William W. Pfaff

Patterns of recurrence following surgery alone for adenocarcinoma of the colon and rectum

Two hundred and eighty patients with previously untreated large bowel adenocarcinoma were retrospectively evaluated following complete primary resection to determine patterns of recurrence. One hundred and five patients (37%) subsequently developed recurrent disease. Sixty percent (63/105) presented with local recurrence alone, 14% (15/105) with concomitant local recurrence and distant metastases, and 26% (27/105) with distant metastases alone. Ninety‐two percent of local recurrences developed in structures contiguous to the operative area of the incision. The degree of tumor anaplasia and depth of tumor penetration into the bowel wall influenced the rate of local recurrence. Through 5 years, local recurrence without clinical evidence of distant metastases was the most common cause of death. Plans for adjuvant radiation therapy are discussed.

The changing causes of graft loss and death after kidney transplantation.

Background. The results of kidney transplantation have improved markedly over the last three decades. Despite this, patients still lose grafts and die. We sought to determine whether the causes of graft loss and death have changed over the last 30 years. Methods. We reviewed patients who underwent transplantation or who died between January 1, 1970 and December 31, 1999. We compared the causes of graft loss or death for three decades: 1970 to 1979, 1980 to 1989, and 1990 to 1999. Results. From January 1, 1970 to December 31, 1999, we performed 2501 kidney transplantations in 2225 patients. For the three periods, 210, 588, and 383 patients lost their grafts, respectively. Graft survival increased substantially. Graft loss occurred later after transplantation, with 36.0% losing grafts in the first year during 1970 to 1970, 22.8% during 1980 to 1989, and 11.4% during 1990 to 1999. Death with a functioning graft increased from 23.8% for 1970 to 1979 to 37.5% for 1990 to 1999. Concomitantly, rejection as a cause of graft loss fell from 65.7% for 1970 to 1979 to 44.6% for 1990 to 1999. Approximately two thirds of the patients who died after transplantation died with a functioning graft and one third died after returning to dialysis. Cardiac disease as a cause of death increased from 9.6% for 1970 to 1979 to 30.3% for 1990 to 1999. Deaths from cancer and stroke also increased significantly over the three decades from 1.2% and 2.4%, respectively, for 1970 to 1979, to 13.2% and 8.0%, respectively, for 1990 to 1999. Conclusions. The causes of graft loss and death have changed over the last three decades. By better addressing the main causes of death, cardiac disease, and stroke with better prevention, graft loss due to death with a functioning graft will be reduced.

Delayed graft function after renal transplantation.

BACKGROUND There is a strong association between delayed graft function (DGF) and reduced graft survival (GS) of cadaveric renal transplants. This study was performed to identify donor characteristics that might predict adverse outcomes. METHODS We reviewed the folders of 509 consecutive organ donors for 586 renal transplant recipients receiving grafts between 1990 and 1995. A uniform immunosuppression protocol was employed. RESULTS The factors that did not alter the rate of DGF were procurement year, local versus shared organs, donor gender, race, hypotension, serum creatinine level and trend, blood transfusions, and vasopressor use and dose. The factors that did alter the frequency of DGF were cause of death (P=0.0053), donor age (P=0.0017), cold ischemic time (P=0.0009), anastomotic time (P=0.0012), combined cold ischemic time and anastomotic time (P=0.00018), and body mass index (P=0.009). All of the factors with the exception of body mass index were of comparable import when analyzed by multiple logistic regression. One-year GS of patients without DGF was 93.2%, and the GS of those with DGF was 76.6% (P < 0.0001). However, none of the donor factors correlated with 1-year GS. Seventy-seven donors were the source of paired transplants performed by our program. Sixty percent were concordant for immediate function, 32% were discordant for DGF with equal numbers affecting the first or second graft, and in only 8% did DGF affect both grafts. CONCLUSIONS Donor factors associated with DGF were increased ischemia, donor age, and cause of death. Although there is a close association between DGF and reduced GS, there is no association between these donor factors and GS. This seeming paradox suggests that unknown variables contribute heavily to early graft outcome.

Hyperacute and acute kidney graft rejection due to antibodies against B cells

Because of the perception of its uncertain clinical significance, the B cell crossmatch is not universally performed before renal transplantation. Even though sporadic cases of hyperacute rejection associated with B cell antibodies have been reported, doubts remain in light of other studies suggesting no effect on graft survival. This report describes 4 cases of graft rejection (3 hyperacute and 1 acute) that occurred in patients with anti-B-cell antibodies specific against donor HLA-DR or DQ antigens. Absence of anti-donor class I antibodies was confirmed in all cases by 2-color flow cytometry. Strong evidence for an antibody-mediated mechanism was found in one patient with anti-class I and anti-class II antibodies in serum transplanted with a class II mismatched kidney. In this case, only anti-class II antibodies were recovered in the eluate of the nephrectomy specimen. These four cases were compiled from three different institutions over a four-year period, which confirms the infrequent occurrence of these events. While anti-class II antibodies may not always be detrimental for graft survival, these results also confirm that they have the potential to cause hyperacute or acute graft loss. We conclude that the information provided by the B cell crossmatch should be available at the time that a decision to proceed with a renal transplant is made.

Preoperative radiation therapy for clinically resectable adenocarcinoma of the rectum.

: This is an analysis of 71 patients with clinically resectable adenocarcinoma of the rectum treated with preoperative irradiation and surgery at the University of Florida from July 1975 through December 1981. Seven patients were found to have liver metastasis at surgery; six had a complete resection of their primary rectal lesion and one had an incomplete resection of the rectal tumor. The remaining 64 patients had no evidence of metastasis at the time of surgery and underwent a complete resection of their rectal cancer. In the early years of the trial, the maximum tumor dose consisted of 3000 to 3500 rad in 3.5 to 4 weeks; the dose was subsequently increased to 4500 rad in 5 weeks. Patients were taken to surgery between 2 and 11 weeks (mean, 3.5 weeks) following the completion of radiation therapy. All patients have a minimum follow-up of 3 years and 63% have a minimum follow-up of 5 years. The acute complications of treatment have been acceptable, with only one patient requiring a treatment rest for moist desquamation of the perineum. All patients completed the irradiation course and all were operated on. Pathologic examination of the surgical specimen revealed no tumor in 11%, and the incidence of positive lymph nodes was 19%, which was half the incidence of positive lymph nodes in a series of historical controls treated from 1959 to 1976 with surgery alone. Comparison of patients treated with preoperative irradiation and surgery with those treated with surgery alone revealed that the postoperative complications have been similar in incidence, distribution, and severity. There have been no postoperative deaths. The overall incidence of local-regional recurrence is 5/64 (7.8%), and the combined incidence of local-regional recurrence and/or distant metastasis is 18/64 (28%). The incidence of local-regional recurrence by preoperative dose is 3/23 (13%) for doses of 3000 to 3500 rad and 2/41 (5%) for doses of 4000 to 5000 rad. The 5-year local-regional failure rate is 3/40 (7.5%) for the group irradiated before surgery, and 39/135 (29%) for the historical controls managed by surgery alone (significance level = 0.015). The 5-year determinate disease-free survival is 27/38 (71%) for the patients irradiated before surgery, and 47/114 (41%) for the historical group of patients treated with surgery alone (significance level = 0.008).

Initially unresectable rectal adenocarcinoma treated with preoperative irradiation and surgery.

This is an analysis of 23 patients with clinically and/or surgically unresectable adenocarcinoma of the rectum on initial evaluation who were treated with preoperative irradiation and surgery between March 1970 and April 1981. All patients have had follow-up for at least 5 years. Five patients (22%) had exploratory laparotomy and diverting colostomy before irradiation. All patients were irradiated with megavoltage equipment to the pelvis at 180 rad/fraction, continuous-course technique. Total doses ranged from 3500 to 6000 rad with a mean of 4800 rad and a median of 5000 rad. All patients had surgery 2-11 weeks (mean: 4.9 weeks; median: 4 weeks) after radiation therapy. Twelve patients (52%) had lesions that were incompletely resected because of positive margins (7 patients), distant metastasis (1 patient), or both (4 patients). All of these patients died of cancer within 5 years of treatment. Eleven patients had an apparent complete excision of their rectal cancer; six patients (55%) subsequently had a local recurrence. The 5-year absolute survival rate for patients who had complete resection was 18% (2 of 11 patients). The 5-year absolute and determinate survival rates for the entire study were 9% (2 of 23 patients) and 9% (2 of 22 patients), respectively. One patient (in the incomplete resection group) died after operation secondary to sepsis and diffuse intravascular coagulation.

The crossmatch in renal transplantation : evaluation of flow cytometry as a replacement for standard cytotoxicity

Flow cytometry (FC) is increasingly being used as a crossmatch procedure in addition to the standard complement-dependent cytotoxicity (CDC) test. In fact, FC offers a number of advantages over CDC and has the potential to become the primary crossmatch technique for cadaveric donor renal transplantation. We evaluated this possibility in 230 patients crossmatched by both CDC and FC. The results showed that when the T cell crossmatch was negative by FC it was always negative by CDC, and that when the T cell results were positive by CDC (IgM antibodies excluded) they were also positive by FC. As expected, a number of tests were T cell-positive by FC but negative by CDC. A T cell CDC crossmatch was more likely to be positive when FC was positive for both T and B cells and when FC results were quantitatively higher. However, FC was unable to consistently predict a positive, dithiothreitol-resistant B cell CDC crossmatch. A policy to transplant patients with negative FC results (70% of the patients evaluated) and not to transplant sensitized patients with FC+ T cell results (10%) would allow us to make a final decision with only FC in 80% of the cases. Actual graft survival was similar for nonsensitized first-transplant candidates with positive (83%) or all patients with negative (86%) FC results. We conclude that FC is sufficient to make a final decision in most cases. Wider utilization will require improvements in the ability of FC to measure B cell antibodies and to quantitate antibodies to T cells.

Clinically resectable adenocarcinoma of the rectum treated with preoperative irradiation and surgery.

Seventy-four patients with clinically resectable adenocarcinoma of the rectum were treated with preoperative irradiation and surgery at the University of Florida between August 1975 and February 1982. All patients have been folloved for at least five years. Between 1975 and 1978, 29 patients received 3500 cGy; thereafter the dose was increased to 4000 to 5000 cGy for the remaining 45 patients. All patients were treated at 180 cGy per fraction. Following preoperative irradiation, 65 of 74 patients (88 percent) underwent complete resection of their lesions. Compared with a series of historical controls treated with surgery alone, the local recurrence rate at five years was 5 of 65 (7.7 percent)vs. 39 of 135 (29 percent) (P=.001), and the five-year absolute survival was 43 of 65 (66 percent)vs. 51 or 135 (38 percent) (P<.001). The local recurrence rate was 13 percent for patients receiving 3500 cGy and 5 percent for doses of 4000 to 5000 cGy. There was no apparent increased incidence in postoperative complications in the preoperatively irradiated patients.

Assessment of the risk for broad sensitization by blood transfusions.

The risk factors associated with the production of lymphocyte antibodies were studied by evaluating the conditions of sensitization in 73 renal failure patients and by searching for lymphocyte antibodies by flow cytometry before the induction of overt sensitization by blood transfusions. In 14 patients the lymphocytotoxic antibodies were not broadly reactive and became undetectable within 5 months. These patients were mostly first transplant candidates who received transfusions prior to the rise of panel antibody reactivity. The remaining 59 patients developed broadly reactive antibodies that persisted for longer than 5 months, regardless of whether or not they were given subsequent blood transfusions. This group was made up almost exclusively of multiparous women or patients who had previously lost a kidney graft. There were 13 patients having no lymphocytotoxic antibodies who developed broad sensitization after blood transfusions. These patients were also multiparous women or previously transplanted patients, suggesting that previous exposure to alloantigens by transplants or pregnancies appeared to be a precondition for blood transfusions to induce broad sensitization. This was confirmed by detecting lymphocyte antibodies by flow cytometry in the pretransfusion serum of 9 of the 13 patients. In contrast, patients who did not make antibodies after transfusions, or those who developed temporary responses, did not have lymphocyte antibodies in their pretransfusion specimens. These findings suggest that patients with low levels of lymphocyte antibodies, not detectable by standard cytotoxicity, are at high risk of developing broadly reactive cytotoxic antibodies after blood transfusions.

A preliminary report of diltiazem and ketoconazole. Their cyclosporine-sparing effect and impact on transplant outcome.

A prospective randomized trial was conducted to compare the effect of diltiazem (DILT) with ketocon-azole (KETO) on sparing of cyclosporine dose and renal transplant outcome. Renal allograft recipients 18 years old and older were eligible for the study. Triple immunosuppression (TRIPLE) including prednisone, azathioprine, and CsA was administered to all patients. The maintenance CsA dose varied by study group. Patients were randomized to receive one of three treatment strategies: group 1—TRIPLE (CsA 8 mg/kg/day); group 2—TRIPLE (CsA 6 mg/kg/day) + DILT (60 mg b.i.d.); group 3—TRIPLE (CsA 3 mg/kg/ day) + KETO (200 mg/day). Modification of the DILT dose was allowed as needed to effect blood pressure control in group 2 patients. Mean 1-month CsA dose reductions were 30% and 60% of controls in group 2 and 3, respectively. A continued effect over time was observed in patients administered KETO but not DILT. At 1 year patients taking KETO required an average of 77% less CsA than the average dose necessary to effect similar parent CsA blood levels when no enzyme inhibitor was used. The use of KETO and DILT for 1 year allowed for 53% and 14% reductions in CsA cost, respectively. These savings include the cost of the KETO or DILT. Serum creatinines, mean arterial pressure (MAP), and incidence of liver function abnormalities were similar throughout treatment groups. The rate of rejection, time to rejection onset, and survival (GS/PS) were not different among the groups. Fungal infections were fewer in patients treated with KETO (12%) than in controls (16%) and patients randomized to DILT (19%). KETO failed to prevent Aspergillus infection in one individual. The investigation failed to identify any harmful result of treating renal allograft recipients with either DILT or KETO for the purpose of reducing CsA expense.