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BackgroundMost patients with metastatic gastroesophageal adenocarcinoma (mGEA) progress on immune checkpoint inhibitors (ICIs). Novel approaches to overcome resistance to ICI in mGEA are needed. Cabozantinib is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study evaluated the combination of cabozantinib and pembrolizumab in ICI refractory or resistant mGEA.MethodsInvestigator-initiated, single-arm, single institution, and phase II study in patients with mGEA. Patients had progressed on ICI and/or had PD-L1 CPS score ≤10%. Cabozantinib dose was 40 mg p.o. daily on days 1-21 of a 21-day cycle, with pembrolizumab 200 mg i.v. on day 1. The primary endpoint was progression-free survival at 6 months (PFS-6).ResultsTwenty-seven patients were enrolled. Median age 58 years (24-87), female (n = 14), ECOG 0/1 = 13/14, GC/GEJ = 16/11, and non-Hispanic White/Hispanic/Asian = 12/8/7. The primary endpoint was met. After a median follow-up of 31.4 months (range 3.3-42.5), PFS-6 was 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3 months (95% CI 1.7-4.1) and 5.5 months (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). The most common grade (G) treatment-related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension, and muscle cramps (14.8% each). G3-4 TRAE were seen in n = 3 patients (hypertension, thromboembolic event, esophageal perforation; each n = 1). No G5 was observed.ConclusionsThe addition of cabozantinib to pembrolizumab shows clinical benefit in ICI-resistant or refractory mGEA with a tolerable safety profile. (ClinicalTrials.gov Identifier: NCT04164979. IRB Approved: UCI 18-124, University of California Irvine IRB#20195426.).

IntroductionThis study determined the safety and recommended phase 2 dose (RP2D) of the multikinase inhibitor cabozantinib in combination with trifluridine/tipiracil (FTD/TPI) in refractory metastatic colorectal carcinoma (mCRC).Patients and methodsSingle institution investigator-initiated phase 1 study using 3+3 design. Eligible mCRC patients had received prior standard regimens. Cabozantinib was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth-factor support was allowed.ResultsFifteen patients were enrolled. Median age 56 years (31-80), male (12/15), ECOG 0/1 = 9/6. Three patients were treated at DL 0 and another nine were treated at DL 1, none exhibiting a DLT. Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%), and rash (25%). G3-4 TRAE were neutropenia (25%) and thrombocytopenia, hypokalemia, and weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS was 3.8 months (95% CI 1.9-6.8) and disease control rate was 86.7%.ConclusionThe combination of cabozantinib and FTD/TPI is feasible and tolerable at standard doses with the use of growth factors and showed encouraging clinical activity in refractory mCRC.ClinicaltrialsGOV: NCT04868773.

Context.--Two major categories of laboratories performing nonwaived testing under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) are the Certificate of Accreditation (CoA) and Certificate of Compliance (CoC) laboratories. Accreditation organizations collect more detailed laboratory personnel information than the Centers for Medicare & Medicaid Services (CMS) Quality Improvement and Evaluation System (QIES). Objective.--To estimate total numbers of testing personnel and testing volumes in CoA and CoC laboratories, by laboratory type and state. Design.--We developed a statistical inference method by using the respective correlations between testing personnel counts and test volume by laboratory type. Results.--QIES reported 33 033 active CoA and CoC laboratories in July 2021. We estimated testing personnel to be 328 000 (95% CI, 309 000-348 000), which is supported by the count of 318 780 reported by the US Bureau of Labor Statistics. There were twice as many testing personnel in hospital laboratories as in independent laboratories (158 778 versus 74 904, P < .001). Independent laboratories had the highest test volume per person, which was twice as high as physician office laboratories (62 228 versus 30102, P < .001). Hospital and independent laboratories comprised 34% of all CoA and CoC laboratories but performed the largest portion of testing (81 %). Physician office laboratories, accounting for 44% of all CoA and CoC laboratories, performed a comparatively low proportion of total tests (9%). Conclusions.--Numbers of testing personnel vary considerably by laboratory type and across states. These data can provide valuable insight when assessing laboratory workforce training needs and planning for public health emergencies. doi: 10.5858/arpa.2022-0345-0A, Clinical laboratory testing plays a critical role in health care, public health surveillance, and emergency response. A detailed study by the Lewin Group for the Centers for Disease Control and [...]

2047 Background: Standard GBM therapy is associated with early progression and poor overall survival (OS). DC-ATA AV-GBM-1, a personal vaccine consisting of autologous DC pulsed with ATA, was investigated in a multicenter trial in patients with newly diagnosed GBM. Methods: Key eligibility criteria for surgical collection of tumor were clinical suspicion of new primary GBM & age 18-70 years. ATA lysate was prepared from irradiated tumor cells that were self-renewing in serum-free media. Autologous monocytes (MC) were collected by leukapheresis. Prior to initiating concurrent radiation therapy (RT) and temozolomide (TMZ), patients were enrolled with intent-to-treat (ITT) with DC-ATA after RT/TMZ. Eligibility included confirmation of primary GBM, availability of ATA & MC, KPS > 70 and plans for RT/TMZ. DC-ATA was manufactured during RT/TMZ. MC were differentiated into DC by culturing with IL-4 & GM-CSF, then DC were incubated with ATA. DC-ATA was suspended in 500 mg GM-CSF just prior to s.c. injections at weeks 1, 2, 3, 8, 12,16, 20, & 24 (8 doses). Patients were not excluded based on apparent disease progression or PFS. Standard adjuvant TMZ regimens were started after the 3 weekly injections. Primary endpoint was > 75% OS 14.6 months from ITT enrollment. Secondary endpoints included median OS & progression-free survival (PFS). Results: Cell line and MC collection were successful for 97% of patients. Median age of the 60 ITT enrollees was 59 years. 3 patients withdrew before starting DC-ATA; 57 received 392 injections; 68% received all 8. Most common AE attributed to DC-ATA were local injection site reactions (16%) & flu-like symptoms (10%), but 33% experienced seizures. After 3 years of follow up, OS at 14.6 mos is 52.7% (95% CI 39.8,65.8), median OS 16.0 mos (95% CI 12.9,21.7) & median PFS 10.4 mos (95% CI 8.6,11.6). OS rates at 1, 2, & 3 years are 70.1%, 32.4%, & 23.2%. Longer OS was associated with 8 DC-ATA doses (p < 0.0001), on < 2 mg/day dexamethasone (dex) at start of DC-ATA (p = 0.005), > 6 cycles of adjuvant TMZ (p = 0.0054), & KPS 90 or 100 (p = 0.010) at enrollment. Independent variables per multivariate Cox regression analysis were 8 DC-ATA doses, dex dose, IDH mutated, TMZ > 6 cycles, & MGMT promoter methylated. Concurrent TMZ regimens included TMZ alone (n = 28), TMZ + anti-VEGF(n = 14), & TMZ + tumor treating fields (TTF) (n = 10); 8 received no concurrent TMZ. OS was longer in patients treated with concurrent TMZ alone compared to no TMZ (p = 0.0003), TMZ + anti-VEGF (p = 0.045) or TMZ + TTF (p = 0.045). The only common features among 7 patients progression-free at 3 years are 8 DC-ATA injections, age < 60, & < 2 mg dex. Conclusions: DC-ATA was reliably produced and injections well-tolerated in combination with various TMZ-based regimens, but the primary OS objective was not achieved. PFS was encouraging, but did not translate into improved OS, perhaps because DC-ATA was limited to 8 injections. Clinical trial information: NCT03400917 .

After potentially curative treatment, colorectal cancer (CRC) patients remain at high risk for recurrence, second primary CRC, and high-risk adenomas. In combination with existing data, our previous findings provide a rationale for reducing tissue polyamines as tertiary prevention in non-metastatic CRC patients. The goal of this study was to demonstrate rectal tissue polyamine reduction in optimally treated stage I-III CRC patients after intervention with daily oral aspirin + dietary arginine restriction. A single-institution phase IIa clinical trial was conducted. Patients were treated with aspirin 325 mg/day and an individualized dietary regimen designed to reduce arginine intake by ≥30% over a 12-week study period. Dietary intake, endoscopy with rectal biopsies, and phlebotomy were performed pre- and post-intervention. The primary endpoint was to demonstrate ≥50% decrease in rectal tissue putrescine levels from baseline as a measure of polyamine reduction in the target tissue. Twenty eligible patients completed the study. After study intervention, mean dietary arginine intake decreased from 3.7 g/day ± 1.3 SD to 2.6 g/day ± 1.2 SD (29.7% decrease, p < 0.02 by Sign test). Mean plasma arginine levels decreased from 46.0 ng/mL ± 31.5 SD at baseline to 35 ng/mL ± 21.7 SD (p < 0.001). Rectal tissue putrescine levels were 0.90 nMol/mg-protein pre-intervention and 0.99 nMol/mg-protein post-intervention (p < 0.64, NS). No significant differences were observed for the other tissue polyamines investigated: spermidine (p < 0.13), spermine (p < 0.21), spermidine:spermine ratio (p < 0.71). Among CRC survivors, treatment with daily oral aspirin and an individualized dietary arginine restriction intervention resulted in lower calculated dietary arginine intake and plasma arginine levels but did not affect rectal tissue polyamine levels.

TAS-102 is approved for treatment of refractory metastatic gastroesophageal carcinoma (mGEC). This study sought to determine whether the combination of TAS-102 with irinotecan (TASIRI) was safe and effective in previously treated mGEC. This was a single-arm phase 1b study for patients (pts) with mGEC previously treated with at least one line of fluoropyrimidine and platinum-containing regimen. TAS-102 was given at 25 mg/m2 twice daily on days 1 to 5 with irinotecan 180 mg/m2 on day 1 of a 14-day cycle. The primary endpoint was progression-free survival at 6 months ≥ 35% (PFS-6). 20 Pts were enrolled. The study met its primary endpoint. PFS-6 is 40% (95% CI 19.3-60.0). Median PFS and overall survival are 5.3 months and not reached, respectively. 17 of 20 pts had measurable disease by RECIST criteria. Of the 17, 13 had stable disease and 4 had progressive disease as best response (8 pts had tumor shrinkage  5% of pts were anemia (20%) and neutropenia (10%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls.

Current guidelines recommend neoadjuvant (NAC) and/or adjuvant chemotherapy for locally advanced gastric cancers (LAGCs). However, the choice and duration of NAC regimen is standardized, rather than personalized to biologic response, despite the availability of several different classes of agents for the treatment of gastric cancer (GC). The current trial will use a tumor-informed ctDNA assay (Signatera™) and monitor response to NAC. Based on ctDNA kinetics, the treatment regimen is modified. This is a prospective single center, single-arm, open-label study in clinical stage IB-III GC. ctDNA is measured at baseline and repeated every 8 weeks. Imaging is performed at the same intervals. The primary end point is the feasibility of this approach, defined as percentage of patients completing gastrectomy.

BackgroundVaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival.MethodsFresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration.ResultsSuccess rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%.ConclusionsAV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted.Trial registrationNCT, NCT03400917 , Registered 10 January 2018.

BackgroundGlioblastoma (GBM) is the most common primary, malignant brain tumor in adults and has a poor prognosis. The median progression-free survival (mPFS) of newly diagnosed GBM is approximately 6 months. The recurrence rate approaches 100%, and the case-fatality ratio approaches one. Half the patients die within 8 months of recurrence, and 5-year survival is less than 10%. Advances in treatment options are urgently needed. We report on the efficacy and safety of a therapeutic vaccine (SITOIGANAP: Epitopoietic Research Corporation) administered to 21 patients with recurrent GBM (rGBM) under a Right-to-Try/Expanded Access program. SITOIGANAP is composed of both autologous and allogeneic tumor cells and lysates.MethodsTwenty-one patients with rGBM received SITOIGANAP on 28-day cycles in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), cyclophosphamide, bevacizumab, and an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody (either nivolumab or pembrolizumab).ResultsThe mPFS was 9.14 months, and the median overall survival (mOS) was 19.63 months from protocol entry. Currently, 14 patients (67%) are at least 6 months past their first SITOIGANAP cycle; 10 patients (48%) have received at least six cycles and have a mOS of 30.64 months and 1-year survival of 90%. The enrollment and end-of-study CD3+/CD4+ T-lymphocyte counts strongly correlate with OS.ConclusionsThe addition of SITOIGANAP/GM-CSF/cyclophosphamide to bevacizumab and an anti-PD-1 monoclonal antibody resulted in a significant survival benefit compared to historic control values in rGBM with minimal toxicity compared to current therapy.

Abstract: In primary glioblastoma (GBM), overall survival (OS) is poor despite standard aggressive therapy. Adjunctive AV-GBM-1 vaccine immunotherapy may improve OS. In this multi-institutional phase II trial, key eligibility criteria for intent-to-treat (ITT) enrollment were: (1) primary GBM, (2) age < 70 years when GBM was resected, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, (5) KPS > 70 post-surgery, and (6) plan to treat with concurrent RT/TMZ. Dendritic cells (DC) were differentiated from monocytes by culturing in IL-4 and granulocyte-macrophage colony stimulating factor (GM-CSF). AV-GBM-1 consisted of autologous DC incubated with autologous tumor antigens contained in the lysate of irradiated cultured GBM cells. After recovery from RT/TMZ, doses were admixed with 500 mcg GM-CSF; up to 8 doses were injected subcutaneously over 6 months. Patients were not excluded by apparent progression or pseudo-progression post RT/TMZ. OS and progression-free-survival (PFS) were calculated from ITT enrollment. The success rate was 97% for both GBM cell cultures and collection of monocytes; 60/60 vaccines were successfully manufactured. Median age was 59 years. 57 patients received 392 injections. After two weekly injections there were significant increases in plasma lipocalin-2 and angiopoietin-1, and decreases in thrombospondin-5, angiotensinogen, and beta-fibroblast growth factor. The most common adverse events attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). With follow up from 15.2 to 32 months, median PFS and OS were 10.3 (8.5,11.6 95% CI) and 16.0 (13.0,21.3 95% CI) months respectively. OS was better in the 25 patients who had methylguanine-methyltransferase (MGMT) methylation and/or isocitrate dehydrogenase (IDH) mutation. Age was not independently correlated with survival. From date of first injection, OS was not increased in 14 patients who were treated with alternating electrical tumor-treating fields. CONCLUSION: feasibility, safety, and PFS were encouraging. A phase III trial is in development. Clinicaltrials.gov NCT03400917.

Background: Meningiomas are the most common adult primary intracranial tumors in the United States. Despite high recurrence rate of atypical and malignant subtypes, there is no approved drug indicated specifically for meningioma. Since the majority of meningiomas exhibit high density of somatostatin receptors subtypes, somatostatin analogs have been under close investigation. The aim of this study was to evaluate efficacy and safety of Sandostatin LAR (octreotide) in patients with progressive, and/or recurrent meningioma, and identify subset of patients who were more likely to benefit from this treatment. Methods: A total of 43 patients ≥ 18 years old were included in the retrospective chart review. The patients underwent treatment with Sandostatin LAR (octreotide) from 01.01.2010 to 06.01.2017 at the University of California, Irvine after confirmation of the diagnosis. Six months progression free survival (PFS6) was defined as a primary endpoint, and the overall survival (OS), safety, and toxicity were identified as secondary endpoints. Results: The OS for 6 months, 1, and 3 years for all WHO grades was 94.8, 88.1, and 67.0%, respectively. The PFS6 for WHO I, II, III, and all was 89.4, 89, 33.3, and 80% respectively. For patients with no prior surgeries, chemotherapy or radiation, the PFS6 was 88.9, 84.8, and 94.8%, respectively. Interestingly, the PFS6 was 90.5% for skull-based and 80% for 3-6 cm tumors. Patients with tumors in parasagittal location had PFS6 of 83.3% compared to PFS6 of 50.0% for patients with convexity tumors. Evaluation of PFS6 based on the effect of estrogen and progesterone on meningioma identified that ER-PR+ tumors had PFS6 of 87.8% while patients with ER-PR- meningiomas had PFS6 of 62.5%. Median TTP for WHO grade I, II, and III was 3.1, 2.40, and 0.26 years, respectively. Subgroup analysis showed that median TTP was 3.1 years for

Background: UV radiation has been considered the major environmental causative factor for melanoma. Our previous limited epidemiologic study suggested additional causative factors for early age onset melanoma in females. Methods: Melanoma and non-melanoma skin cancer case and population information were retrieved from various cancer registries and public domains. Age-specific and age-standardized incidence rates were calculated and compared between genders and age groups; and correlated with average daily UV index. Results: The current study further compared the age and gender-specific incidence rates for melanoma and non-melanoma skin cancer (NMSC) from the Netherlands (N), UK and Nordic (NOR) countries, and confirmed a peak gender difference at age 20-24 (the peak age for pregnancy) for melanoma in all countries examined( N, RR = 2.40, 95% CI 2.12, 2.72; UK, RR = 2.10, 95% CI: 1.84, 2.38; NOR, RR = 2.14, 95% CI: 2.16, 2.68) which was not observed (N, RR = 0.98, 95% CI: 0.65-1.49; NOR, RR = 1.01, 9%% CI: 0.74, 1.37) or less obvious (UK, RR = 1.36, 95% CI: 1.15, 1.61) in NMSC. We further analyzed the relationship between UV index (UVI) and gender-specific and age-standardized melanoma incidence rates from 14 selected countries and regions, where most populations are Caucasians and have light hair color, and discovered that there was a significant correlation between the male incidence rates and UVI (Pearson’s coefficient r = 0.67, p = 0.009), but only modest and non-significant correlation (r = 0.45, p = 0.109) between the female incidencerates and UVI. Conclusions: These results suggest that UV radiation exhibits a limited effect on development of melanoma in females compared to males. To our knowledge, this study is the first to describe a non-significant association of UV radiation with female melanoma development. This extensive study suggests that melanoma is a gender-enhanced cancer whose development is heavily impacted by gender-specific factors including theimmune changes and hormones

BackgroundIn 2000, seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the USA and resulted in dramatic reductions in invasive pneumococcal disease (IPD) and moderate increases in non-PCV7 type IPD. In 2010, PCV13 replaced PCV7 in the US immunisation schedule. We aimed to assess the effect of use of PCV13 in children on IPD in children and adults in the USA.MethodsWe used laboratory-based and population-based data on incidence of IPD from the Active Bacterial Core surveillance (part of the Centers for Disease Control and Prevention's Emerging Infections Program) in a time-series model to compare rates of IPD before and after the introduction of PCV13. Cases of IPD between July 1, 2004, and June 30, 2013, were classified as being caused by the PCV13 serotypes against which PCV7 has no effect (PCV13 minus PCV7). In a time-series model, we used an expected outcomes approach to compare the reported incidence of IPD to that which would have been expected if PCV13 had not replaced PCV7.FindingsCompared with incidence expected among children younger than 5 years if PCV7 alone had been continued, incidence of IPD overall declined by 64% (95% interval estimate [95% IE] 59-68) and IPD caused by PCV13 minus PCV7 serotypes declined by 93% (91-94), by July, 2012, to June, 2013. Among adults, incidence of IPD overall also declined by 12-32% and IPD caused by PCV13 minus PCV7 type IPD declined by 58-72%, depending on age. We estimated that over 30 000 cases of IPD and 3000 deaths were averted in the first 3 years after the introduction of PCV13.InterpretationPCV13 reduced IPD across all age groups when used routinely in children in the USA. These findings provide reassurance that, similar to PCV7, PCVs with additional serotypes can also prevent transmission to unvaccinated populations.FundingCenters for Disease Control and Prevention.

Purpose: Colorectal cancer (CRC) incidence has decreased over the past three decades, due largely to screening efforts. Relatively little is known about CRC incidence among the young adult (YA) population ages 20-39, as screening typically commences at age 50 for average-risk individuals. We examined CRC incidence with a focus on YAs in order to identify high-risk subgroups. Methods: We analyzed 231,544 incident CRC cases from 1988-2009 (including 5617 YAs 20-39 years of age) from the California Cancer Registry. We assessed age-specific incidence rates by race/ethnicity, gender, and colorectal tumor location, and calculated the biannual percent change (BAPC) to monitor change in incidence over the 22-year study period. Results: The absolute incidence of CRC per 100,000 was low among YAs 20-29 and 30-39 years old (ranging from 0.7 per 100,000 among Hispanic and African American females aged 20-29 up to 5.0 per 100,000 among Asian/Pacific Islander males aged 30-39). However, we observed increasing CRC incidence rates over time among both males and females in the YA population, particularly for distal colon cancer in Hispanic females aged 20-29 (BAPC=+15.9%; p

Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering "Green" chemoprevention.

Using US SEER17 Registry data, age-specific melanoma incidence rates were calculated and comparisons were made between males and females. Relative Risk (RR) for males and females in each age group was computed and compared with that from Nordic Cancer Registry data set and to that for non-melanoma skin cancer (NMSC). For age groups 44 and younger, females showed higher incidence rates, with a peak difference at age 20-24 (RR = 2.01, 95% CI = 1.21-3.33). Males exhibited higher incidence rates after age 44. The same bimodal gender difference was confirmed by the Nordic Cancer Registry data set, but it was not observed for NMSC, which is known to be strongly associated with cumulative exposure to solar UV radiation. We conclude that exposure to solar ultraviolet (UV) radiation is the major causative factor for melanoma at older age (>44 yr), but that other factors may play a role in early onset melanomas, particularly in females.

BackgroundPancreatic adenosquamous carcinoma has historically been characterized as having a more aggressive clinical course than ductal adenocarcinoma. The natural history of this disease, however, is essentially unknown.MethodsWe evaluated the clinical characteristics of all patients with pancreatic adenosquamous carcinoma recorded in the California Cancer Registry 2000-2007 and compared them to those of patients with ductal adenocarcinoma.ResultsNinety-five patients with pancreatic adenosquamous carcinoma and 14,746 patients with ductal adenocarcinoma were identified. Demographics were similar between subtypes (p > 0.05). Disease stage at presentation was also similar; over 50% of each diagnostic group presented with metastatic disease (p = 0.62). Surgical resection was more common among patients with locoregional adenosquamous carcinoma than adenocarcinoma (p = 0.0004), but rates of adjuvant therapy administration were similar (p > 0.05). The cohorts' median overall survival durations were similar in a Cox proportional hazards model (p = 0.45); overall survival was also similar when only patients with resected disease were considered (p = 0.65). Early stage, resection and receipt of radiation or chemotherapy were favorable independent prognostic factors among patients with adenosquamous carcinoma. The median overall survival duration of patients with resected adenosquamous carcinoma was 12 months (95% CI, 8-52).ConclusionsAdenosquamous carcinoma has a natural history similar to that of ductal adenocarcinoma when treated with prevalent clinical patterns of care.

We sought to compare the quality of life (QOL), characteristics, and survival of patients with non-Hodgkin lymphoma (NHL) with and without human immunodeficiency virus (HIV) infection.Using the population-based cancer registry for Orange and San Diego Counties, We recruited 50 patients with HIV and systemic NHL (cases) and 50 age, sex and race-matched NHL patients without HIV (controls) diagnosed with NHL during 2002–2006. Patients completed a medical history survey and QOL instrument, the Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) for cases and Functional Assessment of Cancer Therapy-General (FACT G) for controls.HIV-infected patients had worse overall QOL and survival than uninfected patients. QOL differences were more marked in the areas of functional, physical and social well-being than in the area of emotional well-being. HIV-infected patients had lower income and were less likely to have private insurance and more likely to have diffuse large B cell histology than uninfected patients.HIV-infected NHL patients had worse QOL and survival than uninfected patients, due to a combination of co-morbidity, aggressive histology and lack of social support. However, their emotional well-being was comparable to that of uninfected NHL patients and better than historical norms for the HIV-infected.

Change in the area of premalignant lesions is an end point in estimating the efficacy of chemopreventive agents. When examiners round measurements of lesion length and width, they introduce variability, which perturbs the relative percent change in lesion area and, consequently, the percent of subjects showing a clinical response. We use simulations to illustrate the resulting bias when the agent under test is effective in reducing lesion area. We simulated 500 oral leukoplakia lesions per run, with 2,500 runs at each of five levels of agent effectiveness, namely, true relative percent reduction in area of 25%, 45%, 50%, 55%, and 75%. Realistic values of lesion lengths and widths were generated randomly and then rounded to the nearest multiple of five. The product is the distribution of mean relative percent change in lesion area and the corresponding percent of subjects showing a clinical response. Even the fifth percentile of the distribution of mean relative percent change in lesion area consistently underestimated the true value, by about 6 percentage points. The percent showing a clinical response was underestimated by 50%, 37%, and 11% for true values of reduction in lesion area of 50%, 55%, and 75%, respectively. This could easily double the required sample size for a modest phase II study. We suggest that it is cost-effective to train observers of lesion length and width to eschew rounding of measurements in the chemoprevention setting.

IntroductionInflammatory breast cancer (IBC) is an aggressive form of breast cancer associated with overexpression of Her2/Neu (human epidermal growth factor-like receptor 2 (HER2)) and poor survival. We investigated survival differences for IBC patient cases based on hormone receptor status and HER2 receptor status using data from the California Cancer Registry, as contrasted with locally advanced breast cancer (LABC), metastatic breast cancer (MBC) and non-T4 breast cancer.MethodsA case-only analysis of 80,099 incident female breast cancer patient cases in the California Cancer Registry during 1999 to 2003 was performed, with follow-up through March 2007. Overall survival (OS) and breast cancer-specific survival (BC-SS) were analyzed using Kaplan-Meier methods and Cox proportional hazards ratios.ResultsA total of 2,014 IBC, 1,268 LABC, 3,059 MBC, and 73,758 non-T4 breast cancer patient cases were identified. HER2+ was associated with advanced tumor stage (P < 0.0001). IBC patient cases were more likely to be HER2+ (40%) and less likely to be hormone receptor-positive (HmR+) (59%) compared with LABC (35% and 69%, respectively), MBC (35% and 74%), and non-T4 patient cases (22% and 82%). HmR+ status was associated with improved OS and BC-SS for each breast cancer subtype after adjustment for clinically relevant factors. In multivariate analysis, HER2+ (versus HER2-) status was associated with poor BC-SS for non-T4 patient cases (hazards ratio = 1.16, 95% confidence interval 1.05 to 1.28) and had a borderline significant association with improved BC-SS for IBC (hazards ratio = 0.82, 95% confidence interval = 0.68 to 0.99).ConclusionsDespite an association with advanced tumor stage, HER2+ status is not an independent adverse prognostic factor for survival among IBC patient cases.

ObjectiveWe sought to determine the accuracy of cancer registry data regarding the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) status of patients with non-Hodgkin's lymphoma (NHL).MethodsWe used the population-based San Diego/Orange County cancer registry to identify 392 patients with HIV-related NHL diagnosed 1994-1999. After matching for age, sex, race, period of NHL diagnosis, and hospital type, we were able to find 324 corresponding patients among the remaining 4,863 NHL patients diagnosed 1994-1999 (who did not have HIV infection according to cancer registry records). We sought to review these patients' charts at 41 hospitals with 15 separate institutional review boards to determine if the HIV serostatus from the cancer registry was correct. We performed a forward conditional multivariate logistic regression to determine characteristics associated with a false positive HIV status.ResultsThe false positive rate was 8% while the false negative rate was 3%. The positive predictive value was 93% while the negative predictive value was 97%. Compared to correctly identified patients, false positives were more likely to be > or =50 years old, female, and treated with chemotherapy and less likely to be single with high grade or extranodal disease.ConclusionUsing cancer registry data to identify AIDS-related NHL is a valid research practice.

Objectives. Some risk factors for cervical cancer in situ convey risk for malignancies of the cervix and other sites. We estimate risk of several malignancies following in situ cancer of the cervix for Hispanic Americans and non-Hispanic Whites. Methods. Using California Cancer Registry data (1988-1999) we identify 56,020 women with cervical cancer in situ and observe subsequent malignancies in that cohort, with over three million woman-months of follow-up, We focus on cancers of the reproductive system and cancers related to smoking. Risk estimates are standardized incidence ratios, accounting for age, time at risk, cancer type, and race/ethnicity. Results. There is elevated risk for invasive cervical cancer (SIR=4.1, 95% Cl: 3.5-4.7), which is significantly higher for Hispanics than for non-Hispanic Whites (SlRs = 5.2 and 3.2, respectively, X-2(l)=7.66, P=0.006). Excluding cervix, non-Hispanic Whites show elevated risk for a pool of reproductive cancers (SIR= 1.8, 95% Cl: 1.4-2.4). While both groups show elevated risk for a pool of smoking-related cancers, only non-Hispanic Whites show significant risk specifically for lung cancer (SIR= 1.7, 95% CI: 1.4-2.1). Non-Hispanic Whites show elevated risk for ovarian cancer (SIR = 1.8, 95% CI: 1.3-2.4). Ovarian cancer following in situ cervical cancer is disproportionately of borderline histology (G(2)(l)=7.43, P=0.006). Conclusions. These results have implications for public health planning for women, as well as better understanding of disparities in care or biologic paths to malignancies in women with in situ cancer of the cervix. (c) 2006 Elsevier Inc. All rights reserved.

We used the San Diego/Orange County cancer registry to identify 64 cases of systemic non-Hodgkin's lymphoma (NHL) with AIDS who received highly active antiretroviral therapy (HAART) at the time of NHL diagnosis or thereafter and 64 NHL controls without AIDS, matched on age, sex, race, time of NHL diagnosis (1994-1995 and 1996-1999), and hospital type (academic, large community, and small community). We compared cases and controls by chi-squared tests and Kaplan-Meier methods. Thirty-three percent of cases had high grade histology versus 11% of controls (p < 0.01); 69% had baseline hemoglobin

Background and aimsColorectal cancer screening beginning at age 50 is recommended for all Americans considered at average risk for the development of colorectal cancer regardless of gender or race/ethnicity. We determined the influence of gender and race/ethnicity on the cost-effectiveness of recommended colorectal cancer screening regimens.MethodsWe determined age-specific colorectal cancer incidence rates; the proportion of left-sided cancers; and the proportion of localized cancers in Asian, black, Latino and white men and women using the California Cancer Registry. We incorporated these data and available data for life expectancy and colorectal cancer survival to model the cost-effectiveness of two 35-year colorectal cancer-screening interventions.ResultsAge-specific colorectal cancer incidence rates were highest in black men and lowest in Latino women. Screening beginning at age 50 was most cost-effective in black men and least cost-effective in Latino women (measured as dollars spent per year of life saved) using annual fecal occult blood testing combined with flexible sigmoidoscopy every five years and using colonoscopy every 10 years. The cost-effectiveness of a 35-year screening program in black men beginning at age 45 was similar to the cost-effectiveness of screening white men and black women beginning at age 50 and more cost-effective than screening nonblack women as well as Asian and Latino men beginning at age 50.ConclusionsScreening is most cost-effective in black men because of high age-specific colorectal cancer incidence rates. Initiation of colorectal cancer screening in this high-risk group prior to age 50 should be strongly considered.

Carcinogenesis proceeds through a very long preclinical period. Our collective hope is that multiple opportunities exist for chemoprevention to arrest or reverse progression towards malignancy. In the hope of faster progress with fewer subjects and lower total cost, much effort is being expended on the search for reliable biomarkers to predict the likelihood of developing cancer and/or to signal the effectiveness of chemopreventive therapy. Considerable attention is paid to identifying those markers that can act as surrogate markers for cancer development, since favorable modulation of the surrogate end-point biomarker (SEBM) may demonstrate effectiveness of a putative preventive treatment. However, the complexity of the biology challenges our ability to measure the effectiveness of attempts to arrest or reverse carcinogenesis, other than through costly and time-consuming prospective trials with disease state as the endpoint. Despite much work, to date no prehistologic biological or molecular intermediate marker has been validated for sporadic cancers. Several factors accounting for the difficulties encountered in SEBM development are reviewed. Discussion is focused on the common thread of the complexity of the underlying biological changes in carcinogenesis limiting the effectiveness of any single biomarker. Additionally, the incidence of sporadic cancers is also low, further limiting the positive predictive value of any putative prognostic marker. Recent successes in development of chemopreventive agents show the concept is valid and worth pursuing, but the current strategies to develop biochemical and genetic markers to identify surrogate biomarkers is flawed, and need to be reassessed in light of the difficulties faced over the last 20 years.

Cancer chemoprevention is a rapidly evolving approach to reverse or inhibit carcinogenesis, and there is active interest in development of effective chemopreventive agents against head and neck cancers. The retinoids are archetypal chemopreventive agents for oral premalignant lesions. They have significant clinical effect, but widespread use is limited by significant clinical toxicity. The Bowman-Birk Inhibitor is one of several nontoxic compounds exhibiting both potent anticarcinogenic activity and minimal toxicity. The purposes of the study were to summarize the preclinical and clinical development of Bowman-Birk Inhibitor and a Bowman-Birk Inhibitor concentrate against oral premalignant lesions and to evaluate Neu immunohistochemical staining intensity for lesions and simultaneously obtained biopsy specimens of normal-appearing mucosa from the Phase IIa Bowman-Birk Inhibitor concentrate oral leukoplakia chemoprevention trial.Part I is a selected literature review. Part II is a retrospective analysis of pathological specimens prospectively obtained from the Phase IIa clinical trial of Bowman-Birk Inhibitor concentrate.Thirty-two sets of biopsy specimens from lesions and uninvolved oral mucosa before and after treatment with Bowman-Birk Inhibitor concentrate in doses ranging from 200 to 1066 chymotrypsin inhibitory units were examined in blinded fashion for Neu immunohistochemical staining intensity using the 3B-5 monoclonal antibody. Staining intensity scores among the lesion and control biopsy specimens before and after Bowman-Birk Inhibitor concentrate treatment were analyzed and compared with previously obtained values for serum Neu, oral mucosal cell Neu, protease activity, and clinical response to treatment.Mean Neu staining score was significantly higher in lesions compared with uninvolved mucosa (P