Genetic features of Lynch syndrome in the Israeli population.

Diagnosis of Lynch syndrome (LS) may be complex. Knowledge of mutation spectrum and founder mutations in specific populations facilitates the diagnostic process. Aim of the study is to describe genetic features of LS in the Israeli population and report novel and founder mutations. Patients were studied at high-risk clinics. Diagnostics followed a multi-step process, including tumor testing, gene analysis and testing for founder mutations. LS was defined by positive mutation testing. We diagnosed LS in 242 subjects from 113 families coming from different ethnicities. We identified 54 different mutations; 13 of them are novel. Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2; 27% of the MSH2 mutations were large deletions. Seven founder mutations were detected in 61/113 (54%) families. Constitutional mismatch repair deficiency (CMMR-D) was identified in five families. Gene distribution in the Israeli population is unique, with relatively high incidence of mutations in MSH2 and MSH6. The mutation spectrum is wide; however, 54% of cases are caused by one of seven founder mutations. CMMR-D occurs in the context of founder mutations and consanguinity. These features should guide the diagnostic process, risk estimation, and genetic counseling.

Impact of "critical lesions" on outcomes following cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy.

BACKGROUND: Peritoneal Cancer Index (PCI) and complete cytoreduction are the best outcome predictors following cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Lesions in critical areas, regardless of PCI, complicate surgery and impact oncological outcomes. We prospectively defined "Critical lesions" (CL) as penetrating the hepatic hilum, diaphragm at hepatic outflow, major blood vessels, pancreas, or urinary tract. METHODS: Retrospective analysis of a prospective database of 352 CRS + HIPEC patients from 2015 to 2019. Excluded patients with aborted/redo operation (n = 112), or incomplete data (n = 19). Patients categorized by CL status and compared: operative time, estimated blood loss (EBL), PCI, transfusions, hospital stay, post-operative complications and mortality, overall survival (OS) and disease-free survival (DFS). RESULTS: Included 221 patients (78 CL; 143 no-CL). No difference in patients' characteristics: age, BMI, gender or co-morbidities noted. Operative time longer (5.3 h vs 4.3 h, p < 0.01), EBL higher (769 ml vs 405 ml, p < 0.01), transfusions higher (1.9 vs 0.7 Units, p < 0.001) and PCI higher (15.5 vs 9.5, p < 0.01) in CL. No difference in major complications. Postoperative complications, CL, OR-time and transfusions were predictive of OS in univariate analysis, while only complications remained on multivariate analysis. Median follow up of 21.4 months, 3-year DFS/OS was 22% vs 30% (p < 0.037) and 73% vs 87% (p < 0.014) in CL and non-CL, respectively. Despite CL complete resection, 17/38 patients (44.7%) that recurred had recurrence at previous CL site. CONCLUSIONS: Critical lesions complicate surgery and may be associated with poor oncological outcomes with high local recurrence rate, despite no significant difference in complications. Utilizing adjuvant or intra-operative radiation may be beneficial.

Treating sepsis with vitamin C, thiamine, and hydrocortisone: Exploring the quest for the magic elixir.

The administration of ascorbic acid (vitamin C) alone or in combination with thiamine (vitamin B1) and corticosteroids (VCTS) has recently been hypothesized to improve hemodynamics, end-organ function, and may even increase survival in critically ill patients. There are several clinical studies that have investigated the use of vitamin C alone or VCTS in patients with sepsis and septic shock or are ongoing. Some of these studies have demonstrated its safety and potential benefit in septic patients. However, many questions remain regarding the optimal dosing regimens and plasma concentrations, timing of administration, and adverse effects of vitamin C and thiamine. These questions exist because the bulk of research regarding the efficacy of vitamin C alone or in combination with thiamine and corticosteroids in sepsis is limited to a few randomized controlled trials, retrospective before-and-after studies, and case reports. Thus, although the underlying rationale and mechanistic pathways of vitamin C and thiamine in sepsis have been well described, the clinical impact of the VCTS regimen is complex and remains to be determined. This review aims to explore the current evidence and potential benefits and adverse effects of the VCTS regimen for the treatment of sepsis.

A safety evaluation of drotrecogin alfa (activated) in hematopoietic stem cell transplant patients with severe sepsis: lessons in clinical research.

We conducted an open-label, multicenter, single-arm clinical trial to investigate the safety and efficacy of drotrecogin alfa (activated) (Drot AA) in hematopoietic stem cell transplant (HSCT) patients with severe sepsis. Drot AA was administered as a continuous i.v. infusion of 24 microg/kg/h for 96 h. The target enrollment was 250 patients in 15-20 transplant centers over a 2-year period (March 2003-March 2005). However, after only 10 months, in December 2003, the trial was stopped due to a low enrollment of seven patients at three of the 15 sites that were open for accrual. Six of the seven patients completed the drug infusion. Two patients experienced serious bleeding events. The first patient developed a nonfatal diffuse alveolar hemorrhage 2 days after study-drug completion. The second patient had severe coagulopathy and developed a fatal intracranial hemorrhage on the third day of drug infusion. Three of the seven patients were alive 100 days after the HSCT. The slow enrollment rate was attributed to changes in transplant preparatory regimens, enhancements in antimicrobial prophylactic protocols and the use of antimicrobial-coated catheters. The small number of patients in this report precludes a definitive assessment of the safety and efficacy of Drot AA in HSCT patients.

A prospective randomized study of inpatient iv. antibiotics for community-acquired pneumonia. The optimal duration of therapy.

STUDY OBJECTIVE: To compare therapeutic outcome and perform a cost-benefit analysis of inpatients with community-acquired pneumonia (CAP) treated with a shortened course of i.v. antibiotic therapy. DESIGN: A prospective, randomized, parallel group study with a follow-up period of 28 days. SETTING: Bronx Veterans Affairs Medical Center (VAMC) and the Castle Point VAMC; university-affiliated VAMC general medical wards from September 1993 to March 1995. PATIENTS: Seventy-two male veterans and 1 female veteran with 75 episodes of CAP defined by a new infiltrate on chest radiograph and either history or physical findings consistent with pneumonia. Study population was 42%(31) black, 33%(24) white, and 25%(18) Hispanic. INTERVENTIONS: Patients were randomized (1:1:1) to 1 of 3 treatment groups: group 1 received 2 days of i.v. and 8 days of oral therapy; group 2 received 5 days of i.v. and 5 days of oral therapy; and group 3 received 10 days of i.v. therapy. Antibiotics consisted of cefuroxime, 750 mg every 8 h for the i.v. course, and cefuroxime axetil, 500 mg every 12 h for the oral therapy. MEASUREMENTS AND RESULTS: No differences were found in the clinical course, cure rates, or resolution of chest radiograph abnormalities among the three groups. A significant difference was found in the length of stay (LOS) among the three groups. The mean +/- SD LOS was 6 +/- 3 days in group 1, 8 +/- 2 days in group 2, and 11 +/- 1 days in group 3. The shortened LOS could potentially save $95.5 million for the Department of Veterans Affairs and $2.9 billion for the US private sector. CONCLUSIONS: Adult patients hospitalized for CAP who are not severely ill can be successfully treated with an abbreviated (2-day) course of i.v. antibiotics and then switched to oral therapy. A longer course of i.v. therapy prolongs hospital stay and cost, without improving the therapeutic cure rate.

Septic shock and multiple organ failure after hematopoietic stem cell transplantation: treatment with recombinant human activated protein C.

Severe sepsis with multiple organ failure after hematopoietic stem cell transplantation (HSCT) results in extremely high morbidity and mortality. Recent studies have highlighted the importance of sepsis-induced activation of the coagulation system in the pathophysiology of severe sepsis. Activated protein C is an important modulator of coagulation and inflammatory derangements during severe sepsis. Low levels of protein C occur in severe sepsis and are predictive of poor outcome. Recombinant human activated protein C (drotrecogin alfa (activated)) was recently approved by the Food and Drug Administration (FDA) for severe sepsis. The phase III trial that resulted in the approval of this agent, however, enrolled a general sepsis population and excluded patients undergoing HSCT. We report a case of fulminant septic shock and multiple organ failure after HSCT that was treated with drotrecogin alfa (activated) in addition to standard therapy, and recovered. The high mortality rates of patients who develop severe sepsis after HSCT demand that new avenues of treatment be considered for this very high-risk patient population. This case illustrates the potential application of a novel therapeutic approach. Clinical trials are warranted to further investigate the safety and efficacy of drotrecogin alfa (activated) in patients with severe sepsis after HSCT.

Point-of-care testing in the intensive care unit. The intensive care physician's perspective.

Technological advancements have, for the first time, made the entire laboratory testing process feasible at the bedside. Physicians working in the intensive care unit have always had immediate access to patients' medical history, physical examination, and physiologic monitoring data, but had to wait for laboratory results. Using point-of-care testing, laboratory parameters targeted to critical illnesses can now be integrated into initial diagnostic assessments, on patient rounds, and during therapeutic maneuvers. The concept of point-of-care testing in the intensive care unit is relatively new, but as technology progresses, physicians will undoubtedly become aware and use it in the intensive care unit. This article focuses on the intensive care physician's perspective on laboratory testing, the evolution of the intensive care unit laboratory, advantages of point-of-care testing in that setting, new developments in arterial blood gas analyzers and monitors, and cost-effectiveness and incorporation of point-of-care testing.

Economics of pancreatoduodenectomy in the elderly.

BACKGROUND: Managed care and the increasing percentage of surgical procedures performed in the elderly have renewed the focus on hospital charges and expenditures. The objective of this study was to determine whether septuagenarians and octogenarians accrue more hospital charges or have a higher risk of morbidity and death. METHODS: We retrospectively reviewed the charges and pertinent clinical outcomes data that were available on 70 of the last 100 pancreatoduodenectomies performed at our institution (1989 to 1994). Charges from four cost centers were analyzed and normalized to 1995 dollars by using the Consumer Price Index and Wilcoxon rank sum test. Patients were divided into two groups: group 1, 70 years of age or older (n = 21); group 2, younger than 70 years of age (n = 49). RESULTS: Anesthetic charges were $2657 +/- $835 for group 1 versus $2815 +/- $826 for group 2, which was not a statistically significant difference. Laboratory charges were $4650 +/- $3284 for group 1 versus $5969 +/- $5169 for group 2, which was not a significant difference. Pharmaceutical charges were $5424 +/- $4435 for group 1 versus $9243 +/- $9695 for group 2, which was not a significant difference. Charges for operative units were $6198 +/- $1671 for group 1 versus $7469 +/- $2116 for group 2, p < 0.02. Total charges were $41,180 +/- $20,635 for group 1 versus $50,968 +/- $33,783 for group 2, which was not a significant difference. No difference was noted in morbidity, mortality, length of stay, or survival. CONCLUSIONS: Pancreatoduodenectomy in the elderly can be performed safely without accruing higher cost, increased morbidity, or increased mortality.

The effect of various postphlebotomy storage conditions on drug levels.

Monitoring drug levels in patients is standard practice in presentday critical care medicine. Clinical laboratories, however, are often unable to assay drug levels immediately following phlebotomy. This may result in blood samples being kept under a variety of storage conditions for nonuniform periods of time. The current study evaluated the stability of eight frequently monitored medications and one of their metabolities, in whole blood and plasma, at 4 degrees C or 25 degrees C, for up to 72 hours. The drugs included antibiotics, a bronchodilator, antiarrhythmics, and an anticonvulsant. Significant changes in drug levels were not identified at the time points studied. Our data suggests that meticulous postphlebotomy handling of blood samples may not be essential to obtain accurate levels of the drugs studied.

Pancreaticoduodenectomy for metastatic tumors to the periampullary region.

Although operative resection of metastatic lesions to the liver, lung, and brain has proved to be useful, only recently have there been a few reports of pancreaticoduodenectomies in selected cases of metastases to the periampullary region. In this report we present four cases of proven metastatic disease to the periampullary region in which the lesions were treated by pancreaticoduodenectomy. Metastatic tumors corresponded to a melanoma of unknown primary site, choriocarcinoma, high-grade liposarcoma of the leg, and a small cell cancer of the lung. All four patients survived the operation and had no major complications. Two patients died of recurrence of their tumors, 6 and 63 months, respectively, after operation; the other two patients are alive 21 and 12 months, respectively, after operation. It can be inferred from this small but documented experience, as well as a review of the literature, that pancreaticoduodenectomy for metastatic disease can be considered in selected patients, as long as this operation is performed by experienced surgeons who have achieved minimal or no morbidity and mortality with it.

Factors influencing mortality and morbidity from injuries to tha abdominal aorta and inferior vena cava.

Fifty patients having undergone operation for injury to the abdominal aorta and/or vena cava at the University of Alabama Hospital are reviewed. Factors influencing mortality include mechanism and location of injury, presence of shock, associated vascular and visceral organ injuries, and delay in treatment. Rapid restoration of blood volume and control of hemorrhage are the primary goals of resuscitative measures. Only with a preconceived and coordinated plan can the surgeon fully employ the necessary skills in the management of these serious injuries.

Peritoneovenous shunt for intractable ascites of hepatic, nephrogenic, and malignant causes.

A retrospective analysis of 54 patients with a peritoneovenous shunt inserted to control massive ascites refractory to conventional medical treatment is presented. The cause of ascites was hepatic in 29 patients (Group 1, 54 percent), malignant in 13 (Group 2, 24 percent), and nephrogenic in 12 (Group 3, 22 percent). The peritoneovenous shunt failed in 11 patients (20 percent): 6 in Group 1, 3 in Group 2, and 2 in Group 3. Shunt outflow obstruction (thrombosis) was the principal cause. Systemic sepsis in five patients and variceal hemorrhage in three were the factors responsible for most of the deaths (22 percent). Of the 42 patients who survived operation, the peritoneovenous shunt was effective in controlling the massive ascites in 37 (86 percent). Eight patients (15 percent), four with hepatic and four with nephrogenic ascites, survived 3 years or more without ascites. Removal of at least 50 to 70 percent of ascitic fluid at the time of shunt insertion was considered an important factor in decreasing morbidity and mortality. A peritoneovenous shunt can be effective for a long-term period in controlling massive ascites with an hepatic or nephrogenic cause in a selected group of patients; however, in patients with malignant ascites, although the benefit was substantial in half, the survival period did not exceed 6 months.

The difficult laparoscopy.

As others have emphasized, a progressive and structured training process is necessary to understand and avoid the potential pitfalls of laparoscopy. A surgeon who is poorly trained or has minimal skills and experience finds that many cases are "difficult." Nevertheless, even those with appropriate skill and experience encounter intellectual and technical challenges in laparoscopy. It is also very important to realize that some procedures simply should not be done laparoscopically. A review of 77,604 laparoscopic cholecystectomies documented that more than half the deaths were from technical complications occurring during the procedure. Traditional methods of surgery may have their own characteristics of limitations and morbidity, but in most cases, the old operation might still be a very good one in the face of unfavorable laparoscopic conditions.

Postural kinematics of trumpet playing.

This paper examines the effects of anthropometry on body posture of trumpeters playing in standing position. Sixteen virtuosi trumpeters were photographed while hitting three notes (low C, high F and high F sustained) during performance of musical tasks. Initial standing posture and anthropometric data were recorded. Six body segment angles were computed and a vectorial sum was obtained to describe whole body posture in neutral and playing conditions. Horn angle and dental overbite were also computed. Earlier results showed that the musical task has no effect on playing posture. One-way ANOVA showed notable differences between the neutral posture and the note-related playing postures. A multiple regression model showed that in addition to the note effect, anthropometric variables, mainly neck length, explain the changes in playing posture. Horn angle is determined by the dental overbite. The importance of the anthropometric variables in playing the more demanding notes indicate that anthropometry may act to constrain trumpeters' performance.

Point of care diagnostics and networks.

The new paradigm of POCT as integrated into the ICU will allow for an improved and more efficient critical care workplace and possibly improvements in outcome and costs. Technologic advances in POCT will focus on enhancements of current devices, connectivity, and data management and on the introduction of novel diagnostic and therapeutic approaches. It is hoped that in the future the regulatory, laboratory, and L/HIS communities will recognize the need to accept, integrate, accommodate, and expand POCT, thereby promoting bedside diagnostics. For ongoing follow-up of the myriad of POCT projects, refer to the POCT websites listed in Table 1.

Point of care testing informatics. The critical care-hospital interface.

Point of care testing (POCT), a new paradigm in laboratory testing, has recently been introduced to the critical care setting. In this model, laboratory testing is performed in the critical care vicinity by local bedside personnel. POCT devices perform user selected critical care tests on whole blood in a timely and accurate fashion. The POCT data, while used immediately at the bedside, must still be managed in accordance with regulatory guidelines and incorporated into the laboratory or hospital information system. Currently, critical care physicians are not educated and trained in the intricacies of laboratory data management and device interfacing. This article addresses the technical, political, and implementation issues surrounding POCT data management and interfacing as well as the philosophical and practical differences in laboratory data management between the central laboratory and POCT sites.

Acquisition strategies for critical care technology.

Technological advances in critical care will undoubtedly find their way into the ICU of the 21st century. The challenge for critical care practitioners is to meticulously assess these innovations and adopt the most appropriate and efficient technologies that will improve unit function and staff efficiencies, support educational programs, and most importantly, enhance patient outcome at a reasonable cost. Hospital-based intensivists have excellent opportunities to establish leadership roles in the technology evaluation process by cultivating relationships with administrators, and through active participation in the hospital-based Technology Committee and the ICU-based multidisciplinary committee. The authors' experience has left them with the lasting impression that the evaluation and introduction of new technology is time consuming and requires perseverance and patience. Ultimately, it is hoped that technological breakthroughs coupled with a standardized approach to delivery of ICU services in the coming decades will ensure better and more efficient care to critically ill patients.

Bioartificial organ support for hepatic, renal, and hematologic failure.

The current strategy to the treatment of SIRS and MODS uses a multidisciplinary approach that emphasizes supportive therapy. Herein, we have presented a futuristic approach that focuses on replacing the function of failed organs using bioartificial technology (Table 1). Bioartificial organ technology may allow the intensivist to provide physiologic organ replacement either as a bridge to transplantation or as a "time-buying" element until native organs that have become acutely dysfunctional or nonfunctional in a variety of clinical settings, can recover their function or regenerate their mass. As bioartificial organ technology matures, it is conceivable as an ultimate goal that non-immunogenic bioartificial organs would be miniaturized or redesigned and acutely placed within the intracorporeal space as replacement organs.

Myocardial ischemia during the weaning period.

OBJECTIVES: To estimate the incidence of silent myocardial ischemia, its pattern over time and its relationship to the time and mode of weaning high-risk cardiac patients after noncardiac surgery. DESIGN: Prospective study with random assignment to one of three weaning modes. SETTING: A surgical intensive care unit in a university hospital and a Veterans Administration hospital. PATIENTS: Sixty-two patients meeting standard criteria for extubation were randomized to one of three modes of weaning: synchronized intermittent mandatory ventilation (n = 19), T-Bar (n = 21) or continuous positive airway pressure (n = 22). METHODS: Ischemia was monitored with a continuous two-lead (V5, III) ST segment analyzer. Tracings were reviewed by a cardiologist. Ischemia was defined as greater than 1 mm ST segment depression 60 milliseconds after the J point. The monitoring period included a prewean (mean 654.0 minutes), wean (mean 46.5 minutes) and postwean (mean 1223.4 minutes) period. RESULTS: Of 62 patients, 12 (19.3%) experienced ischemia at some time during the monitoring period, most often during the weaning period. Ischemia during weaning was detected in 3 of 21 (14.3%) T-Bar patients and 2 of 22 (9.1%) continuous positive airway pressure patients but in no synchronized intermittent mandatory ventilation patients. CONCLUSION: This study demonstrates that silent myocardial ischemia occurs frequently in high-risk postoperative patients, with the highest incidence during weaning.