Worldwide Esophageal Cancer Collaboration: pathologic staging data.

We report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for patients with pathologically staged cancer of the esophagus and esophagogastric junction after resection or ablation with no preoperative therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted de-identified data using standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 13,300 patients, 5,631 had squamous cell carcinoma, 7,558 adenocarcinoma, 85 adenosquamous carcinoma, and 26 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (51%), little weight loss (1.8 kg), 0-2 ECOG performance status (83%), and a history of smoking (70%). Cancers were pT1 (24%), pT2 (15%), pT3 (50%), pN0 (52%), pM0 (93%), and pG2-G3 (78%); most involved distal esophagus (71%). Non-risk-adjusted survival for both squamous cell carcinoma and adenocarcinoma was monotonic and distinctive across pTNM. Survival was more distinctive for adenocarcinoma than squamous cell carcinoma when pT was ordered by pN. Survival for pTis-1 adenocarcinoma was better than for squamous cell carcinoma, although monotonic and distinctive for both. WECC pathologic staging data is improved over that of the 7th edition, with more patients studied and patient and cancer variables collected. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics, and should direct 9th edition data collection. However, the role of pure pathologic staging as the principal point of reference for esophageal cancer staging is waning.

Worldwide Esophageal Cancer Collaboration: clinical staging data.

To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5-25 mg/kg2 , 47%), little weight loss (2.4 ± 7.8 kg), 0-1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cN0 (44%), cM0 (95%), and cG2-G3 (89%); most involved the distal esophagus (73%). Non-risk-adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cN0 versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre-treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection.

Worldwide Esophageal Cancer Collaboration: neoadjuvant pathologic staging data.

To address uncertainty of whether pathologic stage groupings after neoadjuvant therapy (ypTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for pathologically staged cancers after neoadjuvant therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 7,773 pathologically staged neoadjuvant patients, 2,045 had squamous cell carcinoma, 5,686 adenocarcinoma, 31 adenosquamous carcinoma, and 11 undifferentiated carcinoma. Patients were older (61 years) men (83%) with normal (40%) or overweight (35%) body mass index, 0-1 Eastern Cooperative Oncology Group performance status (96%), and a history of smoking (69%). Cancers were ypT0 (20%), ypT1 (13%), ypT2 (18%), ypT3 (44%), ypN0 (55%), ypM0 (94%), and G2-G3 (72%); most involved the distal esophagus (80%). Non-risk-adjusted survival for yp categories was unequally depressed, more for earlier categories than later, compared with equivalent categories from prior WECC data for esophagectomy-alone patients. Thus, survival of patients with ypT0-2N0M0 cancers was intermediate and similar regardless of ypT; survival for ypN+ cancers was poor. Because prognoses for ypTNM and pTNM categories are dissimilar, prognostication should be based on separate ypTNM categories and groupings. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics and should direct 9th edition data collection.

Ultrasonography to investigate the effect of supplementing whole milk with complex carbohydrates and specific amino acids on curd retention in the abomasum of dairy calves.

AIM: To determine whether the retention time of curd in the abomasum of calves was influenced by supplementing milk with a plant-derived carbohydrate and amino acid supplement, evaluated non-invasively using ultrasonography. METHODS: Female dairy calves aged between 2-6 days of age were sourced from a commercial farm in March 2013. All calves were fed whole milk until weaning (4 L per day); 21 calves were supplemented with a probiotic until 18 days of age, and thereafter with a plant-derived complex carbohydrate and amino acid supplement until weaning, and 22 calves were just fed whole milk. Treatment groups were balanced for age, weight and breed. At 9-14, 24-29 and 52-57 days of age, the abomasum of each calf was examined using ultrasonography immediately before and after feeding, 1 and 2 hours after feeding, and then at 30 minute intervals until curd was no longer visible in the abomasum. Abomasal volume and curd size were recorded to assess retention time of curd in the abomasum. RESULTS: At 9-14 days of age, mean retention time of curd in the abomasum was similar (4.6 hours) in both groups. At 24-29 days of age, when the supplemented calves had been receiving the supplement for approximately 10 days, mean curd retention time was longer by 1.4 (SE 0.28) hours in supplemented compared with unsupplemented calves (p<0.001). At 52-57 days of age, mean retention time was longer by 0.7 (SE 0.34) hours compared to unsupplemented calves (p=0.05). CONCLUSION: Using ultrasonography, changes in abomasal content could be followed non-invasively over time and it was demonstrated that the plant-derived complex carbohydrate supplement increased the curd retention time in the abomasum. We speculate that the increased retention time enables an increased availability of nutrients following a more complete digestion of milk, thereby improving animal performance.

Association of gastroesophageal reflux and O2 desaturation: a novel study of simultaneous 24-h MII-pH and continuous pulse oximetry.

BACKGROUND: Proof of the relationship between gastroesophageal reflux disease (GERD) and respiratory symptoms remains a challenge. Our aim was to determine the association between reflux events and O(2) desaturation in GERD patients with primary respiratory symptoms (RS) compared to those with primary esophageal symptoms (ES) using ambulatory monitoring systems. METHODS: One thousand eight hundred fifty-one reflux episodes were detected by multichannel intraluminal impedance (MII)-pH testing in 30 patients with symptoms of GERD (20 RS, ten ES.) All patients underwent simultaneous 24-h MII-pH and continuous O(2) saturation monitoring via pulse oximetry. Reflux-associated desaturation events were determined by correlating synchronized 24-h esophageal pH and/or impedance and O(2) desaturation. RESULTS: One thousand one hundred seventeen reflux events occurred in patients with RS and 734 in those with ES. Nearly 60% of these 1,851 reflux events were associated with O(2) desaturation. Markedly more events were associated with O(2) desaturation in patients with RS (74.5%, 832/1,117) than in patients with ES (30.4%, 223/734, p < 0.0001). The difference in reflux desaturation association was more profound with proximal reflux--80.3% with RS vs. 29.4% with ES (p < 0.0001). CONCLUSIONS: A remarkably high prevalence of O(2) desaturation associated with gastroesophageal reflux was noted in patients with RS. Given further study, simultaneous combined esophageal reflux and O(2) saturation monitoring may prove a useful diagnostic tool in this difficult group of patients.

Worldwide esophageal cancer collaboration.

The aim of this study is to report assemblage of a large multi-institutional international database of esophageal cancer patients, patient and tumor characteristics, and survival of patients undergoing esophagectomy alone and its correlates. Forty-eight institutions were approached and agreed to participate in a worldwide esophageal cancer collaboration (WECC), and 13 (Asia, 2; Europe, 2; North America, 9) submitted data as of July 1, 2007. These were used to construct a de-identified database of 7884 esophageal cancer patients who underwent esophagectomy. Four thousand six hundred and twenty-seven esophagectomy patients had no induction or adjuvant therapy. Mean age was 62 +/- 11 years, 77% were men, and 33% were Asian. Mean tumor length was 3.3 +/- 2.5 cm, and esophageal location was upper in 4.1%, middle in 27%, and lower in 69%. Histopathologic cell type was adenocarcinoma in 60% and squamous cell in 40%. Histologic grade was G1 in 32%, G2 in 33%, G3 in 35%, and G4 in 0.18%. pT classification was pTis in 7.3%, pT1 in 23%, pT2 in 16%, pT3 in 51%, and pT4 in 3.3%. pN classification was pN0 in 56% and pN1 in 44%. The number of lymph nodes positive for cancer was 1 in 12%, 2 in 8%, 3 in 5%, and >3 in 18%. Resection was R0 in 87%, R1 in 11%, and R2 in 3%. Overall survival was 78, 42, and 31% at 1, 5, and 10 years, respectively. Unlike single-institution studies, in this worldwide collaboration, survival progressively decreases and is distinctively stratified by all variables except region of the world. A worldwide esophageal cancer database has been assembled that overcomes problems of rarity of this cancer. It reveals that survival progressively (monotonically) decreased and was distinctively stratified by all variables except region of the world. Thus, it forms the basis for data-driven esophageal cancer staging. More centers are needed and encouraged to join WECC.

Future developments in total Barrett's eradication: the surgeon's view.

Endoscopic therapies for the treatment of complicated Barret's esophagus should be embraced by the surgical community. While esophagectomy remains the standard of care for early esophageal neoplasia in many centers, endoscopic techniques are being increasingly utilizid. As refinements in both endoscopic and surgical approaches continue to evolve, accurate and contempary assessments of outcomes are critical in assuring that each is applied in appropriate circumstances.

Endoscopic and symptomatic assessment of anastomotic strictures following esophagectomy and cervical esophagogastrostomy.

BACKGROUND: Dysphagia following esophagectomy with cervical esophagogastric anastomosis is common and often can be attributed to anastomotic stricture. The prevalence, risk factors, symptomatic and endoscopic severity, and response to dilation of such strictures, however, are poorly defined. METHODS: In the present study the population consisted of 42 patients undergoing esophagectomy with gastric pull-up and cervical anastomosis. Any complaint of postoperative dysphagia was investigated with upper endoscopy. Patients undergoing endoscopy were entered into a prospective randomized trial of graduated balloon versus bougie-over-a-guidewire dilation that will be part of a future report. Dysphagia was assigned a standardized severity score, and stricture diameter pre-dilation was classified as minimal (>12 mm), mild (9-12 mm), moderate (5-8 mm), or severe (<5 mm). Outcome measures included the incidence, time to first dilation, symptomatic and endoscopic severity of anastomotic strictures, number of dilations, and influence of co-morbidities and anastomotic technique on stricture occurrence. RESULTS: Twenty-seven of 41 (66%) surviving patients underwent endoscopy and dilation. Median time to presentation was 2.4 months (min, 27 days; max, 11 months). Most patients (63%) with stricture complained of dysphagia with every meal. The majority (93%) of strictures were mild to moderate (5-12 mm), and there was no correlation between dysphagia frequency and stricture size. Tolerance of an unrestricted diet decreased with increasing stricture severity. In all, 98 dilation sessions were performed without complication. A higher stricture rate was noted following handsewn anastomoses as compared to combined stapled and handsewn anastomoses (85.7% versus 55.5%; p = 0.044). CONCLUSIONS: Most patients with symptomatic anastomotic strictures following esophagectomy with cervical esophagogastrostomy present within the first few months following surgery. Half of such strictures are minimal to mild as endoscopically assessed. Dilation is safe, and most patients experience symptomatic relief after only a few dilation sessions. A combined handsewn and stapled anastomosis may decrease the risk of stricture formation relative to a two-layer handsewn technique.

Possible extrathymic development of nonfunctional T cells in a patient with complete DiGeorge syndrome.

Complete DiGeorge syndrome is characterized by the clinical triad of cardiac malformation, hypocalcemia, and T cell immunodeficiency due to congenital athymia. We describe an infant with complete DiGeorge syndrome who at presentation had no circulating T cells detectable by flow cytometry. The patient spontaneously developed circulating T cells but these cells did not proliferate in response to mitogens. The T cell receptor Vbeta repertoire was severely restricted. All T cells were host, not maternal, as assessed by fluorescent in situ hybridization evaluation of 22q11 hemizygosity. At autopsy, this patient had no grossly detectable thymus tissue and no microscopic evidence for thymopoiesis. These findings suggest that appearance of T cells in infants with complete DiGeorge syndrome may represent oligoclonal expansions of a small number of T cells that may have matured extrathymically and which do not respond in vitro to mitogen stimulation.

Esophageal replacement for end-stage benign esophageal disease.

BACKGROUND: Benign esophageal diseases constitute a common group of disorders that are generally managed with medical therapy or surgery designed to improve foregut function. A small subset of patients, however, has advanced disease that requires esophageal replacement to achieve symptomatic relief. PATIENTS AND METHODS: One hundred four patients with benign esophageal disease who underwent esophageal reconstruction over a 21-year period (1975 to 1996) were reviewed retrospectively. Dysphagia was the major symptom driving surgery in 80% of the patients. Colon was used to reconstruct the esophagus in 85 patients; stomach, in 10 patients; and jejunum, in 9 patients. Forty-two patients who had lived with their reconstruction for 1 year or more answered a postoperative questionnaire concerning their long-term functional outcome. RESULTS: In the 104 patients, the primary underlying abnormality leading to esophageal replacement was end-stage gastroesophageal reflux (37 patients), an advanced motility disorder (37 patients), traumatic, iatrogenic or spontaneous perforation (15 patients), corrosive injury (8 patients), congenital abnormality (6 patients), or extensive leiomyoma (1 patient). Ninety-eight percent of patients reported that the operation had cured or improved the symptom driving surgery. Ninety-three percent were satisfied with the outcome of the operation. The overall hospital mortality rate was 2%, and the median hospital stay was 17 days. Graft necrosis occurred in 3% of patients, and anastomotic leak occurred in 6% of patients (or 2% of the total number of anastomoses). CONCLUSIONS: Esophageal replacement for benign disease can be accomplished with a low mortality rate and a marked improvement in alimentation. Reconstruction restores the pleasure of eating and is viewed by the patient to be highly successful.

Esophageal replacement for end-stage benign esophageal disease.

The fact that esophageal resection and foregut reconstruction for benign disease can be performed with only a 2% mortality and minimal morbidity is encouraging news to patients who are crippled by the various manifestations of end-stage disease. The continuation of slow, anxious, and socially restricted alimentation or the maintenance of nutrition by enteral or parenteral means is unnecessary. The patient should be referred to a unit skilled in evaluating foregut function, performing esophageal replacement surgery, and caring for patients in the perioperative period. In our experience, the colon, when available, is the preferred conduit for esophageal replacement over the long term. Even though some subtle preoperative symptoms of foregut dysfunction may persist after surgery, the overall outcome is generally judged to be satisfactory. Indeed, patients can re-enter society and live a normal and fulfilled life after remedial surgery. Prolonged attempts at medical management of patients with severe derangements of esophageal structure and function are not warranted. Long-term esophageal replacement for severe end-stage benign disease can be accomplished with low mortality, a high degree of success, and a marked improvement in the quality of alimentation. Reconstruction restores the pleasure of eating and is viewed by the patient to be highly successful.

Normalization of the peripheral blood T cell receptor V beta repertoire after cultured postnatal human thymic transplantation in DiGeorge syndrome.

Complete DiGeorge syndrome is an immunodeficiency disease characterized by thymic aplasia and the absence of functioning peripheral T cells. A patient with this syndrome was transplanted with cultured postnatal human thymic tissue. Within 5 weeks of transplantation, flow cytometry, T cell receptor V beta sequence analysis, and cell function studies showed the presence of oligoclonal populations of nonfunctional clonally expanded peripheral T cells that were derived from pretransplantation T cells present in the skin. However, at 3 months posttransplantation, a biopsy of the transplanted thymus showed normal intrathymic T cell maturation of host T cells with normal TCR V beta expression on thymocytes. By 9 months postransplantation, peripheral T cell function was restored and the TCR V beta repertoire became polyclonal, coincident with the appearance of normal T cell function. These data suggest that the transplanted thymus was responsible for the establishment of a new T cell repertoire via thymopoiesis in the chimeric thymic graft.

The human thymic microenvironment during organ culture.

Cultured human thymic tissue has been transplanted into many patients with T cell dysfunction; however, little is known about the effect of in vitro culture on thymic tissue. Human postnatal thymic organ cultures were established in vitro to study the growth potential of the thymic epithelium and the expression of intracellular and surface antigens with time in culture. Marked depletion of bone marrow-derived cells was observed within 3 weeks of initiation of organ cultures although some viable CD3+ cells could still be detected. Thymic epithelial cells in in vitro explants continued to express MHC class I and class II antigens as well as cytokeratins. Thymic epithelial cells within cultured thymic organ slices maintained their postnatal growth potential, in that cytokeratin-positive epithelial monolayers could be established in vitro from these thymic slices up to 12 weeks after initiation of organ culture. Thus, thymic explants remained viable in culture and could potentially be used to reconstitute immunity in T cell deficient patients.

Successful formation of a chimeric human thymus allograft following transplantation of cultured postnatal human thymus.

Transplantation of cultured postnatal human thymus was performed in a patient with complete DiGeorge syndrome. Biopsy of the graft 3 mo after implantation revealed normal CD1+ thymocytes in thymic cortical epithelial regions and CD1- thymocytes in thymic medullary epithelial regions, respectively. HLA analysis of graft thymocyte and thymic microenvironment components demonstrated that developing thymocytes and thymic macrophages were recipient derived, while thymic epithelial components were of donor origin. The patient, who initially had no T cells and had profoundly defective T cell function, developed normal T cell responses to mitogens and Ags, tolerance to donor in a mixed lymphocyte reaction, and normal Ab titers after tetanus toxoid and pneumovax immunization. Thus, transplantation of cultured postnatal human thymic tissue in humans can form functional chimeric thymic tissue, and may provide a strategy to reconstitute the peripheral T cell pool in select congenital and acquired immune deficiency syndromes.

Mutations in purine nucleoside phosphorylase deficiency.

Purine nucleoside phosphorylase deficiency is an inherited disease of purine metabolism characterized clinically as combined immunodeficiency. The molecular defects have been published for 4 different alleles in 3 patients. We report four new mutations including two amino acid substitutions, A174P and G190V, a single codon deletion, delta I129, and a point mutation in intron 3 which leads to aberrant splicing and creation of a premature stop codon in exon 4 (286-18G-->A). Of the previously reported mutations, E89K was found in one additional patient, and R234P was found in 3 unrelated patients, making R234P the most common mutation reported to date in this disease.

Mapping cross-linking sites in modified proteins with mass spectrometry: an application to cross-linked hemoglobins.

The combined use of trypsin digestion and peptide mass mapping by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is reported here as an effective and rapid means for identifying the cross-linking sites in human oxy hemoglobin A (HbA) cross-linked with either bis(3,5-dibromosalicyl)-succinate or -glutarate. MALDI-MS analysis of a nondigested sample of oxy HbA modified with bis(3,5-dibromosalicyl)-glutarate showed that cross-linking only occurred between the beta 1- and beta 2-protomers and not between alpha 1- and alpha 2- or alpha- and beta-protomers, along with a modification reaction on an un-cross-linked beta-chain. Results of the MALDI tryptic peptide mass maps of cross-linked hemoglobins showed several cross-linked peptides having masses consistent with: beta Val67-Lys95-XL-beta Val67-Lys95, beta Val67-Lys95-XL-beta Val67-Arg104, beta Val67-Arg104-XL-beta Val67-Arg104, where XL represents the succinyl or glutaryl bridging span moiety. Each of these peptides contains Lys82, the targeted residue for these reagents, substantiating the cross-linking sites at beta 1Lys82-beta 2Lys82. This approach in general will enable rapid identification of the cross-linking sites in engineered proteins or intracellularly recombinant cross-linked proteins when the mass of the cross-linker and the protein primary structure are known.

Pediatric lobar lung transplantation.

The disparity between available donors and potential recipients of lung transplants has demanded a certain degree of flexibility on the part of transplantation surgeons. Marginal donors are now being used more frequently, and downsizing lungs from larger donors to fit into small recipients is quite common. In some instances, particularly in the circumstances of children, a single lobe from a much larger donor may serve very well as an entire lung in the recipient. Although either the upper or lower lobes from either side may be used, the lower lobes, especially the left, are better suited for this purpose because of the anatomy of the arterial, venous, and bronchial systems. As an extension of this concept, living-donor lung transplantation is now an accepted practice in carefully selected patients. Most children are best treated with bilateral lobar transplantation, particularly when cystic fibrosis is the indication. For living-donor transplantation, this obviously involves engaging two willing donors able to pass a rigorous physical and psychological evaluation. Although the recipients are generally sicker than the average cadaveric lung transplant recipient, early results to date have been similar to those receiving cadaveric lungs. In this article, we will describe our experience with this procedure, including the evaluation process, the technical aspects of the donor and recipient operations, and the results in the donors and recipients.

Next-of-kin attitudes regarding participation in an epidemiologic case-control study.

We assessed next-of-kin's attitudes about participating in an epidemiologic case-control study of adult acute nonlymphocytic leukemia. Responses from a mailed questionnaire indicated that 95 per cent were glad they participated. While 74 per cent benefited, 18.5 per cent were bothered in some way. Results concerning the need to obtain physician permission before contacting next-of-kin were inconclusive; however, 8 of 10 females contacted by the case's physician considered consent necessary.

Fc-mediated endocytosis by human neutrophils. Ultrastructural studies.

Fc Receptors (FcR) mediate the binding and uptake by polymorphonuclear leukocytes (PMN) of antibody-coated particles and soluble immune complexes. We have studied Fc-mediated endocytosis by PMN ultrastructurally using a gold-conjugated monoclonal antibody (3G8) to block or to mark the location of FcR. Phagocytosis of antibody-coated erythrocytes (EIgG) was initiated rapidly after binding to discrete foci on the PMN plasma membrane. After the phagocytosis of EIgG, we examined the distribution of FcR remaining on the PMN plasma membrane. 3G8-Colloidal gold continued to bind to PMN after ingestion of up to three EIgG, demonstrating that all PMN FcR are not utilized during a brief phagocytic event. The endocytosis of soluble immune complexes was examined by labeling plasma membrane-bound rabbit immune complexes with goat anti-rabbit IgG conjugated to colloidal gold. Gold was found in clusters randomly distributed over the plasma membrane at 4 degrees C. When cells were warmed to 37 degrees C, numerous endocytic vesicles were observed as early as 2.5 minutes after warming. After 30 minutes at 37 degrees C, large vesicles, 1 micron in diameter, were found to contain 20 to 30 gold particles. The endocytosis of 3G8 was also examined using colloidal gold. After binding of 3G8-gold at 4 degrees C, clusters of large vesicles, up to 2 micron in diameter, were rapidly formed at 37 degrees C.