Total Mesorectal Excision for Mid-Rectal Cancer Without Anastomosis: Low Hartmann's Operation or Intersphincteric Abdomino-Perineal Excision?

BACKGROUND AND AIMS: In mid-rectal cancer, the low colorectal anastomosis is, although feasible, sometimes avoided. The aim was to compare low Hartmann's procedure with intersphincteric abdomino-perineal excision of the rectum, in patients operated with total mesorectal excision for mid-rectal cancer in whom the low anastomosis was technically feasible but for patient-related reasons undesired. MATERIAL AND METHODS: A total of 64 consecutive patients with mid-rectal cancer who underwent low Hartmann's procedure (n = 34) or intersphincteric abdomino-perineal excision (n = 30) at one colorectal unit were compared regarding patient demography, short-term oncology, surgical outcome at 3 and 24 months, and long-term overall survival. RESULTS: There were no significant differences between intersphincteric abdomino-perineal excision and Hartmann's procedure regarding age, gender distribution, body mass index, preoperative radiotherapy, tumor level, or cancer stages. Operation time was shorter in Hartmann's procedure as compared with intersphincteric abdomino-perineal excision, median 174 and 256 min, (P < 0.001), and intraoperative blood loss was increased, 600 and 500 mL, respectively (P = 0.045). Number of lymph nodes and circumferential resection margin were comparable. In Hartmann's procedure compared with intersphincteric abdomino-perineal excision, the need for reoperation was 24% and 3%, (P = 0.020), complications classified as Clavien-Dindo 3-4 occurred in 32% and 10%, (P = 0.031), pelvic abscess in 21% and 10%, (P = 0.313), and mortality within 90 days was 3% and 0%, respectively, (P = 0.938). In intersphincteric abdomino-perineal excision, the perineal wound was not healed at 3 months in 13%, and in Hartmann's procedure 15% had chronic secretion from the anorectal remnant at 2 years postoperatively. CONCLUSION: The results from this study suggest that intersphincteric abdomino-perineal excision might be an alternative to Hartmann's procedure in patients with mid-rectal cancer, in whom a low colorectal anastomosis is undesired.

Role of indoleamine 2,3-dioxygenase in an inflammatory model of murine gingiva.

BACKGROUND AND OBJECTIVE: Indoleamine 2,3-dioxygenase (IDO) is one of the major pathways for metabolism of tryptophan in a variety of cells, including immune cells. Increasing evidence indicates that IDO is a critical player in establishing the balance between immunity and tolerance and ultimately in the maintenance of homeostasis. By inducing inflammation in gingival tissue, we tested the hypothesis that IDO is a pivotal player in regulating the immune and inflammatory responses of gingiva. MATERIAL AND METHODS: We utilized the IDO knockout mouse model in conjunction with lipopolysaccharide (LPS)-induced inflammation. Accordingly, wild-type and IDO knockout mice were injected with LPS or vehicle in the anterior mandibular gingiva, twice over a 2-wk period, which was followed by procurement of gingival tissue for histopathology and preparation of tissue for flow cytometry-based studies. RESULTS: Clinical and histological examinations revealed a marked adverse impact of IDO deficiency on gingival inflammation. These observations were consistent with a more marked increase in the number of cells positive for the proinflammatory cytokine interleukin (IL)-17, but no significant change in the number of cells positive for the anti-inflammatory cytokine IL-10, in LPS-treated IDO knockout mice. Consistent with the more marked proinflammatory impact of IDO deficiency, the percentage of regulatory T cells was much reduced in gingival tissue of LPS-treated IDO knockout mice than in gingival tissue of wild-type mice. These proinflammatory changes were accompanied with a prominent increase in apoptotic and necrotic cell death in gingival tissue of IDO knockout mice compared with wild-type mice. CONCLUSION: Collectively, our findings support a major role for IDO in the development of gingival inflammation, as an example of an inflammatory condition, and lay the foundation for subsequent studies to explore it as a novel immunotherapy target.

Potassium channels in C. elegans.

Ion channels are the "transistors" (electronic switches) of the brain that generate and propagate electrical signals in the aqueous environment of the brain and nervous system. Potassium channels are particularly important because, not only do they shape dynamic electrical signaling, they also set the resting potentials of almost all animal cells. Without them, animal life as we know it would not exist, much less higher brain function. Until the completion of the C. elegans genome sequencing project the size and diversity of the potassium channel extended gene family was not fully appreciated. Sequence data eventually revealed a total of approximately 70 genes encoding potassium channels out of the more than 19,000 genes in the genome. This seemed to be an unexpectedly high number of genes encoding potassium channels for an animal with a small nervous system of only 302 neurons. However, it became clear that potassium channels are expressed in all cell types, not only neurons, and that many cells express a complex palette of multiple potassium channels. All types of potassium channels found in C. elegans are conserved in mammals. Clearly, C. elegans is "simple" only in having a limited number of cells dedicated to each organ system; it is certainly not simple with respect to its biochemistry and cell physiology.

Possible improved survival of patients with stage IV AJCC melanoma receiving SRL 172 immunotherapy: correlation with induction of increased levels of intracellular interleukin-2 in peripheral blood lymphocytes.

PURPOSE: This phase I-II study was designed to assess safety and clinical efficacy of SRL 172 vaccine in patients with advanced stage IV (AJCC) malignant melanoma. Induction of intracellular cytokines (IL-2 and INF-gamma) in peripheral blood lymphocytes (PBLCs) from these patients was assayed and correlated to clinical outcome. PATIENTS AND METHODS: SRL 172 was administered intradermally to 24 patients with stage IV malignant melanoma, initially at 15-day intervals for three vaccinations and then at monthly intervals. Lymphocyte activation for cytokines in PBLCs was assayed prior to each vaccine administration using a FACS-based intracellular cytokine assay. Survival was compared to historical controls. RESULTS: The vaccination schedule resulted in sustained intracellular IL-2 induction in PBLCs in 9 of 23 patients (39%) who received at least three doses. Cytokine induction became apparent within the first three administrations of vaccine and was maximal at 8-12 weeks. Induction of intracellular IL-2 production (group 1) was associated with improved survival (P < 0.036). The median survival of the nine patients demonstrating IL-2 induction was 59 (95% confidence interval (95% CI): 47-71) weeks compared to 31 (95% CI: 18-44) weeks for the non-inducers. Induction of INF-gamma (group 2) was found in 10 patients and 6 patients had IL-2 and INF-gamma induction (group 3). There was no survival advantage for these patient groups. Although no objective responses were documented the group as a whole had a median survival of 44 (95% CI: 31-59) weeks which is better than that of historical controls. SRL 172 was safe and well tolerated. CONCLUSION: SRL 172 is effective in inducing intracellular IL-2 responses in PBLCs of a significant number of patients with stage IV (AJCC) melanoma. This is correlated with improved survival. The survival analysis is sufficiently encouraging to suggest that further prospective trials are justified. The methodology we present in this study may help in developing surrogate markers that will allow rational immunotherapeutic strategies to be designed for cancer patients.

Immunotherapy of advanced prostate cancer: a phase I/II trial using Mycobacterium vaccae (SRL172).

OBJECTIVE: To assess whether a new heat-killed Mycobacterium vaccae preparation (SRL172), which enhances cell-mediated immunity and has been proposed for use as an immunotherapeutic agent against cancer, is safe in patients with advanced hormone-refractory prostate cancer, can stimulate desirable cytokine changes in these patients and modulate the progression of the disease. PATIENTS AND METHODS: Ten patients were given SRL172 intradermally at regular intervals. The serum prostate specific antigen (PSA) level was used as a surrogate marker of response. The proportion of peripheral blood mononuclear cells (PBMC) secreting interleukin 2 (IL2), interferon gamma (IFNgamma) and interleukin 4 (IL4) was measured by flow cytometry (FACS) before and after vaccination to assess whether the treatment induced a Th2 (predominantly humoral) to Th1 (predominantly cell-mediated) switch. RESULTS: There were no significant adverse events. In five patients the serum PSA declined during the trial and in two of these there was no concomitant change of therapy apart from vaccination with SRL172. Before vaccination with SRL172 patients had a low proportion of PBMC producing IFNgamma and IL2 (all 10) and a higher proportion secreting IL4 (all three tested), suggesting a predominantly Th2 cytokine profile. After vaccination the proportion of IL4 secreting PBMC fell in all three patients tested. The proportion of IL2 secreting PBMC increased in three patients whose PSA fell. The proportion of IFNgamma-secreting cells remained depressed in nine of 10 patients. CONCLUSION: Two patients with advanced hormone-refractory prostate cancer had a PSA response to the vaccination with SRL172. The proportion of PBMC secreting IL2 is a potential marker of response to immunotherapy.

The first survey of Hendersonula toruloidea as a human pathogen in Iran.

The possible presence of Hendersonula toruloidea in the environment and its role as a human pathogen in Iran was studied. Samples were collected both from trees likely to be infected and from patients who presented with suspected fungal infections of the hands and feet. The samples were mainly collected in areas of southern Iran where the climate is similar to that of areas where H. toruloidea has been found previously to infect humans. H. toruloidea type B was isolated from plant samples (eucalyptus trees) for the first time in Iran but it could not be isolated as a human pathogen.