Rarity of CDK4 germline mutations in familial melanoma

To date, two genes have been implicated in melanoma pathogenesis. The first, CDKN2A, is a tumour suppressor gene with germline mutations detected in 20% of melanoma-prone families. The second, CDK4, is an oncogene with co-segregating germline mutations detected in only three kindreds worldwide. We examined 16 American melanoma-prone families for mutations in all coding exons of CDK4 and screened additional members of two previously reported families with the Arg24Cys germline CDK4 mutation to evaluate the penetrance of the mutation. No new CDK4 mutations were identified. In the two Arg24Cys families, the penetrance was estimated to be 63%. Overall, 12 out of 12 invasive melanoma patients, none out of one in situ melanoma patient, five out of 13 dysplastic naevi patients, two out of 15 unaffected family members, and none out of 10 spouses carried the Arg24Cys mutation. Dysplastic naevi did not strongly co-segregate with the Arg24Cys mutation. Thus the phenotype observed in melanoma-prone CDK4 families appears to be more complex than just the CDK4 mutation. Both genetic and environmental factors are likely to contribute to the occurrence of melanoma and dysplastic naevi in these families. In summary, although CDK4 is a melanoma susceptibility gene, it plays a minor role in hereditary melanoma.     

Serotonin depolarizes type A and C primary afferents: an intracellular study in bullfrog dorsal root ganglion

Intracellular recordings were obtained from the somata of type A and C primary afferents in the isolated bullfrog dorsal root ganglion (DRG) preparation. Bath application of serotonin (5-HT) in concentrations of 0.25-1.0 mM led to slow and fast depolarizing responses. Slow, maintained 5-HT depolarizations were observed in 47% of type A and 70% of type C neurons. These slow depolarizations were associated with an underlying increase in input resistance (Rin). In some type A neurons, the Rin increase was masked by a decrease in Rin due to depolarization-induced rectification. The slow 5-HT depolarization of type A, but not type C neurons showed pronounced tachyphylaxis to repeated 5-HT applications. In type C afferents, serotonin's slow action was often accompanied by spontaneous firing. Manganese decreased slow 5-HT depolarizations of both cell types. A slow depolarization and excitation of type C afferents by methysergide and cinanserin was also observed. Fast transient 5-HT depolarizations accompanied by a rapid decrease in Rin were observed in 7% of type A and 24% of type C neurons. In some DRG cells the fast and slow depolarizations combined to form a biphasic response. The actions of 5-HT reported here resemble in some ways 5-HT responses recorded extracellularly from the spinal terminations of primary afferents.     

Periodic Hematopoiesis in Human Cyclic Neutropenia

Human cyclic neutropenia is characterized by severe depression of blood neutrophil levels approximately every 21 days. To investigate the mechanism of cyclic neutropenia four patients were studied with daily complete blood counts, serial bone marrow examinations, marrow reserve testing, serum muramidase determinations, DF²²P granulocytokinetic studies, and, in one patient, in vivo [³H]TdR labeling. Periodogram analysis of the serial blood counts in the latter patient and visual inspection of multiple cycles in the others revealed periodic fluctuations in the levels of blood neutrophils, monocytes, lymphocytes, reticulocytes, and platelets. Rhythmic changes in the morphologic and radioisotopic studies as well as the marrow reserve tests and muramidase measurements were consonant with a mechanism of periodic failure of marrow production rather than peripheral destruction. Human cyclic neutropenia is analogous to cyclic neutropenia in the grey collie dog and may be viewed as the consequence of cyclic hematopoiesis.     

Bone morphogenesis in implants of residues of radioisotope labelled bone matrix

Bone matrix demineralized in 0.6 N HCl at 2° for 24 h and implanted in muscle in allogeneic rats possesses consistently reproducible bone morphogenetic activity. Experiments on implants of matrix, obtained from donors injected with³H-tyrosine or³H-tryptophan, or Na³⁵SO₄, suggest that bone morphogenetic property is a protein or apart of a protein that is (1) insoluble in buffer solutions, pH 3.6 and 5.0; (2) degraded in buffer solutions at pH 7.4 by an endogenous sulfhydryl-group neutral proteinase; (3) digested by trypsin at 15° within 8 h without solubilization of the helical regions, possibly even without degradation of the nonhelical ends of the bone collagen molecule, and without any loss of the periodic ultrastructure of the collagen fibrils; (4) degraded or removed by 0.1 N NaOH at 2° within 24 h without solubilization of collagen; (5) biologically active even after nitration of tyrosyl groups with tetranitromethane. The release of only one-third of the radioactivity with loss of nearly all yield of new bone by limited tryptic digestion of³H-borohydride-reduced matrix indicates that the bone morphogenetic response is the function of a non-collagenous component. Autoradiographs of implants of matrix with non-collagenous proteins labelled with³H-tryptophan,³H-tyrosine, or both³H-tyrosine and³H-phenyl-alanine demonstrate random dissemination of the radioactive constituents and no evidence of local transfer of labelled proteins or soluble protein derivatives. Hypothetically, the bone morphogenetic response is controlled by an insoluble acidic bone morphogenetic protein or polypeptide (BMP) and a soluble neutral proteinase (BMP-ase) resembling trypsin in activity except functionally more specific for BMP. Firmly bound but separable from bone collagen, BMP is one of many short-lived morphogenetic substances appearing and disappearing throughout embryonic development and persisting in postfetal life. Where the BMP receptor resides and how it activates cell mechanisms of differential repression and derepression of such genes as code for osteogenesis is unknown.     

Use of the ACE inhibitor perindopril in patients with chronic obstructive lung diseases, complicated by cor pulmonale

The purpose of the study was to evaluate hemodynamic effects and safety of the ACE inhibitor perindopril in treatment of secondary pulmonary hypertension (PH) in patients with chronic obstructive bronchitis (COB). The subjects were 42 patients with COB and secondary PH (functional class (FC) III-IV), whose treatment included 4-week administration of perindopril. Studied were hemodynamic parameters and day profile of blood pressure (24-hour monitoring). Treatment of these patients with perindopril resulted in improvement of PH, positive changes in the right heart, and normalization of blood pressure day profile. Both course treatment and prolonged administration of perindopril were effective in COB patients with clinical manifestations of FC III and IV PH. Long outpatient administration of perindopril in individual doses led to good clinical results and significant positive hemodynamic changes. According to the authors, the ACE inhibitor perindopril may be recommended for correction of hemodynamic disturbances in cases of chronic cor pulmonale in patients with chronic obstructive lung diseases.     

Surgical Debulking and Intraperitoneal Chemotherapy for Established Peritoneal Metastases From Colon and Appendix Cancer

Background: Aggressive treatment of peritoneal metastases from colon cancer by surgical cytoreduction and infusional intraperitoneal (IP) chemotherapy may benefit selected patients. We reviewed our institutional experience to assess patient selection, complications, and outcome.Methods: Patients having surgical debulking and IP 5-fluoro-2-deoxyuridine (FUDR) plus leucovorin (LV) for peritoneal metastases from 1987 to 1999 were evaluated retrospectively.Results: There were 64 patients with a mean age of 50 years. Primary tumor sites were 47 in the colon and 17 in the appendix. Peritoneal metastases were synchronous in 48 patients and metachronous in 16 patients. Patients received IP FUDR (1000 mg/m² daily for 3 days) and IP leucovorin (240 mg/m²) with a median cycle number of 4 (range, 1–28). The median number of complications was 1 (range, 0–5), with no treatment related mortality. Only six patients (9%) required termination of IP chemotherapy because of complications. The median follow-up was 17 months (range, 0–132 months). The median survival was 34 months (range, 2–132); 5-year survival was 28%. Lymph node status, tumor grade, and interval to peritoneal metastasis were not statistically significant prognostic factors for survival. Complete tumor resection was significant on multivariate analysis (P = .04), with a 5-year survival of 54% for complete (n = 19) and 16% for incomplete (n = 45) resection.Conclusions: Surgical debulking and IP FUDR for peritoneal metastases from colon cancer can be accomplished safely and has yielded an overall 5-year survival of 28%. Complete resection is associated with improved survival (54% at 5 years) and is the most important prognostic indicator.Presented in part at the 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.     

Peri-operative outcomes of patients with stage IV endometriosis undergoing robotic-assisted laparoscopic surgery

We analyzed peri-operative outcomes of 80 patients who underwent robotic-assisted laparoscopic surgery and were diagnosed with stage IV endometriosis (revised American Society for Reproductive Medicine) between January 2007 and December 2010 at a tertiary gynecologic oncology referral center with a fellowship training program. Eligible women had a combination of one or more factors: pelvic mass, sub-acute or chronic pelvic pain, dysmenorrhea, dyspareunia, elevated serum CA-125, diagnosed with stage IV endometriosis at surgery with robotic-assisted gynecologic procedures using the da Vinci^? Surgical System. The mean age was 43.7?±?7.0?years, body mass index 27.5?±?7.4?kg/m², and 23 (28.9%) patients had prior endometriosis surgery. Presenting symptoms included: chronic pelvic pain (48.8%), dysmenorrhea (40.3%), and dyspareunia (33.8%). Sixty-nine (86%) patients had pelvic masses (43 unilateral and 26 bilateral). Thirty-seven (46.3%) had elevated CA-125 levels (mean 97.9?±?71.6 U/ml). Forty-eight (60%) underwent robotic-assisted laparoscopic hysterectomy (RALH)/bilateral salpingo-oophorectomy (BSO), 9 (11.3%) RALH/unilateral salpingo-oophorectomy (USO), 5 (6.3%) modified radical hysterectomy, and 10 (13%) USO or BSO only. Four (5%) had ovarian cystectomies with excision of endometriotic implants. Three (3.8%) underwent appendectomy and no patient required bowel resection. Four (5%) patients required conversion to laparotomy during the first 15 cases of this series [dense adhesions (3) and ureteral injury (1)]. Mean operative time was 115?±?46?min, blood loss 88?±?67?ml, and length of stay 1.0?±?0.4?days. There were four (5%) complications (ureteral injury, cuff abscess, cuff hematoma, re-admission for nausea and vomiting secondary to narcotics) and no transfusions. One (1.3%) patient underwent a second surgery for pain (dyspareunia). Robotic-assisted surgery for stage IV endometriosis resulted in excellent pain relief, with few laparotomy conversions or complications during a robotic learning-curve experience.