Adjuvant therapy for adenocarcinoma of the rectum

Surgical resection continues to be the primary curative modality for patients with adenocarcinoma of the rectum. However, local tumor recurrence in the pelvis and/or distant metastasis may occur in spite of complete excision of grossly visible malignant disease. Surgical and pathologic staging can identify a subset of surgically treated rectal cancer patients at high risk for tumor relapse and death. Irradiation and chemotherapy have been used as adjuvant therapy in conjunction with surgery as single modalities and in combination for patients with high risk rectal cancer. Evidence from controlled clinical trials indicates a significant decrease in local tumor recurrence, and a significant improvement in disease-free and overall survival with the use of combined postoperative irradiation and chemotherapy in this setting. A current national clinical trial in the United States of America is studying whether irradiation can be combined with new chemotherapy regimens which have shown significant therapeutic benefit as surgical adjuvant therapy for patients with high risk colon cancer (5FU + levamisole) and for patients with metastatic colorectal cancer (5FU + leucovorin) to further improve the efficacy of surgical adjuvant therapy for adenocarcinoma of the rectum.

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Resumen La resección quirúrgica continúa siendo la modalidad curativa primaria en pacientes con adenocarcinoma del recto. Sin embargo, la recurrencia local del tumor en la pelvis y/o las metástasis distantes puede ocurrir a pesar de la resección completa de la enfermedad maligna macroscópicamente visible. La estadificación operatoria y patológica puede indentificar un subgrupo de pacientes tratados quirúrgicamente con alto riesgo de relapso tumoral y meserte. La irradiación y la quimioterapia han sido utlizados como terapia adyuvante en unión con la cirugía como modalidades únicas y en combinación para pacientes con cáncer rectal de alto riesgo. La evidencia surgida de ensayos clínicos controlados señala una disminución significativa en las tasas de recurrencia tumoral local, y una superación significativa en las tasas globales de sobrevida y de sobrevida libre de enfermedad con el uso de la combinación postoperatoria de irradiación y quimioterapia. Un ensayo clínico nacional que se ejecute en el momento actual en los Estados Unidos investiga si la irradiación puede ser combinada con los nuevos regímenes quimioterapéuticos que han demostrado beneficio significantivo como terapia quirúrgica adyuvante en pacientes con cáncer de colon de alto riesgo (5 FU + levamisol) y en pacientes con cáncer colorrectal metastásico (5 FU + leucovorin) con el propósito de mejorar aún más la eficicacia de la terapia quirúrgica adyuvante en el adenocarcinoma del recto.

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Résumé La chirurgie est le principal moyen thérapeutique de l'adénocarcinome du rectum. La récidive tumorale pelvienne et/ou à distance peut cependant se produire malgré une résection apparemment complète. Un bilan d'extension chirurgical et anatomopathologique peut identifier un sous-groupe de patients susceptible de présenter une récidive ou d'en mourir. La radio-et chimiothérapie ont été préconisées comme traitement adjuvant après l'exérèse chirurgicale, soit seule, soit combinée, chez cez patients à risque. Les résultats de plusieurs essais thérapeutiques semblent indiquer que la radio-et la chimiothérapie combinée à la chirurgie diminuent significativement le taux de récidives locales et améliorent significativement la survie globale et la survie sans maladie. Un essai actuellement en cours aux Etats-Unis étudie si la radiothérapie peut être utilement combinée avec les nouveaux régimes chimiothérapeutiques ayant fait preuve de leur efficacité chez les patients à risque (5FU + lévamisole) ou chez les patients ayant des métastases (5FU + leucovin).

     

The diagnostic interview for personality disorders: Interrater and test-retest reliability

The Diagnostic Interview for Personality Disorders (DIPD) is a semistructured interview of 252 questions that encompasses all 11 Axis II disorders described in the DSM-III. Its interrater reliability was assessed using a sample of 43 patients and its test-retest reliability was assessed using a separate sample of 54 patients. Adequate kappas were obtained in both situations for all disorders except schizoid personality disorder, which was never diagnosed. Interrater coefficients ranged from .52 to 1.0, with nine in the excellent range (κ > .75). Test-retest coefficients ranged from .46 to .85, with four in the excellent range. These results compara very favorably to those achieved using the other two Axis II interviews that have appeared in the literature, the Structured Interview for the DSM-III Personality Disorders (SIDP) and the Personality Disorder Examination (PDE).     

Auditory evoked heart rate responses in pigtailed macaques (Macaca nemestrina) raised in isolation

Heart rate (HR) responses evoked by 1 sec of 85-dB white noise were studied in 12 1-year-old pigtailed macaques, 6 of which were raised in social isolation and 6 with mothers and peers. Tests were given for 5 days, with 25 trials each day. Although baseline HR did not differ between groups, the pattern of change from baseline was not the same. Isolates showed only HR acceleration, returning to baseline within 10-11 sec of stimulus onset. Socially reared monkeys had a 10- to 11-sec biphasic response of acceleration followed by deceleration, with subsequent return to baseline. The same group difference in HR pattern occurred when subjects were tested with a less intense 65-dB stimulus. These findings were discussed in terms of activity, emotionality, and autonomic regulatory functions. It was concluded that early rearing experiences may affect later physiological processes involving autonomic nervous system balance. This conclusion was related to observations of persistent individual differences in HR by human children classified as inhibited.     

The presence of the casein kinase II phosphorylation sites of Vpu enhances the CD4(+) T cell loss caused by the simian-human immunodeficiency virus SHIV(KU-lbMC33) in pig-tailed macaques

The simian-human immunodeficiency virus (SHIV)/ macaque model for human immunodeficiency virus type 1 has become a useful tool to assess the role of Vpu in lentivirus pathogenesis. In this report, we have mutated the two phosphorylated serine residues of the HIV-1 Vpu to glycine residues and have reconstructed a SHIV expressing this nonphosphorylated Vpu (SHIV(S52,56G)). Expression studies revealed that this protein was localized to the same intracellular compartment as wild-type Vpu. To determine if this virus was pathogenic, four pig-tailed macaques were inoculated with SHIV(S52,56G) and virus burdens and circulating CD4(+) T cells monitored up to 1 year. Our results indicate that SHIV(S52,56G) caused rapid loss in the circulating CD4(+) T cells within 3 weeks of inoculation in one macaque (CC8X), while the other three macaques developed no or gradual numbers of CD4(+) T cells and a wasting syndrome. Histological examination of tissues revealed that macaque CC8X had lesions in lymphoid tissues (spleen, lymph nodes, and thymus) that were typical for macaques inoculated with pathogenic parental SHIV(KU-1bMC33) and had no lesions within the CNS. To rule out that macaque CC8X had selected for a virus in which there was reversion of the glycine residues at positions 52 and 56 to serine residues and/or compensating mutations occurred in other genes associated with CD4 down-regulation, sequence analysis was performed on amplified vpu sequences isolated from PBMC and from several lymphoid tissues at necropsy. Sequence analysis revealed a reversion of the glycine residues back to serine residues in this macaque. The other macaques maintained low virus burdens, with one macaque (P003) developing a wasting syndrome between months 9 and 11. Histological examination of tissues from this macaque revealed a thymus with severe atrophy that was similar to that of a previously reported macaque inoculated with a SHIV lacking vpu (Virology 293, 2002, 252). Sequence analysis revealed no reversion of the glycine residues in the vpu sequences isolated from this macaque. These results contrast with those from four macaques inoculated with the parental pathogenic SHIV(KU-1bMC33), all of which developed severe CD4(+) T cell loss within 1 month after inoculation. Taken together, these results indicate that casein kinase II phosphorylation sites of Vpu contributes to the pathogenicity of the SHIV(KU-1bMC33) and suggest that the SHIV(KU-1bMC33)/pig-tailed macaque model will be useful in analyzing amino acids/domains of Vpu that contribute to the pathogenesis of HIV-1.     

Extrapelvic colon--areas of failure in a reoperation series: implications for adjuvant therapy

A total of 230 patients had planned single or multiple reoperative procedures following "curative" resection of colorectal cancer at the University of Minnesota. The site of the primary lesion was extrapelvic in 91, and later evidence of cancer was found in 58 patients (64%) at re-operation and/or other follow-up. Eight of the 58 (14%) were converted to disease-free status. Incidence and patterns of failure were correlated with initial operative-pathologic extent of disease (87 of the 91 at risk had initial tumor extension beyond the bowel wall, involved nodes or both) and comparisons were made with the previously analyzed rectal reoperation patients. While a component of local-regional failure was more common with rectal lesions (48/74 at risk, 65%), it was not uncommon with extrapelvic primaries (44/91-48%). The incidence of hematogenous metastasis (DM) was equal, but the pattern of initial DM differed (extrapelvic colon--primarily liver; rectum--liver and lung). Peritoneal seeding was a more common component of failure with the extrapelvic primaries (19/91--21% vs 3/74-4%). Since surgery alone is inadequate treatment for many patients with colon as well as rectal cancer, the rationale of adjuvant radiation and systemic therapy, alone or in combination, is discussed.     

Primary myocutaneous flap closure following resection of locally advanced pelvic malignancies

BACKGROUND: Perineal wounds, created at the time of extended resection for locally advanced malignancy and following chemoradiation, are at risk of serious complications. METHODS: To determine whether immediate myocutaneous flap closure prevents complications, 57 patients treated with multimodality therapy and proctectomy (35 perineal wounds) or sacrectomy (22 posterior wounds) were studied. Patients were categorized according to whether they underwent primary skin and pelvic closure (group 1; ,n = 20); primary skin and omental pelvic closure (group 2; n = 24); or immediate myocutaneous flap closure (group 3; n = 13). RESULTS: Groups were similar with respect to age and sex; however, group 1 had more primary tumours and required less radical surgery and chemoirradiation than groups 2 and 3. Groups 1 and 2 experienced more complications overall (eight of 20, nine of 24 and three of 13 patients in groups 1, 2 and 3 respectively), more acute wound complications (seven of 20, nine of 24 and two of 13), delayed wound healing (three of 20, six of 24 and one of 13) and more reoperations for perineal wound problems (five of 20, seven of 24 and zero of 13). Patients in group 2 had a significantly longer hospital stay than those in group 1. Flap closure (group 3) did not increase the length of stay. The routine use of primary flap closure reduced overall wound complications (eight of 31 versus ten of 26 patients) and length of hospitalization (13 versus 17 days). CONCLUSION: Complete wound healing was achieved in all patients; however, immediate myocutaneous flap closure reduced the need for readmission and reoperation.     

Co-occurrence of mood and personality disorders: a report from the Collaborative Longitudinal Personality Disorders Study (CLPS)

The purpose of this study was to examine the relationship of subtypes and particular clinical features of mood disorders to co-occurrence with specific personality disorders. Five hundred and seventy-one subjects recruited for the Collaborative Longitudinal Personality Disorders Study (CLPS) were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the Diagnostic Interview for DSM-IV Personality Disorders (DIPD-IV). Percent co-occurrence rates for current and lifetime mood disorders with personality disorders were calculated. Logistic regression analyses examined the effects of clinical characteristics of depressive disorders (e.g., age at onset, recurrence, symptom severity, double depression, and atypical features) on personality disorder co-occurrence. In comparison with other DSM-IV personality disorders, avoidant, borderline, and dependent personality disorders (PDs) were most specifically associated with mood disorders, particularly depressive disorders. Severity and recurrence of major depressive disorder and comorbid dysthymic disorder predicted co-occurrence with borderline and to a lesser extent research criteria depressive personality disorders. The results are consistent with the view that a mood disorder with an insidious onset and recurrence, chronicity, and progression in severity leads to a personality disorder diagnosis in young adults.