Patient-Reported Quality of Life Before and After Chemoradiation for Intact Pancreas Cancer: A Prospective Registry Study

PurposeOur purpose was to determine the effect of chemoradiotherapy (CRT) on patient-reported quality of life (QOL) for patients with intact pancreas cancer.Methods and MaterialsWe reviewed a prospective QOL registry for patients with intact, clinically localized pancreatic ductal adenocarcinoma treated with CRT between June 2015 and November 2018. QOL was assessed pre-CRT (immediately before CRT, after neoadjuvant chemotherapy) and at the completion of CRT with the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) and its component parts: FACT-General (FACT-G) and hepatobiliary cancer subscore (HCS). A minimally important difference from pre-CRT was defined as ≥ 6, 5, and 8 points for FACT-G, HCS, and FACT-Hep, respectively.ResultsOf 157 patients who underwent CRT, 100 completed both pre- and post-CRT surveys and were included in the primary analysis. Median age at diagnosis was 65 years (range, 23-90). National Comprehensive Cancer Network resectability status was resectable (3%), borderline resectable (40%), or locally advanced (57%). Folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) (75%) or gemcitabine and nab-paclitaxel (42%) were given for a median of 6 cycles (range, 0-42) before CRT. Radiation therapy techniques included 3-dimensional conformal (22%), intensity modulated photon (55%), and intensity modulated proton (23%) radiation therapy to a median dose of 50 Gy (range, 36-62.5). Concurrent chemotherapy was most commonly capecitabine (82%). Sixty-three patients (63%) had surgery after CRT. The mean decline in FACT-G, HCS subscale, and FACT-Hep from pre- to post-CRT was 3.5 (standard deviation [SD], 13.7), 1.7 (SD 7.8), and 5.2 (SD 19.4), respectively. Each of these changes were statistically significant, but did not meet the minimally important difference threshold. Pancreatic head tumor location was associated with decline in FACT-Hep. Nausea was the toxicity with the greatest increase from pre- to post-CRT by both physician-assessment and patient-reported QOL.ConclusionsFor patients with intact pancreatic adenocarcinoma, modern CRT is well tolerated with minimal decline in QOL during treatment.     

Osteonecrosis of the jaws associated with use of risedronate: report of 2 new cases.

Use of various bisphosphonates has been associated with the development of osteonecrosis of the jaws (ONJ). At least 865 cases of ONJ attributed to these agents have been reported in the English-language literature. Approximately 96% of these published cases were seen with administration of the intravenous agents pamidronate and zoledronate, whereas only 26 cases have been associated with oral bisphosphonates, 25 of them with alendronate. Only a single case of ONJ associated with the oral bisphosphonate risedronate has been previously cited. We report 2 cases of ONJ attributed to risedronate administration. The patients developed osteonecrosis 15 and 24 months after treatment for osteopenia. A regimen of antibiotics and chlorhexidine mouthrinse resolved the osseous defect in the mandible caused by complete exfoliation of a lingual torus in 1 patient. The other patient required sequestrectomy, repeated courses of antibiotics, surgical debridement, and steroids to promote closure of an oroantral fistula and management of sinusitis after bone grafting and implant placement in the posterior maxilla. A demographic profile of reported oral bisphosphonate users affected by ONJ is also provided. With the millions of patients receiving various oral bisphosphonates for osteopenia and osteoporosis, health care practitioners should be aware of the potential for the onset of osteonecrosis and familiar with its management.     

Effect of incubation temperature on mitogen responses of lymphocytes from adult peripheral blood and from cord blood

Lymphocytes from normal adults, when cultured with phytohaemagglutinin (PHA) or Concanavalin A (Con A) at 39°C, showed an enhancement and earlier onset of ³H-thymidine incorporation compared with cultures incubated at 37°C. In contrast, the peak responses of cord blood lymphocytes incubated at either 35°C or 39°C did not differ significantly from those incubated at 37°C. Cultures of adult lymphocytes showed an exponential rise and fall in ³H-thymidine incorporation, which was much more rapid at 39°C than at 37°C. However, the kinetics of thymidine incorporation into mitogen-stimulated cord blood lymphocytes incubated at 39°C were similar to those at 37°C. The following results suggested that temperature acted predominantly on the proliferative phase of the transformation response. Firstly, by inhibiting binding of Con A using methyl-α-D-mannopyranoside, it was found that activation of adult lymphocytes took place within the same time period at both 39°C and 37°C. Secondly, cultures incubated at 37°C for 3 days, and labelled for 4 hr at either 37°C or 39°C showed no significant difference in ³H-thymidine uptake, whereas cultures incubated at 39°C for 3 days, and labelled for 4 hr at 37°C showed significantly higher responses than those both incubated and labelled at 37°C. Thirdly, the major increase in thymidine uptake occurred after incubation at 39°C for the second and third days of culture. These findings were consistent with a shortening of the cell cycle at the higher temperature. Thus, the failure of cord blood lymphocytes to show increased thymidine uptake after incubation at 39°C apparently reflects an insensitivity to temperature of certain of the metabolic pathways involved in cell replication in the neonate.     

Specificity of the passive antibody-induced suppression of the humoral immune response of mice to surface antigens on human cells

The effect of passively administered antibody on the humoral immune response of BALB/c mice to antigenic determinants on human cells has been examined. Antiserum raised by immunizing mice with the human leukaemic cell line K562, which lacks HLA-A,B,C antigens, was administered to mice, together with the HLA-A,B,C-positive cell line, BALM-1. The antibody response to the unique antigen was assessed by measuring the ability of the resultant antiserum to inhibit the binding to BALM-1 cells of a labelled monoclonal antibody, 7B6, which is specific for a monomorphic HLA-A,B,C determinant. As an indication of the immune response to antigens common to K562 and BALM-1, the ability of the same antiserum to inhibit the binding of monoclonal antibody 6B1, which detects an epitope common to both cell lines, was measured. Passive antibody to K562 blocked the immune response of mice to the common antigen on BALM-1 cells. However, the response to the antigen not recognized by the passive antibody was unaffected, even though the two antigens were present on the same immunizing cell. Thus, the effect of passive antibody was 'determinant specific'. Similar results were obtained, irrespective of whether the i.v. or i.p. route of immunization was used, and whether the passive antibody was adsorbed onto the immunizing cells prior to injection, or administered separately. The blocking of the immune response did not depend on simple masking of the antigenic determinants by the passive antibody, since non-saturating amounts of antibody were effective. In addition, blocking activity was dependent on antibody class and on an intact Fc region. The latter considerations also imply that the outcome of passive antibody administration in this system was determined by factors other than the ability of the antigen-antibody complexes to interact directly with B cells, and indicate the importance of antigen processing and/or a mechanism such as antigen-reactive cell opsonization.     

Susceptibility of beige mutant mice to candidiasis may be linked to a defect in granulocyte production by bone marrow stem cells.

The beige mutation in mice has a pervasive effect on mechanisms of host resistance to infectious agents. Best characterized are defects in granulocyte chemotaxis and phagocytosis, which are associated with increased susceptibility to bacteria, and a deficiency in the levels of natural killer (NK) cells, which has been linked to decreased resistance to both murine cytomegalovirus and the yeast Cryptococcus neoformans. The objective of the present experiments was to explore the cellular basis of the enhanced susceptibility of beige mice to systemic infection with the yeast Candida albicans. In contrast to murine cytomegalovirus and C. neoformans, infection with C. albicans did not induce any detectable NK cell activity in the spleen of bg/bg or bg/+ mice. Unfractionated bone marrow (BM) displayed some candidacidal activity, mediated by both phagocytic and nonphagocytic cells; however, there was no difference between homozygous and heterozygous mice in the effector function of normal BM cells or mononuclear cells derived from either short- or long-term BM cultures. On the other hand, peritoneal granulocytes from bg/bg mice were significantly more effective than those from bg/+ mice in killing Candida blastoconidia in vitro. A similar comparison of granulocytes from short-term BM cultures showed that the activities of cells from bg/bg and bg/+ mice were equivalent, indicating that the granulocytes derived from the peritoneal cavity of bg/bg mice had probably been exposed to some form of nonspecific stimulation in vivo. Somewhat surprisingly, long-term BM cultures did not support the continual growth of bg/bg granulocytes, and it is possible that the beige mutation may be associated with a lesion in the differentiation pathway that leads to the production of granulocytes. Taken together, the data indicate that, in beige mice, granulocytes rather than NK cells are a major determinant of natural resistance to C. albicans infections.     

Enhanced clearance of Candida albicans from the oral cavities of mice following oral administration of Lactobacillus acidophilus

Orally administered live Lactobacillus acidophilus was assessed for its capacity to enhance clearance from the oral cavity of DBA/2 mice shown previously to be 'infection prone'. L. acidophilus fed to DBA/2 mice significantly shortened the duration of colonization of the oral cavity compared to controls. Enhanced clearance of Candida albicans correlated with both early mRNA gene expression for interleukin (IL)-4 and interferon (IFN)-gamma and expression of their secreted products in cultures of cervical lymph nodes stimulated with Candida antigen. In addition rapid clearance correlated with higher levels of IFN-gamma and nitric oxide in saliva. Delayed clearance, less pronounced levels of the cytokine response, saliva IFN-gamma and nitric oxide, and later mRNA expression for IL-4 and IFN-gamma relative to feeding with the L. acidophilus isolate were noted in mice fed a different Lactobacillus isolate (L. fermentum). These observations indicate significant variations in individual isolates to activate the common mucosal system.     

Expression of CD31 epitopes on human lymphocytes: CD31 monoclonal antibodies differentiate between naive (CD45RA+) and memory (CD45RA-) CD4-positive T cells

The CD31 antigen, a member of the immunoglobulin superfamily with a possible cell adhesion function, is expressed on approximately 50% of peripheral blood lymphoid cells at relatively low intensity (10-20% of the level on monocytes). In the accompanying paper we showed that a mAb, 5A2.G5, which identifies a glycosylation-dependent epitope of the CD31 antigen, bound to fewer lymphocytes than two other CD31 mAb, B2B1 and 2BD4, although the 3 antibodies bound equally well to monocytes. We have now analyzed the pattern of expression of epitopes of the CD31 antigen on lymphoid cell subpopulations using two-color immunofluorescence and flow cytometry. Large granular lymphocytes (CD16+), CD8-positive T cells and B cells (SMIg+) were mostly CD31-positive as indicated by the binding of mAb B2B1 and 2BD4. Single populations displaying some overlap with the negative control were obtained in each case. In contrast, CD4-positive T cells fell into two discrete populations with respect to CD31 antigen expression. mAb 5A2.G5 displayed weaker binding to all lymphoid cell types, indicating that the pattern of glycosylation of the CD31 antigen differs between lymphocytes (of all types) and cells of the myeloid lineages. The heterogeneity of CD31 antigen expression by CD4-positive cells was further examined by dual-labelling of purified CD4 cells with mAb B2B1 and CD45RA or CD29 mAb which identify naive and memory T cells respectively. The CD31 antigen was found to be preferentially expressed by the CD45RA-positive, naive cell population.