Morbidity following salvage esophagectomy for squamous cell carcinoma: the MD Anderson experience.

The survival advantage associated with the addition of surgical therapy in esophageal squamous cell carcinoma (ESCC) patients who demonstrate a complete clinical response to chemoradiotherapy is unclear, and many institutions have adopted an organ-preserving strategy of selective surgery in this population. We sought to characterize our institutional experience of salvage esophagectomy (for failure of definitive bimodality therapy) and planned esophagectomy (as a component of trimodality therapy) by retrospectively analyzing patients with ESCC of the thoracic esophagus and GEJ who underwent esophagectomy following chemoradiotherapy between 2004 and 2016. Of 76 patients who met inclusion criteria, 46.1% (35) underwent salvage esophagectomy. Major postoperative complications (major cardiovascular and pulmonary events, anastomotic leak [grade ≥ 2], and 90-day mortality) were frequent and occurred in 52.6% of the cohort (planned resection: 36.6% [15/41]; salvage esophagectomy: 71.4% [25/35]). Observed rates of 30- and 90-day mortality for the entire cohort were 7.9% (planned: 7.3% [3/41]; salvage: 8.6% [3/35]) and 13.2% (planned: 9.8% [4/41]; salvage: 17.1% [6/35]), respectively. In summary, esophagectomy following chemoradiotherapy for ESCC at our institution has been associated with frequent postoperative morbidity and considerable rates of mortality in both planned and salvage settings. Although a selective approach to surgery may permit organ preservation in many patients with ESCC, these results highlight that salvage esophagectomy for failure of definitive-intent treatment of ESCC may also constitute a difficult clinical undertaking in some cases.

Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials.

BACKGROUND: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. PATIENTS AND METHODS: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. RESULTS: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. CONCLUSIONS: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. CLINICAL TRIALS NUMBER: The study NCT number is NCT01196130.

Association between KRAS mutation and lung metastasis in advanced colorectal cancer.

BACKGROUND: KRAS mutations have been associated with lung metastases at diagnosis of metastatic colorectal cancer (mCRC), but the impact of this mutation on subsequent development of lung metastasis is unknown. We investigated KRAS mutation as a predictor of lung metastasis development. METHODS: We retrospectively evaluated data from patients with mCRC whose tumour was tested for KRAS mutation from 2008 to 2010. The relationships of KRAS mutational status with time-to-lung metastasis (TTLM) and overall survival (OS) were analysed. RESULTS: Of the 494 patients identified, 202 (41%) had tumours with KRAS mutation. KRAS mutations were associated with a shorter TTLM (median 15.2 vs 22.4 months; hazard ratio=1.40; P=0.002) and a two-fold greater odds of developing lung metastases during the disease course in patients with liver-limited mCRC at diagnosis (72 vs 56%, P=0.007). Overall survival did not differ by KRAS status. CONCLUSIONS: Lung metastasis was more likely to develop during the disease course in patients whose tumour had a KRAS mutation than in those whose tumour did not have a KRAS mutation. This finding may have an impact on decision making for surgical resection of metastatic disease.

Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment.

INTRODUCTION: KRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs). We investigated the frequency, co-occurrence, and distribution of acquired KRAS and EGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA (ctDNA). PATIENTS AND METHODS: Sixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples from KRAS (wt) mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction for KRAS codon 12, 13, 61, and 146 and EGFR 492 mutations. RESULTS: Plasma analyses showed newly detectable EGFR and KRAS mutations in 5/62 [8%; 95% confidence interval (CI) 0.02-0.18] and 27/62 (44%; 95% CI 0.3-0.56) samples, respectively. KRAS codon 61 and 146 mutations were predominant (33% and 11%, respectively), and multiple EGFR and/or KRAS mutations were detected in 11/27 (41%) cases. The percentage of mutant allele reads was inversely correlated with time since last treatment with EGFR mAbs (P = 0.038). In the matching archival tissue, these mutations were detectable as low-allele-frequency clones in 35% of patients with plasma mutations after treatment with anti-EGFR mAbs and correlated with shorter progression-free survival (PFS) compared with the cases with no new mutations (3.0 versus 8.0 months, P = 0.0004). CONCLUSION: Newly detected KRAS and/or EGFR mutations in plasma ctDNA from patients refractory to anti-EGFR treatment appear to derive from rare, pre-existing clones in the primary tumors. These rare clones were associated with shorter PFS in patients receiving anti-EGFR treatment. Multiple simultaneous mutations in KRAS and EGFR in the ctDNA and the decline in allele frequency after discontinuation of anti-EGFR therapy in a subset of patients suggest that several resistance mechanisms can co-exist and that relative clonal burdens may change over time. Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.

Clinicopathologic characteristics and gene expression analyses of non-KRAS 12/13, RAS-mutated metastatic colorectal cancer.

BACKGROUND: KRAS mutations in codons 12 and 13 are present in ∼40% of all colorectal cancers (CRC). Activating mutations in codons 61 and 146 of KRAS and in codons 12, 13, and 61 of NRAS also occur but are less frequent. The clinicopathologic features and gene expression profiles of this latter subpopulation of RAS-mutant colorectal tumors have not yet been clearly defined but in general are treated similarly to those with KRAS 12 or 13 mutations. PATIENTS AND METHODS: Records of patients with metastatic CRC (mCRC) treated at MD Anderson Cancer Center between December 2000 and August 2012 were reviewed for RAS (KRAS or NRAS) and BRAF mutation status, clinical characteristics, and survival outcomes. To study further with an independent cohort, data from The Cancer Genome Atlas were analyzed to define a gene expression signature for patients whose tumors feature these atypical RAS mutations and explore differences with KRAS 12/13-mutated colorectal tumors. RESULTS: Among the 484 patients reviewed, KRAS 12/13, KRAS 61/146, NRAS, and BRAF mutations were detected in 47.7%, 3.0%, 4.1%, and 7.4%, respectively, of patients who were tested for each of these aberrations. Lung metastases were more common in both the KRAS 12/13-mutated and atypical RAS-mutated cohorts relative to patients with RAS/BRAF wild-type tumors. Gene expression analyses revealed similar patterns regardless of the site of RAS mutation, and in silico functional algorithms predicted that KRAS and NRAS mutations in codons 12, 13, 61, and 146 alter the protein function and drive tumorgenesis. CONCLUSIONS: Clinicopathologic characteristics, survival outcomes, functional impact, and gene expression profiling were similar between patients with KRAS 12/13 and those with NRAS or KRAS 61/146-mutated mCRC. These clinical and bioinformatic findings support the notion that colorectal tumors driven by these RAS mutations are phenotypically similar.

Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation.

BACKGROUND: Patients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a

Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort.

BACKGROUND: Chemoradiation followed by surgery is the preferred treatment of localized gastroesophageal cancer (GEC). Surgery causes considerable life-altering consequences and achievement of clinical complete response (clinCR; defined as postchemoradiation [but presurgery] endoscopic biopsy negative for cancer and positron emission tomographic (PET) scan showing physiologic uptake) is an enticement to avoid/delay surgery. We examined the association between clinCR and pathologic complete response (pathCR). PATIENTS AND METHODS: Two hundred eighty-four patients with GEC underwent chemoradiation and esophagectomy. The chi-square test, Fisher exact test, t-test, Kaplan-Meier method, and log-rank test were used. RESULTS: Of 284 patients, 218 (77%) achieved clinCR. However, only 67 (31%) of the 218 achieved pathCR. The sensitivity of clinCR for pathCR was 97.1% (67/69), but the specificity was low (29.8%; 64/215). Of the 66 patients who had less than a clinCR, only 2 (3%) had a pathCR. Thus, the rate of pathCR was significantly different in patients with clinCR than in those with less than a clinCR (P < 0.001). CONCLUSIONS: clinCR is not highly associated with pathCR; the specificity of clinCR for pathCR is too low to be used for clinical decision making on delaying/avoiding surgery. Surgery-eligible GEC patients should be encouraged to undergo surgery following chemoradiation despite achieving a clinCR.

A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). METHODS: Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5-6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used. RESULTS: One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63-NA], with median OS 45.62 months (95% CI 25.56-NA) in Arm A and 43.68 months (95% CI 27.63-NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms. CONCLUSIONS: These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).

Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: Approximately 25% of patients with esophageal cancer (EC) who undergo preoperative chemoradiation, achieve a pathologic complete response (pathCR). We hypothesized that a model based on clinical parameters could predict pathCR with a high (≥60%) probability. PATIENTS AND METHODS: We analyzed 322 patients with EC who underwent preoperative chemoradiation. All the patients had baseline and postchemoradiation positron emission tomography (PET) and pre- and postchemoradiation endoscopic biopsy. Logistic regression models were used for analysis, and cross-validation via the bootstrap method was carried out to test the model. RESULTS: The 70 (21.7%) patients who achieved a pathCR lived longer (median overall survival [OS], 79.76 months) than the 252 patients who did not achieve a pathCR (median OS, 39.73 months; OS, P = 0.004; disease-free survival, P = 0.003). In a logistic regression analysis, the following parameters contributed to the prediction model: postchemoradiation PET, postchemoradiation biopsy, sex, histologic tumor grade, and baseline (EUS)T stage. The area under the receiver-operating characteristic curve was 0.72 (95% confidence interval [CI] 0.662-0.787); after the bootstrap validation with 200 repetitions, the bias-corrected AU-ROC was 0.70 (95% CI 0.643-0.728). CONCLUSION: Our data suggest that the logistic regression model can predict pathCR with a high probability. This clinical model could complement others (biomarkers) to predict pathCR.

Patients with high body mass index tend to have lower stage of esophageal carcinoma at diagnosis.

High body mass index (H-BMI; ≥25 kg/m(2) ) is common in US adults. In a small cohort of esophageal cancer (EC) patients treated with surgery, H-BMI and diagnosis of early stage EC appeared associated. We evaluated a much larger cohort of EC patients. From a prospectively maintained database, we analyzed 925 EC patients who had surgery with or without adjunctive therapy. Various statistical methods were used. Among 925 patients, 69% had H-BMI, and 31% had normal body mass index (<25 kg/m(2) ; N-BMI). H-BMI was associated with men (P<0.001), Caucasians (P=0.064; trend), lower esophageal localization (P<0.001), adenocarcinoma histology (P<0.001), low baseline cT-stage (P=0.003), low baseline overall clinical stage (P=0.003), coronary artery disease (P=0.036), and diabetes (P<0.001). N-BMI was associated with weight loss (P<0.001), alcohol abuse (P=0.056; trend), ever/current smoking (P=0.014), and baseline cN+ (P=0.018). H-BMI patients with cT1 tumors (n=110) had significantly higher rates of gastresophageal reflux disease symptoms (P<0.001), gastresophageal reflux disease history (P<0.001), and Barrett's esophagus history (P<0.001) compared with H-BMI patients with cT2 tumors (n=114). Median survival of N-BMI patients was 36.66 months compared with 53.20 months for H-BMI patients (P=0.005). In multivariate analysis, older age (P<0.001), squamous histology (P=0.002), smoking (P=0.040), weight loss (P=0.002), high baseline stage (P<0.001), high number of ypN+ (P=0.005), high surgical stage (P<0.001), and American Society of Anesthesia scores, three out of four (P<0.001) were independent prognosticators for poor overall survival. We were able to perform propensity-based analysis of surgical complications between H-BMI and N-BMI patients. A comparison of fully matched 376 patients (188 with H-BMI and 188 with N-BMI) found no significant differences in the rate of complications between the two groups. This larger data set confirms that a fraction of H-BMI patients with antecedent history is diagnosed with early baseline EC. Upon validation of our data in an independent cohort, refinements in surveillance of symptomatic H-BMI patients are warranted and could be implemented. Our data also suggest that H-BMI patients do not experience higher rate of surgical complications compared with N-BMI patients.

Novel endoscopic application of a new flexible-fiber CO2 laser for esophageal mucosal ablation in a porcine model.

BACKGROUND AND STUDY AIMS: The CO (2) laser is a surgical tool that is widely used because of its predictable penetration depth and minimal collateral damage due to efficient absorption of CO (2) laser energy by tissue water. Until recently, endoscopic use was limited by lack of an efficient, flexible delivery system. The aim of the current study was to evaluate the performance, efficacy, and safety of a novel, photonic band-gap CO (2) laser configured for esophageal mucosal ablation. MATERIALS AND METHODS: This was an endoscopic experimental study in a porcine survival model. Initial evaluation was done on ex vivo tissue followed by endoscopic studies at 7-, 10-, 15-, and 20-W power and at 0-, 1-, 2-, 5-, and 10-mm distances, using continuous and pulsed currents, to determine optimal performance settings. In an IACUC-approved protocol, six pigs underwent circumferential ablation of the distal 6 cm of the esophagus at 10W continuous current. The animals were monitored for 2 or 4 weeks to evaluate delayed effects. Prior to euthanasia, the proximal esophagus was ablated to evaluate the homogeneity of ablation and depth of injury immediately after single and repeat ablation. RESULTS: The animals resumed normal diets within 24 hours and experienced no dysphagia or weight loss. Pathology at 2 and 4 weeks revealed complete re-epithelialization with minimal histologic injury. A single application of the laser produced complete transepithelial ablation of a mean of 83.3 % of the surface area (range 55 % - 100 %); depth of injury was to the muscularis mucosa in five pigs and to the superficial submucosa in one pig. With ablation, sloughing, and re-ablation, a mean of 95 % transepithelial ablation was achieved (range 80 % -100 %) with similar depth of injury. CONCLUSIONS: Using a novel, flexible CO (2) laser, homogeneous ablation was achieved with predictable penetration and minimal deep tissue injury. These results warrant further evaluation of the laser in Barrett's esophagus, as it may overcome the limitations of current technologies including perforation, stricture, and inhomogeneity.

Primary and secondary tuberculosis preventive treatment in HIV clinics: simulating alternative strategies.

BACKGROUND: Isoniazid preventive treatment (IPT) has been recommended for human immunodeficiency virus (HIV) infected individuals. OBJECTIVE/DESIGN: We used a mathematical model to simulate the benefits and risks of preventive treatment delivered through antiretroviral (ARV) clinics using clinical data from Botswana. RESULTS: Preventive treatment was found to reduce the incidence of tuberculosis (TB) by at least 12 cases per 100000 population per year versus the scenario without such treatment over a 50-year simulation. Isoniazid (INH) resistant TB was observed to increase by <1% per year, even when using pessimistic assumptions about resistance emergence. The use of tuberculin skin testing had little impact as a screening procedure, while secondary treatment was observed to nearly double the impact of a preventive treatment program. Regardless of whether or not preventive treatment was implemented, INH-resistant TB rose in the context of increasing HIV prevalence, but was minimally amplified by preventive treatment itself. CONCLUSIONS: IPT programs implemented through ARV clinics may be effective at reducing TB incidence. The resistance contribution of IPT appears unlikely to supersede its overall incidence and mortality benefits.

Therapy-induced expression of NF-kappaB portends poor prognosis in patients with localized esophageal cancer undergoing preoperative chemoradiation.

Activated nuclear factor-kappa B (NF-kappaB) in the pretreatment cancer tissue of patients with localized esophageal adenocarcinoma (LEA) undergoing preoperative chemoradiation is associated with poor prognosis. It is known that constitutively activated NF-kappaB prior to any therapy portends poor prognosis, and it is also known that activated NF-kappaB in the treated specimen is associated with poor prognosis. However, the prognosis of patients who have treatment-induced activation of NF-kappaB (meaning their cancers activate NF-kappaB during or after therapy) is not been reported. We hypothesized that the treatment-induced activation of NF-kappaB would impart poor prognosis similar to that imparted by constitutively activated NF-kappaB cancer. Patients with LEA who had undergone preoperative chemoradiation plus surgery and had pre- and post-therapy cancer tissue available were selected. Pre- and post-therapy cancer tissues were stained by immunohistochemistry for nuclear staining of NF-kappaB. The overall survival (OS) and disease-free survival were assessed and compared for patients who had intrinsic constitutively activated NF-kappaB cancer with those who had induced activation of NF-kappaB only post-therapy. A total of 41 patients with LEA were investigated. Twenty-five patients had NF-kappaB positive cancer at baseline, and 16 had NF-kappaB negative cancer at baseline but became positive post-therapy. There was no difference in the location, histology grade, clinical stage, or the curative resection (RO) resection rate in the two populations. OS (P = 0.71), disease-free survival (P = 0.86), and median survivals (Converters: 24 months [95% confidence intervals: 7.78 to 40.22]vs. Nonconverters: 34.13 months [95% confidence intervals: 3.54 to 64.27]) were not different between the two groups. Our data suggest that activation of NF-kappaB in response to stress/injury of therapy leads to poor OS. These results need to be confirmed in a larger number of patients. It may be that only pre-therapy evaluation of NF-kappaB is insufficient to assess prognosis of patients with LEA. Additional implications include that when effective anti-NF-kappaB therapies become available, they may have to be considered in patients whose cancers do not have constitutively activated NF-kappaB or cancer may have to be monitored during therapy with biomarker assessments.

Adenocarcinoma of the lower esophagus with Barrett's esophagus or without Barrett's esophagus: differences in patients' survival after preoperative chemoradiation.

It remains unclear whether the overall survival (OS) of patients with localized esophageal adenocarcinoma (LEA) with Barrett's esophagus (BE) (Barrett's-positive) and those with LEA without BE (Barrett's-negative) following preoperative chemoradiation is different. Based on the published differences in the molecular biology of the two entities, we hypothesized that the two groups will have a different clinical biology (and OS). In this retrospective analysis, all patients with LEA had surgery following preoperative chemoradiation. Apart from age, gender, baseline clinical stage, location, class of cytotoxics, post-therapy stage, and OS, LEAs were divided up into Barrett's-positive and Barrett's-negative groups based on histologic documentation of BE. The Kaplan-Meier and Cox regression analytic methods were used. We analyzed 362 patients with LEA (137 Barrett's-positive and 225 Barrett's-negative). A higher proportion of Barrett's-positive patients had (EUS)T2 cancers (27%) than those with Barrett's-negative cancer (17%). More Barrett's-negative LEAs involved gastroesophageal junction than Barrett's-positive ones (P = 0.001). The OS was significantly shorter for Barrett's-positive patients than that for Barrett's-negative patients (32 months vs. 51 months; P = 0.04). In a multivariate analysis for OS, Barrett's-positive LEA (P = 0.006), old age (P = 0.016), baseline positive nodes (P = 0.005), more than 2 positive (yp)N (P = 0.0001), higher (yp)T (P = 0.003), and the use of a taxane (0.04) were the independent prognosticators. Our data demonstrate that the clinical biology (reflected in OS) is less favorable for patients with Barrett's-positive LEA than for patients with Barrett's-negative LEA. Our intriguing findings need confirmation followed by in-depth molecular study to explain these differences.

Significance of thromboembolic phenomena occurring before and during chemoradiotherapy for localized carcinoma of the esophagus and gastroesophageal junction.

Thromboembolic event (TEE) is the most common complication and a second cause of mortality in cancer patients. Multiple hypotheses for occurrence of TEE have been proposed. There are no reports on the frequency/impact of TEE in localized gastroesophageal cancer patients. We hypothesized that TEE at baseline and during chemoradiotherapy (CTRT) in gastroesophageal cancer patients would have an impact on overall survival (OS) of these patients. All consecutive patients with gastroesophageal cancer undergoing CTRT from 2001 to 2004 were eligible for this analysis. Baseline and subsequent TEEs were documented and correlated with patient characteristics and OS. One hundred ninety-eight patients were analyzed. TEEs were documented in 9.6% of the patients. At baseline, TEEs were documented in 4.0% of the patients. During CTRT, TEEs were documented in 6.1% of the patients. Pulmonary embolism (43.5%) and lower extremity venous thromboses (39%) were the most frequent TEEs. Median OS for patients with a TEE occurring at anytime was 17.7 versus 32.0 months for patients who never developed a TEE (P = 0.014). TEEs at baseline correlated with poor median survival: 13.1 versus 30.7 months for those without a TEE (P = 0.029). In a multivariable analysis, TEE at baseline and/or during CTRT was an independent predictor of OS (hazard ratio, 1.818; P = 0.040). Our data are the first to document the frequency of TEE in gastroesophageal cancer patients undergoing CTRT, and that TEE is an independent prognosticator of OS. Active research to prevent and treat TEEs is needed to improve survival of patients with localized gastroesophageal cancer.

Outcomes of patients with rejection post-polyomavirus nephropathy.

INTRODUCTION: We sought to determine the effects of rejection in renal transplant recipients with polyomavirus nephropathy (PVN). METHODS: SCr, biopsy findings, BKV serum and urine loads (Taqman PCR), and BKV antibody titers (HA inhibition assay) were analyzed by two-sample median tests and z tests in 11 patients with median follow-up of 7.3 (2.0 to 31.5) months post-PVN. All patients underwent immunosuppression reduction (ISR) as PVN treatment. RESULTS: Post-PVN, 3 (27%) patients had five rejection episodes, with 80% being mild. Median time to rejection was 18 (2 to 60) weeks. One hundred percent of patients who experienced post-PVN rejection also experienced rejection pre-PVN. Rejection episode treatments consisted of: none in one, increased tacrolimus in two, IVIG in one, IVIG and increased tacrolimus in one. Median viral loads in patients with post-PVN rejection versus those without rejection were not different in serum (2.01 x 10(4) vs 9.00 x 10(4) BKV copies/mL; P = .22) or urine (5.37 x 10(5) vs 8.93 x 10(6) BKV copies/mL; P = .28). Median BKV antibody titers were slightly lower (16384 vs 32768 HA units; P = .02) and median SCr values were significantly higher (2.7 vs 1.9 mg/dL, P = .0003) in patients who had experienced post-PVN rejection. Graft losses occurred in one rejection-free patient (chronic allograft nephropathy) and in one patient who experienced multiple acute rejection episodes, humoral rejection, and worsening PVN. CONCLUSIONS: Patients who experience rejection prior to PVN are at high risk of developing rejection post-ISR and post-PVN; however, low graft loss rates may still be achieved.

T-cell depletion of allogeneic bone marrow using anti-alphabetaTCR monoclonal antibody: prevention of graft-versus-host disease without affecting engraftment potential in rats.

Bone marrow chimerism may solve two major limitations in the transplantation of solid organs and cellular grafts: (1) the requirement for life-long immunosuppressive therapy, and (2) acute and chronic rejection. When untreated bone marrow is transplanted into major histocompatibility complex (MHC)-disparate rats, lethal graft-vs-host disease (GVHD) occurs in the majority of recipients. T-cell depletion using anti-CD3 and anti-CD5 monoclonal antibody (mAb) to avoid GVHD led to an increased occurrence of failure of engraftment. We previously identified a cellular population in mouse bone marrow that facilitates engraftment of highly purified hematopoietic stem cells (HSC) across complete MHC barriers. In light of the fact that facilitating cells have a CD8+/CD3+/TCR- phenotype and mostly coexpress CD5, we evaluated in this study whether T-cell depletion of rat bone marrow using anti-alphabetaTCR mAb would retain engraftment potential yet avoid GVHD. T-cell depletion of bone marrow was performed using anti-alphabetaTCR mAb and immunomagnetic beads. Recipients were conditioned with 1100 or 1000 cGy of total body irradiation and reconstituted with 100 x 10(6) T-cell depleted (TCD) MHC- and minor antigen-disparate bone marrow cells. Animals were monitored clinically and histologically for GVHD. Chimerism was assessed by flow cytometry. Immunomagnetic bead depletion resulted in a reduction of T cells from 1.92%+/-0.21% to 0.10%+/-0.04% of total bone marrow. T-cell depletion did not remove facilitating cells (CD8+/alphabetaTCR-/gammadeltaTCR-/NK3.2.3-) from bone marrow. Further, the engraftment potential of TCD bone marrow was not affected, as 100% of animals engrafted and high levels of donor chimerism were detectable. Animals reconstituted with TCD bone marrow showed no clinical evidence of GVHD and histology revealed none to minimal changes, whereas recipients transplanted with untreated bone marrow succumbed to severe lethal GVHD. T-cell depletion using antialphabetaTCR mAb and immunomagnetic beads selectively removes T cells from the bone marrow graft while sparing facilitating cells that are required for engraftment of allogeneic bone marrow across MHC barriers. Moreover, the cells required for engraftment of HSC do not produce GVHD.

ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients.

PURPOSE: Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase-1 (ALDH-1) could be associated with response. METHODS: The labeling indices (LIs) of ALDH-1 by immunohistochemistry in untreated tumor specimens were established in EC patients who had chemoradiation and surgery. Univariate logistic regression and 3-fold cross validation were carried out for the training (67% of patients) and validation (33%) sets. Non-clinical experiments in EC cells were performed to generate complimentary data. RESULTS: Of 167 EC patients analyzed, 40 (24%) had a pathologic complete response (pathCR) and 27 (16%) had an extremely resistant (exCRTR) cancer. The median ALDH-1 LI was 0.2 (range, 0.01-0.85). There was a significant association between pathCR and low ALDH-1 LI (p ≤ 0.001; odds-ratio [OR] = 0.432). The 3-fold cross validation led to a concordance index (C-index) of 0.798 for the fitted model. There was a significant association between exCRTR and high ALDH-1 LI (p ≤ 0.001; OR = 3.782). The 3-fold cross validation led to the C-index of 0.960 for the fitted model. In several cell lines, higher ALDH-1 LIs correlated with resistant/aggressive phenotype. Cells with induced chemotherapy resistance upregulated ALDH-1 and resistance conferring genes (SOX9 and YAP1). Sorted ALDH-1+ cells were more resistant and had an aggressive phenotype in tumor spheres than ALDH-1- cells. CONCLUSIONS: Our clinical and non-clinical data demonstrate that ALDH-1 LIs are predictive of response to therapy and further research could lead to individualized therapeutic strategies and novel therapeutic targets for EC patients.