Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer.

BACKGROUND: SCALOP, a randomised, phase II trial, tested the activity and safety of gemcitabine (GEM)-based and capecitabine (CAP)-based chemoradiation (CRT) for locally advanced pancreatic cancer (LAPC). Here we present the long-term outcomes. METHODS: Eligibility: histologically proven LAPC ⩽7 cm. Following 12 weeks of induction GEMCAP chemotherapy (three cycles: GEM 1000 mg m-2 days 1, 8, 15; CAP 830 mg m-2 days 1-21 q28 days) patients with stable/responding disease, tumour ⩽6 cm, and WHO Performance Status 0-1 were randomised to receive one cycle GEMCAP followed by CAP (830 mg m-2 b.d. on weekdays only) or GEM (300 mg m-2 weekly) with radiation (50.4 Gy per 28 fractions). RESULTS: One-hundred fourteen patients (28 UK centres) were registered between 24 December 2009 and 25 October 2011, and 74 were randomised (CAP-RT=36; GEM-RT=38). At the time of this analysis, 105 of the 114 patients had died and the surviving 9 patients had been followed up for a median of 10.9 months (IQR: 2.9-18.7). Updated median OS was 17.6 months (95% CI: 14.6-22.7) in the CAP-CRT arm and 14.6 months (95% CI: 11.1-16.0) in the GEM-CRT arm (intention-to-treat adjusted hazard ratio (HR): 0.68 (95% CI: 0.38-1.21, P=0.185)); median progression-free survival (PFS) was 12.0 months (95% CI: 10.0-15.2) in the CAP-CRT arm and 10.4 months (95% CI: 8.8-12.7) in the GEM-CRT arm (intention-to-treat adjusted HR: 0.60 (95% CI: 0.32-1.14, P=0.120)). In baseline multivariable model, age ⩾65 years, better performance status, CA19.9<613 IU l-1, and shorter tumour diameter predicted improved OS. CAP-CRT, age ⩾65 years, better performance status, CA19.9 <46 IU ml-1 predicted improved OS and PFS in the pre-radiotherapy model. Nine-month PFS was highly predictive of OS. CONCLUSIONS: CAP-CRT remains the superior regimen. SCALOP showed that patients with CA19.9 <46 IU ml-1 after induction chemotherapy are more likely to benefit from CRT.

Role of chemoradiotherapy in the adjuvant and neoadjuvant settings for resectable pancreatic cancer.

Pancreatic cancer is the 10th most commonly diagnosed malignancy in the USA and the fourth most common cause of cancer-related death. Worldwide, the mortality incidence ratio approaches 98%. Although only 15-20% of patients present with resectable disease, there is international consensus that complete surgical resection (R0, i.e. grossly and microscopically negative margins) is a vital part of any curative treatment paradigm. Despite advances in surgical technique, peri-operative care, chemotherapy and radiation delivery techniques over the past two decades, 5 year overall survival rates for resected pancreatic cancer with modern therapies remain around 20-25%. There is level I evidence for adjuvant chemotherapy in fully resected pancreatic cancer, but randomised trials examining the role of adjuvant chemoradiotherapy to date do not provide clear support for radiation therapy in this setting. In addition, efforts to increase the proportion of long-term survivors have recently centred on increasing the resectability of locoregional disease by incorporating neoadjuvant treatment before definitive surgery. Post-hoc analysis of randomised data as well as retrospective reviews have shown that there are several independent prognostic factors that may have considerable impact on survival outcomes, complicating interpretation and comparison of historical data. There is considerable interest in adjuvant and neoadjuvant therapy, but there is significant controversy as to whether radiation is of value, especially in the adjuvant context. Herein, we explore the sources of those controversies.

Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2b-based chemoradiation: ACOSOG Trial Z05031.

BACKGROUND: The American College of Surgeons Oncology Group sought to confirm the efficacy of a novel interferon-based chemoradiation regimen in a multicenter phase II trial. PATIENTS AND METHODS: Patients with resected (R0/R1) adenocarcinoma of the pancreatic head were treated with adjuvant interferon-alfa-2b (3 million units s.c. on days 1, 3, and 5 of each week for 5.5 weeks), cisplatin (30 mg/m(2) i.v. weekly for 6 weeks), and continuous infusion 5-fluorouracil (5-FU; 175 mg·m(2)/day for 38 days) concurrently with external-beam radiation (50.4 Gy). Chemoradiation was followed by two 6-week courses of continuous infusion 5-FU (200 mg·m(2)/day). The primary study end point was 18-month overall survival from protocol enrollment (OS18); an OS18 ≥65% was considered a positive study outcome. RESULTS: Eighty-nine patients were enrolled. Eighty-four patients were assessable for toxicity. The all-cause grade ≥3 toxicity rate was 95% (80 patients) during therapy. No long-term toxicity or toxicity-related deaths were noted. At 36-month median follow-up, the OS18 was 69% [95% confidence interval (CI) 60% to 80%]; the median disease-free survival and overall survival were 14.1 months (95% CI 11.0-20.1 months) and 25.4 months (95% CI 23.4-34.1 months), respectively. CONCLUSIONS: Notwithstanding promising multi-institutional efficacy results, further development of this regimen will require additional modifications to mitigate toxic effects.

Immunologic recovery following autologous stem-cell transplantation with pre- and posttransplantation rituximab for low-grade or mantle cell lymphoma.

BACKGROUND: Rituximab may improve transplant outcomes but may delay immunologic recovery. PATIENTS AND METHODS: Seventy-seven patients with low-grade or mantle cell lymphoma received autologous stem-cell transplantation (ASCT) on a phase II study. Rituximab 375 mg/m(2) was administered 3 days before mobilization-dose cyclophosphamide, then weekly for four doses after count recovery from ASCT. Immune reconstitution was assessed. RESULTS: Sixty percent of transplants occurred in first remission. Actuarial event-free survival (EFS) and overall survival (OS) were 60% and 73%, respectively, at 5 years, with 7.2-year median follow-up for OS in surviving patients. Median EFS was 8.3 years. Older age and transformed lymphomas were independently associated with inferior EFS, whereas day 60 lymphocyte counts did not predict EFS or late infections. Early and late transplant-related mortality was 1% and 8%, with secondary leukemia in two patients. B-cell counts recovered by 1-2 years; however, the median IgG level remained low at 2 years. Late-onset idiopathic neutropenia, generally inconsequential, was noted in 43%. CONCLUSION: ASCT with rituximab can produce durable remissions on follow-up out to 10 years. Major infections do not appear to be significantly increased or to be predicted by immune monitoring.

Phase I study of escalating doses of low-dose-rate, locoregional irradiation preceding Cytoxan-TBI for patients with chemotherapy-resistant non-Hodgkin's or Hodgkin's lymphoma.

PURPOSE: In patients in whom bone marrow transplantation (BMT) fails, recurrence often occurs at sites known to have contained disease before initiating BMT. The purpose of this study was to find the maximal tolerable dose of locoregional irradiation (LRT) between 1000 and 2000 cGy that could be integrated with our Cytoxan-total body irradiation (TBI) BMT conditioning regimen in the treatment of lymphoma. METHODS AND MATERIALS: Patients had Hodgkin's or non-Hodgkin's lymphoma in chemotherapy-refractory relapse. All patients received LRT to a maximum of three sets of fields encompassing either all current or all previously known sites of disease. Cytoxan-TBI consisted of cyclophosphamide 50 mg/kg daily for 4 days followed by TBI of 1200 cGy given in four fractions. RESULTS: Twenty-one patients were enrolled. Radiation Therapy Oncology Group Grade 3 in-field acute toxicity was observed in 1 patient at each dose level up to 1500 cGy and in 3 of 6 patients receiving 2000 cGy. Clinically evident late toxicities were limited to hypothyroidism and one second malignancy occurring outside the LRT fields. CONCLUSION: Low-dose-rate, LRT with concurrent Cytoxan-TBI before BMT has acceptable rates of in-field toxicity for doses up to 1500 cGy in five fractions. This regimen safely permits the use of a total combined radiation dose of up to 2700 cGy during 2 weeks, with encouraging in-field response rates in treatment-refractory patients.

Prostate cancer DNA ploidy and response to salvage hormone therapy after radiotherapy with or without short-term total androgen blockade: an analysis of RTOG 8610.

PURPOSE: DNA ploidy has consistently been found to be a correlate of prostate cancer patient outcome. However, a minority of studies have used pretreatment diagnostic material and have involved radiotherapy (RT)-treated patients. In this retrospective study, the predictive value of DNA ploidy was evaluated in patients entered into Radiation Therapy Oncology Group protocol 8610. The protocol treatment randomization was RT alone versus RT plus short-course (approximately 4 months) neoadjuvant and concurrent total androgen blockade (RT+TAB). PATIENTS AND METHODS: The study population consisted of 149 patients, of whom 74 received RT alone and 75 received RT+TAB. DNA content was determined by image analysis of Feulgen stained tissue sections; 94 patients were diploid and 55 patients were nondiploid. Kaplan-Meier univariate survival, the cumulative incidence method, and Cox proportional hazards multivariate analyses were used to evaluate the relationship of DNA ploidy to distant metastasis and overall survival. RESULTS: DNA nondiploidy was not associated with any of the other prognostic factors in univariate analyses. In Kaplan-Meier analyses, 5-year overall survival was 70% for those with diploid tumors and 42% for nondiploid tumors. Cox proportional hazards regression revealed that nondiploidy was independently associated with reduced overall survival. No correlation was observed between DNA ploidy and distant metastasis. The diminished survival in the absence of an increase in distant metastasis was related to a reduction in the effect of salvage androgen ablation; patients treated initially with RT+TAB and who had nondiploid tumors had reduced survival after salvage androgen ablation. CONCLUSIONS: Nondiploidy was associated with shorter survival, which seemed to be related to reduced response to salvage hormone therapy for those previously exposed to short-term TAB.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients

The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma.

PURPOSE: SMAD4 (also called Dpc4) is a tumor suppressor in the TGF-beta signaling pathway that is genetically inactivated in approximately 55% of all pancreatic adenocarcinomas. We investigated whether prognosis after surgical resection for invasive pancreatic adenocarcinoma is influenced by SMAD4 status. EXPERIMENTAL DESIGN: Using immunohistochemistry, we characterized the SMAD4 protein status of 249 pancreatic adenocarcinomas resected from patients who underwent pancreaticoduodenectomy (Whipple resection) at The Johns Hopkins Hospital, Baltimore, MD, between 1990 and 1997. The SMAD4 gene status of 56 of 249 (22%) pancreatic carcinomas was also determined. A multivariate Cox proportional hazards model assessed the relative risk of mortality associated with SMAD4 status, adjusting for known prognostic variables. RESULTS: Patients with pancreatic adenocarcinomas with SMAD4 protein expression had significantly longer survival (unadjusted median survival was 19.2 months as compared with 14.7 months in patients with pancreatic cancers lacking SMAD4 protein expression; P = 0.03). This SMAD4 survival benefit persisted after adjustment for prognostic factors including tumor size, margins, lymph node status, pathological stage, blood loss, and use of adjuvant chemoradiotherapy. The relative hazard of mortality for cancers lacking SMAD4 after adjusting for other prognostic factors was 1.36 (95% confidence interval, 1.01-1.83; P = 0.04). CONCLUSION: Patients undergoing Whipple resection for pancreatic adenocarcinoma survive longer if their cancers express SMAD4.

Increased hepatic oxidative DNA damage in patients with hepatocellular carcinoma.

Since oxidative DNA damage plays a role in experimental carcinogen-induced cancers, the purpose of the present study was to determine if hepatic oxidative DNA damage was increased in patients with HCC compared to patients with benign hepatic tumors or hepatic metastases (non-HCC) or to patients with end-stage alcoholic liver disease undergoing liver transplantation. Oxidative DNA damage was assessed by 8-hydroxy-2'-deoxyguanosine (8-OH-dG). Results showed that peritumoral 8-OH-dG was markedly increased in HCC (N= 51) (180 +/- 74 vs 32 +/- 58-OH-dG/10(6)dG for tumor, P < 0.005) in contrast to patients with non-HCC (N = 17), in whom the peritumoral 8-OH-dG did not differ from that in tumor (39 +/- 7 vs. 31 +/- 108-OH-dG/10(6)dG). Oxidative DNA damage can be both mutagenic and carcinogenic; our data suggested it will be important in future studies to determine the chronology of this type of liver injury relative to hepatocarcinogenesis.

The effects of eye and limb movements on working memory.

Three experiments examined the role of eye and limb movements in the maintenance of information in spatial working memory. In Experiment 1, reflexive saccades interfered with memory span for spatial locations but did not interfere with memory span for letters. In Experiment 2, three different types of eye movements (reflexive saccades, pro-saccades, and anti-saccades) interfered with working memory to the same extent. In all three cases, spatial working memory was much more affected than verbal working memory. The results of these two experiments suggest that eye movements interfere with spatial working memory primarily by disrupting processes localised in the visuospatial sketchpad. In Experiment 3, limb movements performed while maintaining fixation produced as much interference with spatial working memory as reflexive saccades. These results suggest that the interference produced by eye movements is not the result of their visual consequences. Rather, all spatially directed movements appear to have similar effects on visuospatial working memory.

Age-related differences in object- and location-based inhibition of return of attention.

Four experiments examined age-related differences in inhibition of return (IOR) of visual attention. Using static stimuli, both young and older adults were slower to detect targets in previously cued objects, showing equivalent IOR. With objects that moved after they had been cued, young adults were slower to detect targets in the cued object (compared with uncued ones), revealing object-based IOR, but older adults were faster to detect targets in such objects, failing to demonstrate object-based IOR. Both age groups were slower to detect targets at the initially cued location (location-based IOR). The results show that age has a differential effect on IOR depending on the frame of reference of the inhibition: Inhibition for objects breaks down with age, but that for location does not. This pattern of results is consistent with the view that there are specific inhibitory deficits in old age.

Acute and late radiotherapy toxicity in patients with inflammatory bowel disease.

PURPOSE: To evaluate the incidence of gastrointestinal complications in patients with inflammatory bowel disease (IBD) receiving radiotherapy (RT) and to identify possibly avoidable factors associated with these complications. METHODS AND MATERIALS: Twenty-four patients were identified and their records reviewed; all had a history of IBD before receiving RT to fields encompassing some portion of the gastrointestinal tract (Crohn's disease) or to the abdomen or pelvis (ulcerative colitis or IBD not otherwise specified). RESULTS: Five of 24 patients (21%) experienced Grade > or =3 acute gastrointestinal toxicity; all 5 received concurrent chemotherapy. Two of 24 patients (8%) experienced Grade > or =3 late gastrointestinal toxicity. There were no significant correlations between complications and IBD type, prior IBD-related surgery, use of medications for IBD, or status of IBD. CONCLUSION: Patients with IBD may have an increased risk for severe acute RT-related gastrointestinal complications that is more modest than generally perceived, because all patients who had Grade > or =3 acute complications in this study had received concurrent chemotherapy (p = 0.04). Further study is needed to assess this risk, as well as the impact of RT on these patients' future gastrointestinal morbidity.

Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation.

PURPOSE: Allogeneic granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines can cure established tumors in the mouse, but their efficacy against human tumors is uncertain. We have developed a novel GM-CSF-secreting pancreatic tumor vaccine. To determine its safety and ability to induce antitumor immune responses, we conducted a phase I trial in patients with surgically resected adenocarcinoma of the pancreas. PATIENTS AND METHODS: Fourteen patients with stage 1, 2, or 3 pancreatic adenocarcinoma were enrolled. Eight weeks after pancreaticoduodenectomy, three patients received 1 x 10(7) vaccine cells, three patients received 5 x 10(7) vaccine cells, three patients received 10 x 10(7) vaccine cells, and five patients received 50 x 10(7) vaccine cells. Twelve of 14 patients then went on to receive a 6-month course of adjuvant radiation and chemotherapy. One month after completing adjuvant treatment, six patients still in remission received up to three additional monthly vaccinations with the same vaccine dose that they had received originally. RESULTS: No dose-limiting toxicities were encountered. Vaccination induced increased delayed-type hypersensitivity (DTH) responses to autologous tumor cells in three patients who had received >or= 10 x 10(7) vaccine cells. These three patients also seemed to have had an increased disease-free survival time, remaining disease-free at least 25 months after diagnosis. CONCLUSION: Allogeneic GM-CSF-secreting tumor vaccines are safe in patients with pancreatic adenocarcinoma. This vaccine approach seems to induce dose-dependent systemic antitumor immunity as measured by increased postvaccination DTH responses against autologous tumors. Further clinical evaluation of this approach in patients with pancreatic cancer is warranted.

Allogeneic bone marrow transplantation in patients with sensitive low-grade lymphoma or mantle cell lymphoma.

PURPOSE: To report survival outcomes of allogeneic BMT in patients with low-grade lymphoma or mantle cell lymphoma (MCL). PATIENTS AND METHODS: Thirty-five patients with low-grade lymphoma (48%), chronic lymphocytic leukemia (26%), or MCL (26%) underwent myeloablative allogeneic BMT from HLA-identical siblings at the Johns Hopkins Oncology Center. Patients had a median age of 46 years, a median of 2 prior treatments, and 31% were in complete remission at the time of transplantation. The preparative regimen was cyclophosphamide/total body irradiation for most patients. All grafts were T-cell depleted by counter flow centrifugal elutriation with CD34+ augmentation. RESULTS: The incidence of acute GVHD grade >2 was 6% and of grades 1 to 2 was 37%. The incidence of chronic GVHD was 6%. The median follow-up time was 25 months. The rate of event-free survival (EFS) was 50% (95% confidence interval [CI], 33%-66%). Only 1 patient relapsed. The transplantation-related mortality (TRM) was 46% for all patients. The TRM was 86% for patients with resistant disease and 14% for patients with sensitive disease and <2 prior treatments; rates of EFS were 0% (95% CI, 0%-0%) and 79% (95% CI, 47%-93%), respectively. CONCLUSION: These data show that, with T-cell depletion, the TRM and relapse rates are modest for patients with sensitive disease and <2 prior treatment courses. Thus, if there is a role for allogeneic BMT in the management of patients with these tumors, it is early in the course of the disease.

Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: acceptable toxicity and suggestion of improved 1-year disease-free survival.

PURPOSE: (1) To determine the toxicity of an intensified postoperative adjuvant regimen for periampullary adenocarcinoma (pancreatic and nonpancreatic) utilizing concurrent 5-fluorouracil (5-FU), leucovorin (LV), dipyridamole (DPM), and mitomycin-C (MMC) combined with split-course locoregional external beam radiotherapy (EBRT) to 50 Gy. This was followed by 4 cycles of the same chemotherapy as adjuvant therapy. (2) To determine preliminary estimates of the overall and disease-free survival associated with the use of this regimen. (3) To compare the toxicities and early survival results of patients treated with the current regimen to those of patients who completed our prior trial of concurrent chemoradiation infusion with 5-FU/LV chemotherapy and regional nodal and prophylactic hepatic irradiation. METHODS: Postpancreaticoduodenectomy, patients received every 4 weeks bolus administration of 5-FU, (400 mg/m(2)), and LV, (20 mg/m(2), Days l-3), DPM (75 mg p.o., 4 times per day, Days 0-3, and every 8 weeks), MMC, (10 mg/m(2); maximum of 20 mg, Day l during EBRT). This was followed by 4 months of the same chemotherapy, beginning 1 month following the completion of EBRT. EBRT consisted of split-course 5000 cGy/20 fractions with a 2-week planned rest after the first 10 fractions (2500 cGy). RESULTS: From 4/96 to 6/99, 45 patients were enrolled and treated. Their experience constitutes the basis of this analysis. There were 29 patients with pancreatic cancer and 16 with nonpancreatic periampullary cancer. Seventeen patients had tumors of 3 cm or more, and 39 patients had at least 1 histologically involved lymph node. Thirteen patients had a histologically positive margin of resection. The mean time to start of treatment was 63 days following surgery. During chemoradiation therapy there were no Grade 3 or worse nonhematologic toxicities and 47% Grade 3 or Grade 4 hematologic toxicities of short duration. Following chemoradiation, during chemotherapy treatment only, there was one Grade 3 hepatic and one Grade 3 pulmonary toxicity which was nondebilitating (2% each case) and 42% Grade 3 or 4 hematologic toxicity. There were 2 episodes of neutropenic fever requiring admission and no treatment-related mortalities. One patient developed a mild case of HUS, which responded to standard management. One patient developed persistent shortness of breath (nondebilitating), and another patient had occasional dyspnea on exertion, both occurring after all therapy. The majority of patients complained of increased fatigue (Grade 1-2), greatest during the combined therapy and improving post all treatment. As of 6/23/99, 20 of 45 patients have relapsed, 13 in the liver. Twelve patients have died. Median follow-up for surviving patients is 14.3 months. Disease-free survival at 12 months following surgery is 66% (as compared to 25% in our prior study), and the median disease-free survival is 17 months (as compared to 8. 3 months in our prior study). Median survival has not yet been reached, but will be greater than 17 months. CONCLUSION: With a 14.3-month median follow-up, acute toxicity has been acceptable and manageable. Observed relapses were seen 9-13 months following surgical resection. Early survival analysis suggests a trend toward increased median disease-free survival (8.3 vs. 17 months), especially for patients with nonpancreatic periampullary adenocarcinoma.

Object-based visual attention with endogenous orienting.

In a series of experiments, we examined covert orienting using endogenous cuing, in which attention is voluntarily directed toward a peripheral location. In one experiment, subjects were cued to attend to one end of an oblong object. They then detected targets on the cued object or elsewhere. In another experiment, subjects provided judgments of the relative temporal order of two flashes after their attention had moved endogenously. In a third experiment, subjects were directed to attend to an empty spatial location and subsequently discriminated features of objects that appeared at or near the locus of attention. In each of these situations, attentional orienting was object based, in the sense that nonattended locations that were on the cued object had an advantage over nonattended locations that were not on the object. The results are discussed in terms of their implications for object-based representations and the differences between exogenous and endogenous orienting of attention.

Anatomical considerations regarding the posterior interosseous nerve during posterolateral approaches to the proximal part of the radius.

BACKGROUND: The purpose of our study was to quantify the dimensions of a surgically safe zone along the proximal part of the radius, from the posterolateral aspect. METHODS: The posterolateral approach between the anconeus and the extensor carpi ulnaris was performed in thirty-two cadaveric specimens, and the posterior interosseous nerve was exposed. Forearms were measured from the radial styloid process to the radiocapitellar joint. The distance from the capitellum to the point where the posterior interosseous nerve crossed the radial shaft and the angle between the nerve and the shaft were measured with forearms in pronation and supination. RESULTS: Pronation of the forearm allowed safe exposure of at least the proximal thirty-eight millimeters of the lateral aspect of the radius, with an average proximal safe zone of 52.0 +/- 7.8 millimeters. Supination decreased this proximal safe zone to as little as twenty-two millimeters and an average of 33.4 +/- 5.7 millimeters. The angle formed by the posterior interosseous nerve and the radial shaft in supination averaged 47.4 +/- 6.8 degrees; this decreased to 27.8 +/- 6.7 degrees with pronation. CONCLUSIONS: Approaching the lateral aspect of the proximal part of the radius is safest in pronation.

Skeletal muscle response to tenotomy.

Tenotomy is a commonly encountered clinical entity, whether traumatic or iatrogenic. This article reviews the response of skeletal muscle to tenotomy. The changes are subdivided into molecular, architectural, and functional categories. Architectural disruption of the muscle includes myofiber disorganization, central core necrosis, Z-line streaming, fibrosis of fibers and Golgi tendon organs, changes in sarcomere number, and alterations in the number of membrane particles. Molecular changes include transient changes in myosin heavy chain composition and expression of neural cell adhesion molecule (NCAM). Functionally, tenotomized muscle produces decreased maximum tetanic and twitch tension. Alterations in normal skeletal muscle structure and function are clinically applicable to the understanding of pathological states that follow tendon rupture and iatrogenic tenotomy.