and 49 died, 26 of posttransplantation complications. The median time to relapse was 7 months and the 5-year OS was 60%. Seven patients had a CNS relapse: 4 of 20 patients (25%) with pre-SCT CNS disease had a post-allo-SCT CNS relapse compared to 3 of 97 (3.1%) without pre-SCT CNS disease. Median time to CNS relapse was 7 months. Patients with post-SCT CNS relapse had median OS of 19 months. AYA patients with CNS disease who undergo an allo-SCT have a high rate of CNS relapse. The addition of additional CNS-directed therapy to transplant protocols warrants further investigation.
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http://dx.doi.org/10.1089/jayao.2019.0121DOI Listing
April 2020

Use of Preoperative Radiation Therapy in Early-stage and Locally Advanced Breast Cancer.

Cureus 2019 Sep 24;11(9):e5748. Epub 2019 Sep 24.

Radiation Oncology, Stanford University, Stanford, USA.

Purpose There is growing interest in delivering radiation preoperatively (preopRT) rather than postoperatively (postopRT) for breast cancer. Using the National Cancer Database, we evaluated the use and outcomes of preopRT in breast cancer. Methods We identified adult females diagnosed with non-metastatic breast cancer treated with definitive surgery and radiation between 2004 and 2014. Logistic regression models evaluated factors associated with use of preopRT in early-stage (clinical T1-3/N0-1) and locally advanced (clinical T4/N2-3) disease. Rates of breast-conserving surgery, breast reconstruction, positive surgical margins, and 30-day surgical readmissions were compared between patients receiving preopRT and postopRT. Results Of 373,595 patients who met our inclusion criteria, 1,245 (0.3%) patients received preopRT. Patients receiving preopRT were more likely to be of lower socioeconomic status and have tumors with higher T stage. Younger age and N1 (vs N0) disease predicted for use of preopRT in early-stage disease, while older age and N0 disease predicted for use of preopRT in the locally advanced setting. PreopRT patients were less likely to undergo breast-conserving surgery and more likely to have positive surgical margins. Rates of unplanned readmissions within 30 days of surgery were similar among patients treated with preopRT and postopRT. Conclusions PreopRT is a new treatment strategy for patients with breast cancer with different clinical and sociodemographic drivers of its use in the early-stage and locally advanced settings. We await the results of clinical trials studying the efficacy of this approach.
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http://dx.doi.org/10.7759/cureus.5748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825433PMC
September 2019

Comparison of definitive chemoradiation with 5-fluorouracil versus capecitabine in anal cancer.

J Gastrointest Oncol 2019 Aug;10(4):605-615

Division of Medical Oncology, Department of Internal Medicine, Stanford University, Stanford, CA, USA.

Background: Capecitabine (Cap) is an established treatment alternative to 5-fluorouracil (5-FU) for chemoradiation in rectal cancer. Few studies have compared the two agents in anal cancer. We compared outcomes and toxicities using Cap versus 5-FU in non-metastatic anal cancer patients at Stanford.

Methods: All non-metastatic anal cancer patients treated with definitive chemoradiation at Stanford from 1997-2016 were included. Fisher's exact and Mann-Whitney U tests were used to compare nominal and continuous variables. Gray's test was used to compare incidence of recurrence and colostomy, and Log-rank test was used to compare survival.

Results: Sixty-eight patients were included. Thirty-six patients received Cap and 32 received 5-FU (12 received standard 5-FU and 20 received low-dose continuous 5-FU). Patient characteristics were similar between the two groups. There was no difference in the 3-year overall and disease-specific survival between Cap and 5-FU (94% 80%, P=0.197; 100% 86%, P=0.051). Overall incidence of recurrence was equivalent between Cap and 5-FU (11% 13%, P=0.703), but incidence of locoregional recurrence was higher in the 5-FU group (0% 13%, P=0.042); patients treated with Cap had longer recurrence-free intervals (18 6 months, P=0.400), and all recurrences were distant. More colostomies were needed with 5-FU (3% 13%, P=0.133). Toxicities were similar between the two groups. The most common grade ≥2 toxicities were dermatitis (77%), anal pain (78%), and diarrhea (56%).

Conclusions: Overall survival (OS), cancer-specific survival and incidence of recurrence were equivalent between Cap and 5-FU in anal cancer. Patients treated with Cap had statistically significant lower incidence of loco-regional relapses.
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http://dx.doi.org/10.21037/jgo.2019.02.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657317PMC
August 2019

SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer.

Mod Pathol 2019 07 8;32(8):1217-1231. Epub 2019 Apr 8.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

DNA mismatch repair protein deficient colon cancer frequently displays reduced CDX2 expression, and recent literature has suggested that negative CDX2 expression is a poor prognostic biomarker in colon cancer. We have recently demonstrated that SATB2 is an immunohistochemical marker that is complementary to CDX2. Using a tissue microarray approach, we evaluated SATB2 and CDX2 immunohistochemical expression in 514 patients with colonic adenocarcinoma including 146 with mismatch repair protein deficient tumors and correlated expression with histopathologic variables, molecular alterations, and survival. Overall, SATB2-negative and/or CDX2-negative expression was identified in 33% of mismatch repair protein deficient tumors compared with only 15% of mismatch repair protein proficient tumors (p < 0.001) and in 36% of BRAF V600E mutated compared with only 13% of BRAF wild-type tumors (p < 0.001). Both SATB2-negative and CDX2-negative colonic adenocarcinomas more often displayed lymphatic invasion, venous invasion, and perineural invasion (all with p < 0.05). SATB2-negative expression was also more frequently identified in tumors with mucinous or signet ring cell differentiation (p < 0.01 for both). In a multivariable analysis of survival in patients with mismatch repair protein deficient tumors (n = 131), only tumor stage (p = 0.01) and SATB2-negative and/or CDX2-negative expression (p = 0.009) independently predicted disease-specific survival. Of the 99 patients with stage II or III mismatch repair protein deficient tumors, death from disease only occurred in patients with either SATB2-negative or CDX2-negative tumors, and no patients with SATB2-positive/CDX2-positive tumors developed recurrence or died of disease. SATB2 and CDX2 expression had no effect on patient survival in mismatch repair protein proficient, BRAF-mutated, or KRAS-mutated tumors. In summary, our results suggest that SATB2 and CDX2 are prognostic biomarkers in patients with mismatch repair protein deficient colon cancer and that inclusion of SATB2 and CDX2 immunohistochemistry may be helpful as part of a comprehensive pathologic risk assessment in mismatch repair protein deficient colon cancer.
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http://dx.doi.org/10.1038/s41379-019-0265-1DOI Listing
July 2019

Adjuvant treatment and survival in older women with triple negative breast cancer: A Surveillance, Epidemiology, and End Results analysis.

Breast J 2019 05 29;25(3):469-473. Epub 2019 Mar 29.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California.

Patients with triple negative breast cancer were identified using the Surveillance, Epidemiology, and End Results database. Competing risks analysis was used to assess the cumulative incidence of breast cancer-specific mortality (BCSM). Multivariable Fine-Gray regression was used to identify predictors of BCSM. Women age 70+ (n = 4221) were less likely to receive chemotherapy and radiation treatment (P < 0.0001) and had higher BCSM compared to younger women (P < 0.0001). There were no differences in BCSM in patients who received adjuvant treatment (P = 0.10). Stage II patients derived the greatest relative and absolute benefit from adjuvant treatment. Age was not a significant predictor of BCSM.
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http://dx.doi.org/10.1111/tbj.13251DOI Listing
May 2019

Depth of invasion alone as a prognostic factor in low-risk early-stage oral cavity carcinoma.

Laryngoscope 2019 09 2;129(9):2082-2086. Epub 2019 Jan 2.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford School of Medicine, Stanford, California.

Objectives: To evaluate the significance of increasing depth of invasion (DOI) as the sole risk factor for recurrence in patients with low-risk early-stage oral cavity squamous cell carcinoma (OCSCC).

Methods: We retrospectively reviewed 560 patients with OCSCC treated at our institution between 2003 and 2013. Patients were included if they had low-risk early-stage OCSCC treated with surgical resection ± neck dissection and no adjuvant therapy. Low risk was defined as absence of positive or close margins, lymphovascular invasion, perineural invasion, and positive lymph nodes. Patients with tumor (T)3-T4 disease were excluded. Pathology specimens were independently re-reviewed by two board-certified pathologists to confirm proper measurement of DOI. Kaplan-Meier and Cox proportional hazards regression analyses were performed to identify factors predictive for recurrence as well as progression-free survival (PFS) and overall survival (OS).

Results: A total of 126 patients with low-risk early-stage T1-2N0 OCSCC were included. Median follow-up time was 42.5 months and median DOI was 4 mm. There was no significant difference in incidence of local (P = 0.95), regional (P = 0.81), or distant recurrence (P = 0.96) among patients with DOI < 4 mm versus ≥4 mm. On multivariable analysis, DOI was significant for both PFS (P = 0.03) and OS (P = 0.002).

Conclusion: In this study, we show that in the absence of other high-risk pathologic features, DOI ≥ 4 mm does not portend for increased incidence of local, regional, or distant relapse in patients treated with surgery alone; however, increasing DOI is a marker for worse PFS and OS in patients with low-risk, early-stage OCSCC.

Level Of Evidence: 4 Laryngoscope, 129:2082-2086, 2019.
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http://dx.doi.org/10.1002/lary.27753DOI Listing
September 2019

Less Than Whole Uterus Irradiation for Locally Advanced Cervical Cancer Maintains Locoregional Control and Decreases Radiation Dose to Bowel.

Pract Radiat Oncol 2019 Mar 2;9(2):e164-e171. Epub 2018 Nov 2.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California. Electronic address:

Objective: This study aimed to evaluate whether our institutional standard of less-than-whole-uterus irradiation affects locoregional control in patients with locally advanced cervical cancer.

Methods And Materials: We retrospectively reviewed 53 patients with stage IB to IVB cervical carcinoma who were treated with image guided intensity modulated radiation therapy and brachytherapy. The entire uterus was not included in the clinical target volume, as per our institutional standard. Dosimetric parameters were obtained, including positron emission tomography gross tumor volume (GTV), uterus volume excluding GTV, proportion of uterus included in the planning target volume (PTV; percentage), volume of overlap between uterus and prescription dose (cm), minimum and mean dose to the uterus, and bowel V40 and D200cc. Local, regional, and distant failure and death were recorded.

Results: The median proportion of the uterus included in the PTV was 66%. With a median follow-up of 44 months, no patient experienced isolated local recurrence, and 2-year locoregional failure was 10.9%. Positron emission tomography GTV correlated significantly with increased chance of any failure (P = .049; 95% confidence interval, 1.000-1.018). Compared with patients who had ≥90% of the uterus included in the PTV (n = 12), patients who had <90% (n = 41) of the uterus included in the PTV had significantly lower bowel V40 (P = .049) and D200cc (P = .006).

Conclusions: Less-than-whole-uterus irradiation for locally advanced cervical cancer does not compromise locoregional control and reduces bowel V40 and D200cc. Further investigation is required to evaluate whether this reduction in bowel dose translates to a clinically significant reduction in bowel toxicity and whether modifications should be made to the recommended definitive cervix intensity modulated radiation therapy volumes.
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http://dx.doi.org/10.1016/j.prro.2018.10.009DOI Listing
March 2019

Hmga2 is dispensable for pancreatic cancer development, metastasis, and therapy resistance.

Sci Rep 2018 09 18;8(1):14008. Epub 2018 Sep 18.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Expression of the chromatin-associated protein HMGA2 correlates with progression, metastasis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Hmga2 has also been identified as a marker of a transient subpopulation of PDAC cells that has increased metastatic ability. Here, we characterize the requirement for Hmga2 during growth, dissemination, and metastasis of PDAC in vivo using conditional inactivation of Hmga2 in well-established autochthonous mouse models of PDAC. Overall survival, primary tumour burden, presence of disseminated tumour cells in the peritoneal cavity or circulating tumour cells in the blood, and presence and number of metastases were not significantly different between mice with Hmga2-wildtype or Hmga2-deficient tumours. Treatment of mice with Hmga2-wildtype and Hmga2-deficient tumours with gemcitabine did not uncover a significant impact of Hmga2-deficiency on gemcitabine sensitivity. Hmga1 and Hmga2 overlap in their expression in both human and murine PDAC, however knockdown of Hmga1 in Hmga2-deficient cancer cells also did not decrease metastatic ability. Thus, Hmga2 remains a prognostic marker which identifies a metastatic cancer cell state in primary PDAC, however Hmga2 has limited if any direct functional impact on PDAC progression and therapy resistance.
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http://dx.doi.org/10.1038/s41598-018-32159-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143627PMC
September 2018

Outcomes Following Neoadjuvant Chemotherapy for Breast Cancer in Women Aged 40 Years and Younger: Impact of Pathologic Nodal Response.

J Natl Compr Canc Netw 2018 07;16(7):845-850

We sought to evaluate whether pathologic nodal response was predictive of outcomes in women aged ≤40 years with breast cancer treated with neoadjuvant chemotherapy (NAC). A total of 220 patients treated with NAC between 1991 and 2015 were retrospectively reviewed. Pathologic complete response (pCR) was defined as no evidence of residual invasive tumor in the breast and lymph nodes (LNs) (ypT0/Tis ypN0); partial response if there was no tumor in the LNs but residual tumor in the breast (ypT+ ypN0) or residual tumor in the LNs (ypT0/Tis ypN+); and limited response if there was residual tumor in both the breast and the LNs (ypT+ ypN+). Kaplan-Meier and Cox proportional hazards analyses were performed to identify factors predictive for overall survival (OS). A total of 155 patients were included. Following NAC, 39 patients (25.2%) achieved pCR, 57 (36.8%) achieved a partial response (either ypT+ ypN0 or ypT0/Tis ypN+), and 59 (38.1%) had a limited response. A total of 22 patients (14.2%) experienced local failure, 20 (12.9%) experienced regional failure, and 59 (38.1%) experienced distant failure. Median OS for patients who achieved pCR was not reached, and was significantly worse for patients who had residual disease in the breast and/or LNs (<.001). No difference in OS was seen among patients who had residual disease in the breast alone versus those who remained LN-positive (97 vs 83 months, respectively; =.25). Subset analysis did not reveal differences in OS based on year of treatment or cN1 disease at the time of initial diagnosis. Women aged ≤40 years who achieved pCR had excellent outcomes; however, those who achieved a pathologic response in the LNs but had residual disease in the breast continued to have outcomes similar to those who remained LN-positive.
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http://dx.doi.org/10.6004/jnccn.2018.7022DOI Listing
July 2018

Loss of SATB2 Expression in Colorectal Carcinoma Is Associated With DNA Mismatch Repair Protein Deficiency and BRAF Mutation.

Am J Surg Pathol 2018 10;42(10):1409-1417

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.

The special AT-rich sequence binding protein (SATB2) has been reported to be a specific immunohistochemical marker for colorectal carcinoma; however, correlation of SATB2 expression with molecular alterations commonly assessed in colorectal carcinoma has not been performed. We examined the immunohistochemical expression of SATB2 in 586 adenocarcinomas of the gastrointestinal (GI) tract and pancreas to assess its utility in diagnosis and analyze the clinicopathologic and molecular characteristics of colorectal carcinoma stratified by SATB2 expression. SATB2 and CDX2 expression were evaluated in 266 adenocarcinomas of lower GI tract origin (246 colorectal and 20 appendiceal mucinous), 208 adenocarcinomas of upper GI tract and small intestinal origin (74 esophagus/esophagogastric junction, 103 stomach, 20 duodenal, and 11 jejunoileal), and 112 pancreatic ductal adenocarcinomas. SATB2 expression was more frequently identified in adenocarcinomas of lower GI tract origin (222/266, 83%) compared with upper GI tract, small intestinal, or pancreatic origin (26/320, 8%) (P<0.001). Compared with CDX2 alone, dual positive expression for SATB2 and CDX2 (SATB2/CDX2) has a significantly higher specificity for adenocarcinoma of lower GI tract origin (94% vs. 57%, P<0.001). In colorectal carcinoma, loss of SATB2 expression was more frequently observed in DNA mismatch repair (MMR) protein deficient tumors (31%) compared with MMR protein proficient tumors (13%) (P<0.01). A BRAF V600E mutation was more frequently identified in colorectal carcinomas with loss of SATB2 expression compared with those with positive SATB2 expression (29% vs. 3%) (P<0.001). In summary, SATB2 expression is a relatively specific marker of lower GI tract origin; however, loss of SATB2 expression is more commonly seen in colorectal carcinoma with MMR protein deficiency and BRAF mutation.
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http://dx.doi.org/10.1097/PAS.0000000000001116DOI Listing
October 2018

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.

Genet Med 2019 01 2;21(1):213-223. Epub 2018 Jul 2.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Purpose: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses.

Methods: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression.

Results: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05).

Conclusion: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.
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http://dx.doi.org/10.1038/s41436-018-0009-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666401PMC
January 2019

Patterns of Distant Failure by Intrinsic Breast Cancer Subtype in Premenopausal Women Treated With Neoadjuvant Chemotherapy.

Clin Breast Cancer 2018 10 7;18(5):e1077-e1085. Epub 2018 May 7.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA. Electronic address:

Purpose: To identify patterns of distant failure (DF) in premenopausal women receiving neoadjuvant chemotherapy (NAC) for breast cancer.

Patients And Methods: Premenopausal patients treated with NAC between 2005 and 2015 at a single institution were retrospectively reviewed. Timing and location of local, regional, and distant metastases were described. Predictors for DF and overall survival (OS) were analyzed.

Results: Of 225 patients, there were 24 (10.7%) local, 30 (13.3%) regional, and 63 (28.0%) distant recurrences. Cumulative incidence of DF was higher in patients younger than age 40 (P = .01), in those with residual tumor size > 2 cm (P < .0001), in those with positive lymph nodes after NAC (P = .0003), and in those without pathologic complete response (P < .0001). Cumulative incidence of brain metastases was most common in patients with human epidermal growth factor receptor 2 (HER2)-positive disease (P = .05). Time from development of metastatic disease to death varied by breast cancer subtype (P = .019), as did 5-year OS (P = .024). Women with HER2-positive and triple-negative disease had the highest incidence of brain metastases and the shortest time from development of metastases to death. On multivariable analysis, luminal B subtype (P = .025), pathologic complete response (P = .0014), young age (P = .0008), lack of hormone therapy (P < .0001), lymphovascular space involvement (P < .0001), and pathologic size of the primary tumor (P < .0001) were all significant predictors for DF.

Conclusion: Patterns of DF after NAC in premenopausal women vary by breast cancer subtype, with DF more common than locoregional failure. Young age remains an independent poor prognostic factor, and OS differs by breast cancer subtype.
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http://dx.doi.org/10.1016/j.clbc.2018.04.020DOI Listing
October 2018

Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma.

JAMA Oncol 2018 Mar 8;4(3):e173420. Epub 2018 Mar 8.

Department of Pathology, University of Rochester Medical Center, Rochester, New York.

Importance: Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes.

Objective: To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection.

Design, Setting, And Participants: This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017.

Main Outcomes And Measures: The DFS and OS among patients with resected pancreatic adenocarcinoma.

Results: Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients with KRAS mutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients with KRAS wild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75; P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59; P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94; P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations.

Conclusions And Relevance: Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.
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http://dx.doi.org/10.1001/jamaoncol.2017.3420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844844PMC
March 2018

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer.

Cancer Cell 2017 10;32(4):460-473.e6

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p53 TAD2 mutant behaves as a "super-tumor suppressor," with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.
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http://dx.doi.org/10.1016/j.ccell.2017.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659188PMC
October 2017

Lymph node metastases in resected pancreatic ductal adenocarcinoma: predictors of disease recurrence and survival.

Br J Cancer 2017 Dec 5;117(12):1874-1882. Epub 2017 Oct 5.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA.

Background: Few studies have simultaneously assessed the prognostic value of the multiple classification systems for lymph node (LN) metastases in resected pancreatic ductal adenocarcinoma (PDAC).

Methods: In 600 patients with resected PDAC, we examined the association of LN parameters (AJCC 7th and 8th editions, LN ratio (LNR), and log odds of metastatic LN (LODDS)) with pattern of recurrence and patient survival using logistic regression and Cox proportional hazards regression, respectively. Regression models adjusted for age, sex, margin status, tumour grade, and perioperative therapy.

Results: Lymph node metastases classified by AJCC 7th and 8th editions, LNR, and LODDS were associated with worse disease free-survival (DFS) and overall survival (OS) (all P<0.01). American Joint Committee on Cancer 8th edition effectively predicted DFS and OS, while minimising model complexity. Lymph node metastases had weaker prognostic value in patients with positive margins and distal resections (both P<0.03). Lymph node metastases by AJCC 7th and 8th editions did not predict the likelihood of local disease as the first site of recurrence.

Conclusions: American Joint Committee on Cancer 8th edition LN classification is an effective and practical tool to predict outcomes in patients with resected PDAC. However, the prognostic value of LN metastases is attenuated in patients with positive resection margins and distal pancreatectomies.
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http://dx.doi.org/10.1038/bjc.2017.349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729468PMC
December 2017

Acridine Derivatives as Inhibitors of the IRE1α-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma.

Mol Cancer Ther 2016 09 15;15(9):2055-65. Epub 2016 Jun 15.

Department of Radiation Oncology, Stanford University, Stanford, California.

Using a luciferase reporter-based high-throughput chemical library screen and topological data analysis, we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as an inhibitor of the inositol requiring kinase 1α (IRE1α)-X-box binding protein-1 (XBP1) pathway of the unfolded protein response. We designed a collection of analogues based on the structure of DAPA to explore structure-activity relationships and identified N(9)-(3-(dimethylamino)propyl)-N(3),N(3),N(6),N(6)-tetramethylacridine-3,6,9-triamine (3,6-DMAD), with 3,6-dimethylamino substitution on the chromophore, as a potent inhibitor. 3,6-DMAD inhibited both IRE1α oligomerization and in vitro endoribonuclease (RNase) activity, whereas the other analogues only blocked IRE1α oligomerization. Consistent with the inhibition of IRE1α-mediated XBP1 splicing, which is critical for multiple myeloma cell survival, these analogues were cytotoxic to multiple myeloma cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing in vivo and the growth of multiple myeloma tumor xenografts. Our study not only confirmed the utilization of topological data analysis in drug discovery but also identified a class of compounds with a unique mechanism of action as potent IRE1α-XBP1 inhibitors in the treatment of multiple myeloma. Mol Cancer Ther; 15(9); 2055-65. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-1023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010920PMC
September 2016

Albumin and Neutrophil-Lymphocyte Ratio (NLR) Predict Survival in Patients With Pancreatic Adenocarcinoma Treated With SBRT.

Am J Clin Oncol 2018 03;41(3):242-247

Department of Radiation Oncology, Stanford University Medical Center, Stanford Cancer Institute.

Purpose: To determine if pretreatment nutritional status and inflammatory markers correlate with survival in patients with locally advanced pancreatic adenocarcinoma treated with stereotactic body radiotherapy (SBRT).

Materials And Methods: We retrospectively reviewed 208 patients with newly diagnosed, locally advanced pancreatic adenocarcinoma treated with SBRT at our institution from 2002 to 2014. Laboratory values were collected before SBRT, including hemoglobin, platelets, albumin, red blood cell, white blood cell, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, and tumor markers CA 19-9 and CEA. Patients were followed every 3 months with computed tomography (CT) and/or positron emission tomography-CT imaging to monitor for local recurrence and overall survival (OS).

Results: Median follow-up after SBRT was 7.5 months (interquartile range, 4.6 to 12.0 mo) for all patients. Median OS for patients with NLR>5 compared with NLR≤5 was 6.9 and 8.5 months, respectively (P=0.0057). On univariate analysis, receipt of chemotherapy (P=0.05, hazard ratio [HR]=0.69), increased albumin (P=0.002, HR=0.64), increased red blood cell (P=0.05, HR=0.75), increased lymphocyte count (P=0.002, HR=0.66), decreased CEA (P=0.01, HR=0.96), and NLR≤5 (P=0.01, HR=0.65) correlated with improved OS. On multivariate analysis, higher albumin (P=0.03, HR=0.70), receipt of chemotherapy (P=0.007, HR=0.56), and NLR≤5 (P=0.02, HR=0.66) correlated with better survival.

Conclusions: Preradiotherapy low albumin levels and NLR>5 correlate with decreased survival in patients with locally advanced pancreatic adenocarcinoma treated with SBRT, indicating the prognostic value of systemic inflammatory markers (such as NLR) and a role of nutritional supplementation to improve outcomes in these patients. Further investigation is warranted.
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http://dx.doi.org/10.1097/COC.0000000000000263DOI Listing
March 2018

Statin and Metformin Use Prolongs Survival in Patients With Resectable Pancreatic Cancer.

Pancreas 2016 Jan;45(1):64-70

From the *Department of Radiation Oncology, Stanford Cancer Institute; and †Department of Surgery, Stanford University Medical Center, Stanford, CA.

Objectives: The aim of this study was to investigate the impact of statin and metformin therapy on disease outcome for patients with pancreatic ductal adenocarcinoma (PDAC).

Methods: This retrospective study included 171 PDAC patients who underwent surgical resection at the Stanford Cancer Institute between 1998 and 2013. No patients received neoadjuvant therapy. Statin and metformin use was defined as use during initial consult and continuing upon discharge from the hospital after surgery. Dose of each medication was recorded, as was the type of statin taken.

Results: The median follow-up for all patients was 11.23 months (range, 0.2-105.0 months). Among the 171 patients included in our analysis, 18 patients (10.5%) took metformin and 34 patients (19.9%) took statins. Statin use was associated with better overall survival (OS) in patients with PDAC (P = 0.011). Metformin use was also associated with better OS (P = 0.035). The use of statins remained significant on multivariate analysis for OS (P = 0.014; hazards ratio, 0.33; 95% confidence interval, 0.139-0.799), but metformin use did not (P = 0.33; hazards ratio 0.60, 95% confidence interval, 0.211-1.675).

Conclusions: Statin and metformin use is associated with improved OS in patients with resectable PDAC. These medications should be further investigated for possible long-term use in the general population.
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http://dx.doi.org/10.1097/MPA.0000000000000470DOI Listing
January 2016

Value of surveillance studies for patients with stage I to II diffuse large B-cell lymphoma in the rituximab era.

Int J Radiat Oncol Biol Phys 2015 May;92(1):99-106

Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California. Electronic address:

Background: 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.

Methods: A retrospective analysis was performed of patients who received definitive treatment between 2000 and 2013.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.ijrobp.2015.01.039DOI Listing
May 2015

The Prognostic Significance of Pretreatment Hematologic Parameters in Patients Undergoing Resection for Colorectal Cancer.

Am J Clin Oncol 2017 Aug;40(4):405-412

*Department of Radiation Oncology, Stanford Cancer Institute †Department of Surgery, Stanford University Medical Center, Stanford, CA.

Objectives: The prognostic value of several hematologic parameters, including platelet, lymphocyte, and neutrophil counts, has been studied in a variety of solid tumors. In this study, we examined the significance of inflammatory markers and their prognostic implications in patients with colorectal cancer (CRC).

Materials And Methods: Patients with stage I-III CRC who underwent surgical resection at the Stanford Cancer Institute between 2005 and 2009 were included. Patients were excluded if they did not have preoperative complete blood counts performed within 1 month of surgical resection, underwent preoperative chemotherapy or radiation, had metastatic disease at diagnosis, or had another previous malignancy. We included 129 eligible patients with available preoperative complete blood counts in the final analysis.

Results: A preoperative neutrophil-to-lymphocyte ratio of>3.3 was significantly associated with worse disease-free (DFS) and overall survival (OS) (P=0.009, 0.003), as was a preoperative lymphocyte-to-monocyte ratio of ≤2.6 (P=0.01, 0.002). Preoperative lymphopenia (P=0.002) was associated with worse OS but not DFS (P=0.09). In addition, preoperative thrombocytosis was associated with worse DFS (P=0.006) and OS (P=0.010). Preoperative leukocytosis was associated with worse OS (P=0.048) but not DFS (P=0.49). Preoperative hemoglobin was neither associated with OS (P=0.24) or DFS (P=0.15).

Conclusions: Pretreatment lymphopenia, thrombocytosis, a decreased lymphocyte-to-monocyte ratio, and an elevated neutrophil-to-lymphocyte ratio independently predict for worse OS in patients with CRC.
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http://dx.doi.org/10.1097/COC.0000000000000183DOI Listing
August 2017

Smad4 inactivation predicts for worse prognosis and response to fluorouracil-based treatment in colorectal cancer.

J Clin Pathol 2015 May 13;68(5):341-5. Epub 2015 Feb 13.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California, USA.

Aims: To determine whether expression of Smad4, a tumour suppressor found to be absent in 10% of colorectal cancer (CRC), is associated with outcomes in patients with CRC.

Methods: Tumour samples from 241 consecutive patients with CRC who underwent upfront colon resection between 2005 and 2009 were obtained. Triplicate tissue cores from resected primary colon tumours and matched normal controls were used to construct the tissue microarrays (TMAs). We examined the expression of Smad4 using immunohistochemistry. Clinicopathological records were obtained for all patients. TMAs were reviewed by two pathologists and scored as either 'positive' or 'negative' for nuclear staining. In total, 21 of 241 tumours (8.6%) were Smad4 negative.

Results: Loss of Smad4 expression correlated with significantly worse overall survival (OS) (p=0.011) and disease-free survival (DFS) (p=0.024). Patients with loss of Smad4 expression had a median OS of 31 months compared with 89 months positive Smad4 expression. Loss of Smad4 remained significant on multivariate analysis for OS (p=0.0097). In patients with node-positive disease, loss of Smad4 predicts for worse DFS (p=0.012). In patients with metastatic and recurrent disease, Smad4 loss predicts for worse OS (p=0.012). Of the patients that received capecitabine over the course of their treatment, those with Smad4 loss (n=13) had significantly worse DFS (p=0.003) and OS (p=0.0007).

Conclusions: Loss of Smad4 expression is associated with worse DFS and OS in multiple subsets of patients with CRC. Further studies are required to validate our findings and ascertain the role of Smad4 status in the management of this disease.
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http://dx.doi.org/10.1136/jclinpath-2014-202660DOI Listing
May 2015

Inappropriate p53 activation during development induces features of CHARGE syndrome.

Nature 2014 Oct 3;514(7521):228-32. Epub 2014 Aug 3.

1] Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.

CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.
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http://dx.doi.org/10.1038/nature13585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192026PMC
October 2014

Impact of chemotherapy on normal tissue complication probability models of acute hematologic toxicity in patients receiving pelvic intensity modulated radiation therapy.

Int J Radiat Oncol Biol Phys 2013 Dec 22;87(5):983-91. Epub 2013 Oct 22.

Department of Radiation Oncology, Stanford University, Stanford, California.

Purpose: To determine how chemotherapy agents affect radiation dose parameters that correlate with acute hematologic toxicity (HT) in patients treated with pelvic intensity modulated radiation therapy (P-IMRT) and concurrent chemotherapy.

Methods And Materials: We assessed HT in 141 patients who received P-IMRT for anal, gynecologic, rectal, or prostate cancers, 95 of whom received concurrent chemotherapy. Patients were separated into 4 groups: mitomycin (MMC) + 5-fluorouracil (5FU, 37 of 141), platinum ± 5FU (Cis, 32 of 141), 5FU (26 of 141), and P-IMRT alone (46 of 141). The pelvic bone was contoured as a surrogate for pelvic bone marrow (PBM) and divided into subsites: ilium, lower pelvis, and lumbosacral spine (LSS). The volumes of each region receiving 5-40 Gy were calculated. The endpoint for HT was grade ≥3 (HT3+) leukopenia, neutropenia or thrombocytopenia. Normal tissue complication probability was calculated using the Lyman-Kutcher-Burman model. Logistic regression was used to analyze association between HT3+ and dosimetric parameters.

Results: Twenty-six patients experienced HT3+: 10 of 37 (27%) MMC, 14 of 32 (44%) Cis, 2 of 26 (8%) 5FU, and 0 of 46 P-IMRT. PBM dosimetric parameters were correlated with HT3+ in the MMC group but not in the Cis group. LSS dosimetric parameters were well correlated with HT3+ in both the MMC and Cis groups. Constrained optimization (0
Conclusions: The incidence of HT3+ depends on type of chemotherapy received. Patients receiving P-IMRT ± 5FU have better bone marrow tolerance than those receiving irradiation concurrent with either Cis or MMC. Treatment with MMC has a lower TD50 and more steeply rising normal tissue complication probability curve compared with treatment with Cis. Dose tolerance of PBM and the LSS subsite may be lower for patients treated with MMC compared with Cis.
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http://dx.doi.org/10.1016/j.ijrobp.2013.09.017DOI Listing
December 2013
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