Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer.

BACKGROUND: Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency [MMRd/microsatellite instability-hypermutated (MSI-H)]. A growing body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed. MATERIALS AND METHODS: This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer. RESULTS: The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79] across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low. CONCLUSIONS: The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials.

Treatment of patients with recurrent epithelial ovarian cancer for whom platinum is still an option.

BACKGROUND: Ovarian cancer remains the most deadly gynecologic cancer with the majority of patients relapsing within 3 years of diagnosis. Traditional treatment paradigms linked to platinum sensitivity or resistance are currently being questioned in the setting of new diagnostic methods and treatment options. DESIGN: Authors carried out review of the literature on key topics in treatment of recurrent epithelial ovarian cancer (EOC) when platinum is still an option; including secondary surgical cytoreduction, chemotherapy, novel treatment options, and maintenance therapy. A treatment algorithm is proposed. RESULTS: Molecular characterization of EOC is critical to help guide treatment decisions. The role of secondary cytoreductive surgery is currently being evaluated with results from Gynecologic Oncology Group (GOG) 213 and anticipated results from DESKTOP III clinical trials. Chemotherapy backbone has remained relatively unchanged but utilizing non-platinum-based regimens is under investigation. In addition, maintenance therapy with anti-angiogenic therapy and Poly (ADP-ribose) Polymerase (PARP) inhibitors has emerged as the standard of care. Novel combinations, including immunotherapy and anti-angiogenesis agents, may further change the current landscape. CONCLUSIONS: The treatment of recurrent EOC is rapidly changing. Clinical trial design will need to continue to evolve as many novel therapies move to the upfront setting. Ultimately, the treatment of patients with recurrent EOC must incorporate individual patient and tumor factors.

Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer.

Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.

Quality of life after radical trachelectomy for early-stage cervical cancer: A 5-year prospective evaluation.

OBJECTIVES: To longitudinally assess quality of life (QOL) in women undergoing radical trachelectomy for early-stage cervical cancer. METHODS: We prospectively enrolled patients with stage IA1-IB1 cervical cancer prior to undergoing radical trachelectomy to complete validated QOL instruments. These instruments included the General Health-Related QOL (SF-12), Functional Assessment of Cancer Therapy-Cervix (FACT-Cx), MD Anderson Symptom Inventory (MDASI), Female Sexual Functioning Index (FSFI), and Satisfaction with Decision scale (SWD). Instruments were filled out at baseline, postoperatively at 6weeks, 6months, 1year, and annually thereafter for 4years. RESULTS: Thirty-nine patients enrolled in the study, and 32 patients were evaluable. The scores for FSFI-arousal (p=0.0002), lubrication (p<0.0001), orgasm (p=0.006), pain (p=0.01), satisfaction (p=0.03) and total score (p=0.004) showed a significant decline at 6weeks then returned to baseline levels by 6 months. The scores for FACT-Cx functional well-being (p=0.02) and physical well-being (p<0.0001), SF-12 bodily pain (p<0.0001), physical functioning (p<0.0001), role physical (p<0.0001), role emotional (p=0.03), social functioning (p=0.002), and MDASI total (p=0.04) showed significantly worsened symptoms at 6weeks then returned to baseline by 6months. The scores for FACT-Cx emotional well-being showed significant worsening of symptoms that persisted at 6-weeks (p=0.004), 6months (p=0.007), 1year (p=0.001), 2years (p=0.002), and 4 years (p=0.03). There was no difference in SWD. CONCLUSIONS: Several quality of life assessments decline immediately postoperatively after radical trachelectomy, however, return to baseline thereafter. The long-term emotional impact of this surgery highlights a need for perioperative counseling in these patients.

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.

BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

Transcriptional activation by NF-kappaB requires multiple coactivators.

Nuclear factor-kappaB (NF-kappaB) plays a role in the transcriptional regulation of genes involved in inflammation and cell survival. In this report we demonstrate that NF-kappaB recruits a coactivator complex that has striking similarities to that recruited by nuclear receptors. Inactivation of either cyclic AMP response element binding protein (CREB)-binding protein (CBP), members of the p160 family of coactivators, or the CBP-associated factor (p/CAF) by nuclear antibody microinjection prevents NF-kappaB-dependent transactivation. Like nuclear receptor-dependent gene expression, NF-kappaB-dependent gene expression requires specific LXXLL motifs in one of the p160 family members, and enhancement of NF-kappaB activity requires the histone acetyltransferase (HAT) activity of p/CAF but not that of CBP. This coactivator complex is differentially recruited by members of the Rel family. The p50 homodimer fails to recruit coactivators, although the p50-p65 heterodimeric form of the transcription factor assembles the integrator complex. These findings provide new mechanistic insights into how this family of dimeric transcription factors has a differential effect on gene expression.

Dual progestin therapy for fertility-sparing treatment of grade 2 endometrial adenocarcinoma.

•A case of grade 2 endometrial adenocarcinoma in a young woman desiring fertility-sparing treatment•Successful conservative management of refractory endometrial adenocarcinoma with dual progestin therapy•A brief review of conservative management in endometrial adenocarcinoma.

Poor oral nutrition after allogeneic stem cell transplantation correlates significantly with severe graft-versus-host disease.

It has previously been shown that enteral nutrition has several advantages compared to parenteral nutrition (PN) in critically ill patients. The nutritional history was studied in 231 patients after allogeneic stem cell transplantation (SCT). Parenteral nutrition was given for a median of 10 (0-74) days. Patients with graft-versus-host disease (GVHD) grades III-IV received more PN (median 20, range 0-67) than patients with GVHD grades 0-II (10, 0-74, P=0.016). Eighty-five (37%) patients were not able to eat anything for a median of 4 days (1-37). We found a correlation between the number of days with no oral intake (before the diagnosis of acute GVHD) and the incidence of acute GVHD grades III-IV. In patients with 1-4 days of no oral intake, the incidence of grades III-IV acute GVHD was 6%, in those with 5-9 days it was 17%, and in those with >9 days it was 38%. On multivariate analysis, we found that more than 9 days with no oral intake was associated with acute GVHD grades III-IV (odds ratio 7.66, confidence interval 1.44-40.7, P=0.016). Poor oral intake early after SCT may be associated with an increased risk of developing severe acute GVHD.

Transcriptional regulation of rat P-450 2C gene subfamily members by the sexually dimorphic pattern of growth hormone secretion.

The onset of the sexually dimorphic pattern of GH secretion and increased hepatic GH-binding capacity in rats at puberty is temporally correlated with the developmental induction of three hepatic cytochrome P-450s with steroid hydroxylase activity, P-450 IIC11, P-450 IIC12, and P-450 IIC13, and one cytochrome P-450 with vitamin A hydroxylase activity, P-450 IIC7. In this study we demonstrate that expression of the 2C11, 2C12, and 2C13 genes is modulated by GH at the level of transcriptional initiation both in vivo and in primary cultures of adult hepatocytes. In an effort to define the minimum sequence responsible for the inductive effects of GH, we have analyzed the ability of a 0.7-kilobase fragment isolated from the 5'-flank of the 2C12 gene, including the natural promoter, to drive transcription of a 320-basepair G-less cassette in vitro. We were unable to detect any substantial difference in RNA polymerase-II-dependent transcriptional efficiency toward the 2C12 promoter between liver nuclear extracts from normal and hypophysectomized rats of both sexes. This observation supports the assumption that the sequence information contained between bases -700 and 1 is sufficient to support basal transcription of the 2C12 gene. Sequence information residing 5' or 3' of the 0.7-kilobase 5'-flank or a higher ordered chromatin structure may be necessary for the sex-specific transcriptional activation of the 2C12 gene.

Metabolic control in 131 juvenile-onset diabetic patients as measured by HbA1c: relation to age, duration, C-peptide, insulin dose, and one or two insulin injections.

Glycosylated hemoglobin A (HbA1c), considered to reflect long-term metabolic control of diabetes, was analyzed in 131 patients, aged 2 5/12-19 6/12 yr, with juvenile-onset diabetes. Using stepwise multiple regression HbA1c, fasting blood glucose and plasma 3-hydroxybutyrate were analyzed as dependent variables versus independent variables such as age of the patients, duration of the disease, level of plasma immunoreactive C-peptide (IRCP), insulin dose, and number of insulin injections (one or two) per day. HbA1c was inversely related only to IRCP concentration. A low but significant, positive correlation was found between HbA1c and the duration of diabetes. Stepwise addition of the other independent variables did not further increase the fraction of explained variance. HbA1c was also correlated with a subjective rating score of the metabolic control performed by the treating physician. Fasting plasma glucose was significantly related to HbA1c but not to any of the independent variables. Fasting 3-hydroxybutyrate showed an inverse correlation to the age of the patient. The present study showed that in juvenile-onset diabetic patients, endogenous insulin secretion as reflected by IRCP was the factor best correlated with a low level of HbA1c. After the cessation of endogenous insulin secretion, there is a progressive deterioration of metabolic control and multiple injections of insulin rather than one or two per day may be needed to reach optimal control in the patients.

CYP2C7 expression in rat liver and hepatocytes: regulation by retinoids.

Rats deficient in vitamin A express low levels of P4502C7 mRNA in the liver. Administration of all-trans retinoic acid (at-RA) or growth hormone (GH) to deficient animals only partially restored the expression whereas the combined treatment returned the P4502C7 mRNA levels to that observed in normal rats. That a retinoid is the predominant inducer of P4502C7 at the cellular level is evident from studies performed with primary hepatocytes, but it became clear that GH is a prerequisite for the vitamin A effect in vivo. The at-RA induction of P4502C7 mRNA in primary rat hepatocytes was inhibited by ketoconazole, an inhibitor of P450 activity, and by cycloheximide, blocking ongoing protein synthesis. In contrast, the at-RA induction of RAR-beta2 mRNA was not affected by any of these compounds. This could indicate previously not recognized mechanisms of at-RA action. Interestingly, at-4-oxo-RA, an at-RA metabolite formed by a P450 catalyzed reaction, also induced P4502C7 mRNA. Induction of P4502C7 mRNA by the retinoic acid receptor (RAR) selective agonist TTNPB indicated that this pathway is preferred over the retinoid X receptor (RXR) pathway. In addition, analysis of RA metabolites in liver cell extracts revealed the formation of several as yet unidentified metabolites. The formation of some of these metabolites was inhibited by ketoconazole and they could therefore constitute potential inducers of CYP2C7. We suggest that metabolism of at-RA, possibly by a P450 enzyme, is an important step in the at-RA induction of P4502C7.

Long-term effects of a factory closure: unemployment and disability during ten years' follow-up.

The consequences of a factory closure on future employment, disability and death were investigated in a 10-year prospective follow-up study in a general practice setting. The study population consisted of 85 persons who lost their jobs when a brisling sardine factory close to Bergen in Norway was shut down in 1975. The employees of a nearby "sister factory" within the same company were chosen as a control population, consisting of 87 persons. After the factory closure, the annual employment rate of the study group showed a steady rise to a maximum level of 44% within 6 years, but even after 10 years never matched the employment rate of the controls. The cumulative rates of disability pension, granted for medical conditions only, was more than three times higher in the study group than among controls from the second through the fourth year of follow-up. This excess of disabilities then stayed relatively constant at approximately 17 per 100 persons from 5 to 10 years after the shut-down. Given present days' unemployment, the results of this investigation point to the importance of acknowledging a long-term effect of job-loss on health and social readjustment.

Medical consequences of a factory closure: illness and disability in a four-year follow-up study.

The effect of a factory shut-down on sick leave and disability pensions was investigated in a four-year controlled follow-up study in a general practice setting. The study population consisted of 85 people, 72 women and 13 men, who lost their jobs when a sardine factory near Bergen in Norway was shut down in 1975. The employees of a nearby sister factory' within the same company were chosen as a control population, consisting of 87 people, 66 women and 21 men. The average amount of sick leave for the study group within the first year of follow-up showed a twofold increase compared to the controls. The rate of disability pensions, estimated by the life table method with appropriate adjustments, was more than three times higher in the study group than in the control group from the second through the fourth year of follow-up. The results of this investigation provide further evidence in support of a causal relationship between job loss and illness.

Structural and regulatory analysis of a cytochrome P450 gene (CYP2C12) expressed predominantly in female rat liver.

Cytochrome P450 15 beta is a female-specific gene product that catalyzes the hydroxylation of steroid sulfates at the 15 beta position. Isolation and analysis of the gene for rat P450 15 beta reveals nine coding exons and encompasses more than 35 kb of chromosomal DNA. The intron-exon junctions are at similar positions with the P450 genes of the II family, whose gene structure has been determined. Sequencing of about 2 kb of the 5'-flanking region indicates the presence of the Alu-like R.dre.1 repetitive sequence, a GA-rich stretch that is also found in the 5'-flanking DNA of the male-specific cytochrome P450 16 alpha gene, the enhancer octamer sequence ATGCAAAT, and three CAAAGTT repeats just upstream from the TATA box. Primer extension reveals a major and a minor transcription start site located 22 and 26 bases 5' to the translation initiation codon, respectively. This gene is developmentally regulated and transcriptional activation accounts, at least partly, for the sexually differentiated expression of cytochrome P450 15 beta.

Ischaemic heart disease mortality among men in Norway: reversal of urban-rural difference between 1966 and 1989.

OBJECTIVE: This study aimed to examine regional urban-rural differences in mortality from ischaemic heart disease, including sudden death of unknown cause (IHD/SUD) in Norway from 1966-89, for men and women aged 30-69 years. DESIGN: Analysis was based on vital statistics. Regional mortality rates were obtained by aggregating the 443 municipalities in Norway into urban, rural, and intermediate municipalities. SETTINGS AND SUBJECTS: Norway. RESULTS: In 1966-70 the age adjusted IHD/SUD mortality in the age group 30-69 years was higher in urban than in rural areas; for men by 31% (95% CI 27%, 36%) and for women by 28% (95% CI 19%, 36%). In 1986-89 the IHD/SUD mortality for men showed a reversed urban-rural gradient: it was 8% (95% CI 2%, 13%) higher in rural than in urban areas. The mortality rates for women were equal for both these aggregates. For men the results indicate that IHD/SUD mortality peaked first in urban municipalities and then, but at a lower level, in rural areas. For women there was a substantial decline in IHD/SUD mortality between 1966 and 1989, but an actual peak could not be demonstrated in any of the three aggregates during the period. The decline in IHD/SUD mortality among women was steepest in urban municipalities and least noticeable in rural municipalities, but the decline tapered off towards the end of the study period. CONCLUSION: The results confirm a phase-shifted peak in IHD/SUD mortality, which began in towns and ended in rural areas, and provides clues to the main underlying factors in the IHD epidemic at the population level.

Trends in health inequalities by educational level in a Norwegian total population study.

OBJECTIVE: To describe levels of inequality and trends in self reported morbidity by educational level in a total Norwegian county population in the mid-1980s and mid-1990s. DESIGN: Two cross sectional health surveys at an interval of 10 years in the Nord-Trøndelag Health Study, HUNT I (1984-86) and HUNT II (1995-97). SETTING: Primary health care, total county population study. PARTICIPANTS: Men and women, 25-69 years. MAIN RESULTS: There was a consistent pattern of increasing self reported health problems with decreasing educational level for three health variables: perceived health, any longstanding health problem, and having a chronic condition. A stable or slight decrease in inequalities over time was found. The prevalence odds ratio for perceived health less than good were 2.71 for men (95% confidence intervals (CI): 2.39 to 3.09) and 2.13 for women (95% CI: 1.85 to 2.46) in the first survey, 2.51 for men (95% CI: 2.27 to 2.78) and 2.06 for women (95% CI: 1.88 to 2.26) 10 years later. CONCLUSIONS: The magnitude of the socioeconomic gradients in health in this population seemed somewhat lower than in Norway as a whole and close to the average in studies from other European countries. There was a slight trend towards smaller differences despite rapid structural changes in working life, turbulence in economy, and more people experiencing unemployment.

Assessment of sports participation levels following knee injuries.

Although there are many published instruments designed to determine outcome following the treatment of knee injuries, only a few incorporate specific assessments of sports activity level and participation into the evaluation. This article reviews 3 of the most commonly used sports activity outcome instruments: the scales devised by Tegner and Lysholm, the Hospital for Special Surgery and the International Knee Documentation Committee. Problems and potential study biases that can arise with improper questionnaire design and data reduction techniques are reviewed, and recommendations are made to correct these problems. The problems identified include: (i) the failure to precisely define sports activity levels according to a specific sport and intensity of participation; (ii) the failure to sort populations according to overall intensity of athletic participation both before and after treatment; (iii) the failure to detect and sort from the population patients who return to sports and experience significant symptoms; (iv) the combination of work and sports activities into the same scale; and (v) the failure to detect alterations in sports participation caused by changes in lifestyle or non-knee-related factors. We have developed a sports assessment instrument, the Cincinnati Sports Activity Scale (CSAS). The methodology used to create this scale, its use in the assessment of return to or change in sports activities, and the assessment of specific functions of daily and sports activities, are briefly reviewed. The CSAS is based on 2 criteria: (i) the frequency of participation; and (ii) the general types of forces experienced by the lower extremity during the sport. The assessment of change in sports activities accounts for modifications in lifestyle and can also detect patients who have returned to sports but are experiencing significant symptoms and problems. Examples of data reduction and reporting are provided to represent practical situations from a prior investigation.

The structure of a factory closure: individual responses to job-loss and unemployment in a 10-year controlled follow-up study.

A prospective study has been conducted of 85 employees (72 women and 13 men) made redundant when a brisling sardine factory on the west coast of Norway was shut down in 1975. 87 employees (66 women and 21 men) in a 'sister factory' which was not shut down, were used as controls. Previous analyses have shown a substantial reduction in future employment of the study group, a two-fold increase in time consumed on sick leave during the first follow-up year, and a more than three-fold increase in the life-table based rates of disability pensions (invalidity) during the first four follow-up years compared to the controls. In this paper the follow-up data regarding six mutually exclusive and inclusive conditions related to employment and health have been analysed on a weeks per person per year basis, permitting the effects of job-loss over 10 years to be compared with what could have been expected had the factory not been closed. For those not subjected to old age pension or death, three kinds of long-term adaptation showed a marked differential effect among study subjects and controls: a substantial long-term reduction in mean time spent in job, an increase in consumption of time on disability pension, and an increase in time spent outside the labour force without social security coverage, the latter being mostly confined to women. These follow-up data provide a comprehensive picture of individual long-term adaptation to involuntary job-loss, emphasizing its effects on future employment, health, social readjustment and social security benefit consumption.

Revision anterior cruciate surgery with use of bone-patellar tendon-bone autogenous grafts.

BACKGROUND: A prospective study was done to determine the functional results, patient satisfaction, and graft failure rate after fifty-seven consecutive revision replacements of the anterior cruciate ligament with use of a bone-patellar tendon-bone autogenous graft. METHODS: Fifty-four patients (fifty-five operations) were followed in this study. Concurrent operative procedures were performed during the revision procedure in thirty-seven knees (67%). These procedures included repair of a meniscal tear in twenty knees (36%) and reconstruction of deficient posterolateral or medial ligament structures in seventeen knees (31%). Nine knees (16%) had a high tibial osteotomy to correct varus malalignment before the revision operation. The results were evaluated with the Cincinnati Knee Rating System. RESULTS: There were significant improvements in the scores for pain (p < 0.0001), activities of daily living (p < 0.01), sports participation (p < 0.001), patient satisfaction (p < 0.0001), and overall rating of the knee (p < 0.0001). Thirty-three (60%) of the replaced ligaments were functional, nine (16%) were partially functional, and thirteen (24%) had failed. CONCLUSIONS: Many knees (93%) had compounding problems, including articular cartilage damage, prior meniscectomy, loss of secondary ligament restraints, varus malalignment, and concomitant ligament replacement or meniscal repair. Therefore, the results were generally less favorable than those following primary operations. The rate of graft failure was three times higher than our previously reported failure rate after primary replacements of the anterior cruciate ligament with a bone-patellar tendon-bone autogenous graft. Even so, symptoms and functional limitations with regard to daily and sports activities were found to have decreased and patient satisfaction improved. We advocate correction of varus malalignment prior to anterior cruciate procedures. Associated posterolateral ligament deficiencies should be surgically corrected during anterior cruciate procedures to prevent excessive loading on the graft from abnormal lateral tibiofemoral joint opening. Meniscal tears, including complex tears that extend into the avascular zone, can be concurrently repaired successfully during the revision.

Reconstruction of the anterior cruciate ligament with human allograft. Comparison of early and later results.

Sixty-eight patients who had had reconstruction of an acute rupture of the anterior cruciate ligament with either a fascia lata or a bone-patellar ligament-bone allograft returned for two follow-up evaluations, at two to four years and at five to nine years (mean, seven years) postoperatively. The early (two to four-year) results in these patients have been reported previously. The mean time between the early and the later evaluation was fifty-six months (range, twenty to ninety-six months). At the early evaluation, fifty-two (78 per cent) of the sixty-seven patients who were tested with an arthrometer at eighty-nine newtons had less than three millimeters of increased anterior-posterior displacement compared with that of the contralateral limb; at the later evaluation, fifty-four (79 per cent) of the sixty-eight patients had this finding (p=0/97). With use of arthrometric and pivot-shift-test data, forty-eight (75 per cent) of sixty-four grafts were classified as functional at the early evaluation and fourteen (22 per cent), as partially functional; two (3 per cent) had failed. (Four grafts could not be classified because of incomplete data.) At the later examination, fifty (74 per cent) of the sixty-eight grafts were functional, thirteen (19 per cent) were partially functional, and five (7 per cent) had failed. At the early evaluation, sixty-two (93 percent) of sixty-seven patients had no palpable patellofemoral crepitus and five (7 per cent) had moderate crepitus. At the later evaluation, fifty-one (75 per cent) of the sixty-eight patients continued to have no crepitus, sixteen (24 per cent) had moderate crepitus, and on (1 per cent) had severe crepitus. An increase in crepitus between the early and the later evaluation was found in twelve (19 per cent) of the sixty-two patients who had normal crepitus at the early evaluation. With the numbers available, no factor, such as the type of graft, associated ligamentous injury, or meniscal repair, correlated significantly with the amount of patellofemoral crepitus at either follow-up evaluation. At the early evaluation, the result was rated excellent or good for thirty-eight (60 per cent) of sixty-three patients, fair for twenty-one (33 per cent), and poor for four (6 per cent). (The result could not be rated for four patients because of incomplete data.) At the later evaluation, the result was rated excellent or good for forty-five (66 per cent) of the sixty-eight patients, fair for eighteen (26 per cent), and poor for five (7 per cent). For nine patients (13 per cent), the over-all rating deteriorated from excellent or good at the early evaluation to fair or poor at the later examination. For six patients (9 per cent), the rating improved from fair at the early evaluation to excellent or good at the later evaluation. With the numbers available, we could detect no significant decrease in anterior-posterior displacement of the knee, patellofemoral crepitus, the pain or the jumping score, or the over-all knee rating over the time-period studied. While we currently recommend arthroscopically assisted reconstruction with a bone-patellar ligament-bone autogenous graft as the first choice for an acute rupture of the anterior cruciate ligament, our study shows that favorable results can be obtained with allografts and justifies their use when the surgeon and patient choose this approach.