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Breast implant-associated anaplastic large cell lymphoma (breast implant-associated ALCL) is a recently described, distinct clinicopathological entity associated with macrotextured breast implants. The diagnostic workup of a patient suspected to have breast implant-associated ALCL includes cytological assessment of effusions and tissue biopsies of any masses or enlarged lymph nodes, with morphologic and immunophenotypic evaluation and possible flow cytometric and molecular testing. We report the case of a woman found to have breast implant-associated ALCL on fine needle aspirate and core biopsy, who on surgical resection, had extensive local disease with involvement of the resection margins and lymph nodes, requiring systemic treatment. We focus on the flow cytometric findings that identified a population of large cells on the CD30/side scatter dot plot and whose immunophenotype was consistent with breast implant-associated ALCL, highlighting the value of flow cytometry as an adjunct to morphological and immunophenotypic evaluation.

AIMS In-situ follicular neoplasia (ISFN) occurs in approximately 2-3% of reactive lymph nodes, and is currently set apart from 'partial involvement by follicular lymphoma' (PFL). ISFN can progress to overt lymphoma, but precise parameters with which to assess this risk and its association with related diseases remain incompletely understood. The aim of this study was to explore these parameters. METHODS AND RESULTS We reviewed 11 cases of ISFN and one of PFL between 2003 and 2018. Ten patients had ISFN in the lymph nodes, and one had ISFN in the spleen. Haematoxylin and eosin and immunohistochemical stains were reviewed. Involvement of follicles by ISFN was scored with a three-tier scheme. Of five patients with low ISFN scores, one had chronic myelomonocytic leukaemia, one had mycosis fungoides, and three were free of haematopoietic disease. Among them, four are alive and one was lost to follow-up. Of the six ISFN patients with high scores, two had concurrent marginal zone lymphomas, one had concurrent diffuse large B-cell lymphoma (DLBCL), one had Castleman-like disease, one had progressive transformation of germinal centres with IgG4-related disease, and one had no haematopoietic disease; all are alive except for one who died of concurrent DLBCL. The patient with PFL developed DLBCL 7 years after diagnosis. CONCLUSIONS On the basis of this limited series, we conclude that only cases with high scores are associated with an overt lymphoma or an abnormal lymphoid process, and that scoring may be a useful parameter with which to assess the risk of associated lymphoma, and deserves further study. We also performed a comprehensive review of the literature.

At the time of intraoperative consultation, cytologic preparations including smears and imprints can be used in combination with frozen sections to increase diagnostic yield; however, these simple and rapid techniques are not adopted by all pathologists and their use varies considerably between institutions. In patients under investigation for suspected lymphoma, optimal triaging of tissue received fresh in pathology for lymphoma workup is paramount to maximize the odds of obtaining an accurate and clinically meaningful diagnosis and to avoid the need for additional procedures and delays in management, particularly in the current context in which core biopsies have become common practice as a first attempt to attain this goal. Imprint cytology is invaluable in this regard, also as these patients may not have a lymphoma but rather one of its clinical mimics. Herein, imprint cytology is used to approach fresh specimens received intraoperatively for lymphoma workup. More specifically, how these specimens are triaged for ancillary studies, such as flow cytometry, florescence in situ hybridization, or molecular analyses based on an interpretation of the touch imprints, is described. Detailed imprint cytological findings of typical benign and malignant lymphoid and nonlymphoid lesions are discussed and illustrated.

Lenalidomide maintenance following autologous stem cell transplantation (ASCT) has emerged as the preferred treatment option for newly diagnosed patients with multiple myeloma (MM). Two large rando...

Transplantation of the pancreas, although not an immediate life-saving procedure, substantially improves the quality of life for patients with type 1 diabetes mellitus and arrests or reverses its established complications. Compared with other types of solid transplantation, the scope of knowledge, experience of treating physicians, and involvement of pathologists in pancreas transplantation are perhaps less established. Nevertheless, pancreatic allografts are susceptible to ischemic injury, surgical complications, allograft rejection, and disease recurrence, and because serum markers of damage are neither specific nor sensitive, the core biopsy guides therapy. Thus, the aim of this chapter is to provide pathologists with the information and tools required to provide expert histopathologic assistance. After a brief introduction, which includes statistics, outcome, indications, and alternatives to whole pancreas transplantation, the chapter will focus on the handling and examination of core biopsies and failed allografts, and an approach to the diagnosis of surgical complications. The chapter will cover the different forms of rejection (according to the latest Banff classification) and mimics of rejection, including infection and recurrent autoimmune isletitis of diabetes. Relevant information is also provided to facilitate correlation of pathologic findings with clinical features and laboratory data.

Pathology is a specialty that bridges basic medical science and clinical practice. In the era of personalised medicine, this specialty is facing unprecedented challenges. Some of these challenges are institution-specific, while many are shared worldwide at different magnitude. This review shares our team efforts in the past 5 years, 2012–2017, to revitalise a century-old academic pathology department in three aspects: administration, clinical service and academic development. The lessons learnt and insights gained from our experience may provide guidance to leaders in pathology or in other related specialties.

A 35-year-old man presented with severe hypo-osmolar hyponatremia (serum sodium 99 mmol/L), profound nonoliguric renal failure (serum creatinine 1240 μmol/L), and nephrotic range proteinuria. Computed tomography of the abdomen revealed nephromegaly and no obstruction. The patient was admitted to the intensive care unit (ICU) and conventional hemodialysis was initiated. To avoid rapid sodium correction, we prescribed concurrent dialysate flow, a low dialysate sodium concentration, a small surface area dialyzer, and a low blood flow rate. We infused dextrose 5% water into the venous return line and adjusted the infusion rate according to hourly sodium concentration. The rate of sodium correction was 7.7 mmol/day over the first 3 days of admission. A subsequent renal biopsy revealed focal segmental glomerulosclerosis and interstitial infiltration with extranodal NK/T-cell lymphoma nasal type. The patient died of massive lower gastrointestinal bleeding secondary to lymphomatous involvement day 19 in the ICU. In the setting of acute kidney injury requiring renal replacement therapy and concomitant severe hyponatremia, it is challenging to avoid overcorrection of serum sodium. We describe several key prescription modifications to conventional hemodialysis, factors that affect sodium diffusion at the level of the dialyzer membrane, and the importance of frequent laboratory monitoring.

Osteonecrosis of the femoral head (ONFH) is a potentially devastating complication that occurs in up to 40% of young adults receiving chronic glucocorticoid (GC) therapy. Through a validated GC therapy rat model, we have previously shown that Wistar Kyoto (WK) rats exhibit a genetic susceptibility to GC-induced ONFH compared to Sasco Fischer (F344) rats. We have undertaken this study in order to investigate differences between these two strains for their bone parameters, alpha-2-macroglobulin (A2M) circulating levels and incidence of GC-induced osteonecrosis of the femoral head. WK and F344 rats were treated either with 1.5 mg/kg/day of prednisone or placebo for 6 months. Blood was taken every month. The femoral heads were harvested for histological examination to detect ONFH and analyzed with micro-computed tomography. After 3 months of GC-therapy, plasma A2M was elevated in treated rats only. GC-treated WK rats exhibited histological evidence of early ONFH through higher rates of cellular apoptosis and empty osteocyte lacunae in the subchondral bone compared to placebos and to F344 rats. Furthermore, micro-CT analysis exhibited femoral head collapse only in GC-treated WK rats. Interestingly, GC-treated F344 rats exhibited significant micro-CT changes, but such changes were less concentrated in the articular region and were accompanied histologically with increased marrow fat. These µCT and histological findings suggest that elevated A2M serum level is not predictive and suitable as an indicative biomarker for early GC-induced ONFH in rodents. Elevated A2M levels observed during GC treatment suggests that it plays role in the host reparative response to GC-associated effects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1183-1194, 2017.

Breast implants are surgically implanted by the hundreds of thousands every year worldwide for reconstructive or aesthetic purposes. Complications related to breast implants include early and late effusions that are often submitted for cytopathological analysis, particularly to exclude the possibility of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), a rare disease that generally follows an indolent clinical course, although it is becoming clearer that a subset of patients with adverse features have a poorer prognosis. Since a late-onset breast implant-associated effusion is the most common initial presentation of BIA-ALCL, cytopathological analysis of these effusions is considered the cornerstone and gold standard for rapid, efficient, reliable diagnosis and is critical for appropriate management and treatment. The National Comprehensive Cancer Network recently published clinical guidelines for the diagnosis and management of BIA-ALCL and stresses the essential role of cytopathological analysis, although it remains a matter of debate if all seromas should undergo immunocytochemistry or flow cytometry, particularly for assessment of expression of CD30 irrespective of morphological appearance on cytology. Herein, we review the current knowledge on BIA-ALCL, review the key cytological findings of reactive and malignant effusions related to breast implants, and present a comprehensive cytopathological workup with the presence of atypical cells as the key and pivotal element triggering further ancillary studies. We believe this approach will ensure appropriate and cost-effective management of effusion specimens from breast implants.

Context.—Despite advances in therapeutic and preventive measures, hematopoietic stem cell transplant recipients remain at risk for a variety of gastrointestinal and liver complications.Objective.—To detail the pathologic features of the various gastrointestinal and liver complications occurring after hematopoietic stem cell transplantation in relation to their clinical context. The specific complications covered include graft-versus-host disease, mycophenolate mofetil–induced injury, timeline of infections, neutropenic enterocolitis, gastrointestinal thrombotic microangiopathy, sinusoidal obstruction syndrome, hepatic iron overload, and the controversy around cord colitis syndrome.Data Sources.—The content of this article is based on pertinent peer-reviewed articles in PubMed, relevant textbooks, and on the authors' personal experiences.Conclusions.—The final histopathologic diagnosis requires the integration of clinical and histologic findings and the exclusion of other competing causes of injury. Review of the clinical data, including the original disease pretransplant, the type of transplant, the timing of the gastrointestinal and/or liver manifestations, the timing of the biopsy after transplant, the presence of graft-versus-host disease in other organs and sites, the list of drug regimens, and the clinical and laboratory evidence of infection, is the key to reaching the proper histologic diagnosis.

Rationale: Richter syndrome (RS) defines the transformation of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma. Although the term RS is most often reserved for transformation of CLL into diffuse large B-cell lymphoma (DLBCL), and less frequently Hodgkin lymphoma , the list of cases with more variable presentations in the literature is growing. Patient concerns: A 71-year-old Caucasian man initially consulted an otolaryngologist for a 1-year history of nasal congestion. Diagnoses: The asynchronous occurrence of 2 rare angiocentric Epstein–Barr virus (EBV)-related lymphoproliferative disorders in a patient with CLL, specifically clonally related lymphomatoid granulomatosis (LYG), and an extranodal NK/T-cell lymphoma, nasal type, are described herein. Interventions: Radiation therapy and a regimen of cis-platinum were administered for the NK/T cell lymphoma, and ibrutinib for LYG. Outcomes: The patient remains in complete clinical remission 8 years after the diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and recurrent extranodal NK/T cell lymphoma, and 2 years after the diagnosis of clonally related LYG. Lessons: Although the precise pathogenesis of RS remains incompletely understood, various molecular alterations, in particular long-term immunosuppression, may lead to RS, similar to the causal link existing between non-Hodgkin lymphomas and HIV infection, and post-transplantation lymphoproliferative disorders. EBV infection is linked to the pathogenesis of several types of lymphomas and found in a subset of patients with RS; immunosuppression, in the context of CLL or other pathological conditions or pharmacological agents, can disrupt the fine balance between virus and the host immune system, and result in EBV-driven lymphoproliferations of B-, T-, or NK-cell origin. The findings of our literature review thus suggest that such non-diffuse large B-cell lymphoma , non-Hodgkin lymphoma CLL transformations, may be considered as rare variants of RS.

A 28-year-old Caucasian female presented with a six-month history of epiphora of the right eye. Diagnostic lacrimal syringing revealed obstruction of the right nasolacrimal duct. During external dacryocystorhinostomy (DCR), the lacrimal sac had an unusual papillary appearance. Frozen sections suggested malignant lymphoid cells. Pathologic examination revealed extranodal NK/T-cell lymphoma, nasal type. Imaging revealed a mass lesion centered on the lacrimal sac. The authors describe the youngest Caucasian patient with a primary NK/T-cell lymphoma of the lacrimal sac, as well as the first case presenting with epiphora as the sole presenting symptom, reported in the literature. Extranodal NK/T-cell lymphomas rarely occur in the orbit, and are known to be rapidly growing, aggressive lesions. Despite chemotherapy, the patient succumbed to her disease twelve months after diagnosis. Lacrimal surgeons should maintain a high index of suspicion in all cases of primary nasolacrimal duct obstruction. Pre- or intra-operative clinical suspicion of malignancy in the lacrimal sac necessitates biopsy.

Auto-immune hepatitis (AIH) is a chronic progressive hepatitis of unknown aetiology whose clinical presentation ranges from asymptomatic to fulminant hepatic failure. Corticosteroids and azathioprine, which are considered standard therapy for AIH, may, however, be associated with treatment failures and toxicities. Among the alternative medications under investigation, rituximab, used to treat successfully various auto-immune disorders, has fewer side effects. We report herein the case of a 68-year-old woman who developed AIH with worsening clinical, laboratory and histological features despite high-dose prednisone. On rituximab, the patient showed rapid and dramatic clinical improvement, suggesting a therapeutic role for this medication in severe AIH. Indeed, prospective controlled studies are needed to assess and validate this role.

Background Mature teratomas, better known as dermoid cysts, are the most common ovarian neoplasms in women in the second and third decade of life. They are invariably benign, and most women are asymptomatic. Ovarian cystectomy is the preferred therapeutic option. Case A 24-year-old woman was planned for elective laparoscopic cystectomy for a suspected teratoma; operative findings led to a unilateral oophorectomy. Pathological analysis of the specimen revealed a focus of large cell lymphoma of unknown lineage arising in a mature cystic teratoma. A total body positron emission tomography (PET) scan revealed no other disease, and the patient was managed conservatively with regular follow-up. Conclusion Lymphoma in a teratoma is an excessively rare finding with only five previously reported cases. A review of the literature revealed very different theories as to its pathogenesis and management.

AIM To investigated the feasibility of using sinusoidal endotheliitis (SE) as a histological marker for liver allograft rejection. METHODS We compared the histological features of 88 liver allograft biopsies with acute cellular rejection (ACR) and 59 cases with no evidence of ACR. SE was scored as: (1) focal linear lifting up of the endothelial cells by lymphocytes with no obvious damage to adjacent hepatocytes; (2) focal disruption of the endothelial lining by a cluster of subendothelial lymphocytes (a group of > 3 lymphocytes); and (3) severe confluent endotheliitis with hemorrhage and adjacent hepatocyte loss. RESULTS The sensitivity and specificity of SE was 81% and 85%, respectively. Using SE as the only parameter, the positive predictive value for ACR (PPV) was 0.89, whereas the negative predictive value for ACR (NPV) was 0.75. The correlation between RAI and SE was moderate (R = 0.44, P < 0.001) (Figure 3A), whereas it became strong (R = 0.65, P < 0.001) when correlating SE with the venous endotheliitis activity index only. CONCLUSION Our data suggest that SE scoring could be a reliable and reproducible supplemental parameter to the existing Banff schema for diagnosing acute liver allograft rejection.

Patients with rheumatoid arthritis, whether treated or not with immunosuppressive agents including methotrexate, have an increased risk of lymphoproliferative disorders. Termed "iatrogenic immunodeficiency-associated lymphoproliferative disorders" in the 2008 World Health Organization classification of lymphoid neoplasms, they include Hodgkin and non-Hodgkin lymphomas. Composite lymphomas are rare, particularly in skin, with none reported in immunodeficiency states. We report the case of a 67 year-old woman with a long history of rheumatoid arthritis, on methotrexate treatment, who developed multiple skin lesions exhibiting a malignant infiltrate displaying both B- and T-cell phenotypes and dual clonal gene rearrangement by polymerase chain reaction, consistent with a cutaneous composite lymphoma. The patient received chemotherapy including rituximab with partial response, but the T-cell component recurred. To the best of our knowledge, this is the first case report of a cutaneous composite lymphoma in a patient with an iatrogenic immunodeficiency representing a dual challenge, diagnostic for the pathologist and therapeutic for the hematologist.

Patients with hepatocellular carcinoma (HCC) have limited curative therapeutic options. In North America, liver transplantation is one of the most commonly used curative therapies. Many potential transplant patients will be treated with another therapeutic modality to prevent local disease progression while awaiting organ donation. We present the case of 60-years old male diagnosed with HCC and awaiting liver transplantation. Prior to registration on the transplant list, the patient had a significant increase of his serum alpha-fetoprotein level. Due to his vascular anatomy and tumor location, he was not a candidate for more standard local ablative therapies. He was thus offered stereotactic radiotherapy as a bridge to liver transplantation. He received 50Gy in 5 fractions using respiratory gating. Following this, he had a complete radiological and serological response without worsening of his baseline Child-Pugh class C cirrhosis. Following transplant, 13 months later, pathological examination of the liver explant revealed only scarring at the site of radiation. This case illustrated the fact that hepatic stereotactic radiotherapy is a promising and safe treatment for patients with HCC. In selected patients, it can be a bridge to transplantation and, on its own, has the potential to induce complete pathological response in non-surgical candidates.

Multicentric Castleman's disease (MDC) is a rare herpesvirus-8-related prelymphomatous condition that may develop in patients infected with human immunodeficiency virus (HIV). Therapy for MCD is not well established and most often includes: corticosteroids, single or combined chemotherapy, anti-CD20 monoclonal antibody and antiretroviral therapy. In order to obtain a rapid and long-lasting clinical response, we are reporting on a short course of anthracycline-based chemotherapy associated with rituximab in HIV-positive patients with MCD. Our study suggests that the combined immuno-chemotherapy approach may represent a valid strategy with acceptable toxicity in patients with severe and extensive MDC. Further studies will be needed to assess the efficacy and safety of such an approach, and to identify risk factors predictive of long-term tolerance in HIV patients with different degrees of immunosuppression.

Hematopoietic stem cell transplantation offers patients the only prospect of long-term survival for a substantial variety of otherwise incurable malignant neoplasms as well as selected non-neoplastic conditions. This therapeutic modality, however, carries significant risks and is associated with a wide range of complications affecting not only the bone marrow but many organ systems, in particular by graft-versus-host disease. Patients before, during, and following stem cell transplantation thus require close monitoring and the pathologist is frequently implicated in this process. The aim of this chapter is to provide the pathologist with the tools required to interpret biopsies from these patients at all stages of the transplantation process. Following an overview of hematopoietic stem cell transplantation and graft-versus-host disease, the chapter will focus on the histopathologic findings of graft-versus-host disease and other complications in several organs and tissue including bone marrow, skin, lung, kidney, gastrointestinal tract and liver, with emphasis on the diagnostic criteria and approaches to graft-versus-host disease.

Patients who have undergone solid organ or hematopoietic stem cell transplants are at an increased risk for developing a wide array of cancers, particularly lymphomas. In recent years, as the number of transplant recipients has been increasing and long-term survival rates improving, the incidence of posttransplant malignancy has risen. These patients often present with a more challenging clinical scenario than immunocompetent cancer patients because they must bear the additional burden of immunosuppression and its deleterious consequences. Since these neoplasms are usually more aggressive clinically than those occurring in their non-transplant counterparts, they warrant rapid diagnostic and therapeutic interventions. This chapter highlights the malignancies associated with both solid organ and hematopoietic stem cell transplants.

Osteonecrosis of the femoral head (ONFH) is a potentially devastating complication that occurs in up to 40% of young adults receiving chronic glucocorticoid (GC) therapy. Through a validated GC therapy rat model, we have previously shown that Wistar Kyoto (WK) rats exhibit a genetic susceptibility to GC-induced ONFH compared to Sasco Fischer (F344) rats. We have undertaken this study in order to investigate differences between these two strains for their bone parameters, alpha-2-macroglobulin (A2M) circulating levels and incidence of GC-induced osteonecrosis of the femoral head. WK and F344 rats were treated either with 1.5 mg/kg/day of prednisone or placebo for 6 months. Blood was taken every month. The femoral heads were harvested for histological examination to detect ONFH and analyzed with micro-computed tomography. After 3 months of GC-therapy, plasma A2M was elevated in treated rats only. GC-treated WK rats exhibited histological evidence of early ONFH through higher rates of cellular apoptosis and empty osteocyte lacunae in the subchondral bone compared to placebos and to F344 rats. Furthermore, micro-CT analysis exhibited femoral head collapse only in GC-treated WK rats. Interestingly, GC-treated F344 rats exhibited significant micro-CT changes, but such changes were less concentrated in the articular region and were accompanied histologically with increased marrow fat. These µCT and histological findings suggest that elevated A2M serum level is not predictive and suitable as an indicative biomarker for early GC-induced ONFH in rodents. Elevated A2M levels observed during GC treatment suggests that it plays role in the host reparative response to GC-associated effects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1183-1194, 2017.

Pulmonary artery occlusion stimulates angiogenesis in the systemic circulation of the ipsilateral lung and increases systemic- to-pulmonary blood flow. Whether this systemic neovascularization decreases after lung revascularization is unknown.To assess the influence of lung revascularization on anatomy and flow of bronchial vessels supplying a chronically ischemic lung in piglets.Piglets were studied before (control) and 5 wk after left pulmonary artery ligation and 5 wk after left pulmonary artery reimplantation into the pulmonary artery trunk. The systemic blood flow to the right and left lungs was measured using colored microspheres, and the bronchial vasculature was assessed using light-microscopic morphometry. Renal and total blood flow, systemic blood pressure, and pulmonary blood pressure were measured in each experimental condition.Systemic blood flow to the left lung increased from 0.4 +/- 0.1 to 11.5 +/- 3.8 ml/min/g (p0.05) after left pulmonary artery ligation and returned toward the control value (1.2 +/- 0.6 ml/min/g) after revascularization, whereas it remained unchanged in the right lung. The number of bronchial vessels increased twofold in the ligated lung (p = 0.01), and did not decrease after reperfusion; however, vessel diameters decreased markedly. Renal and total blood flows, as well as mean pulmonary and systemic arterial pressures, were similar in the three experimental conditions.Revascularization after a period of left pulmonary artery occlusion normalizes the systemic blood flow to the left lung and induces partial loss of collateral vessels.

Objectives Pulmonary vascular resistance decreases dramatically after pulmonary thromboendarterectomy and further improves in time. This may reflect the slow regression of postobstructive pulmonary vasculopathy. We hypothesized that postobstructive pulmonary vasculopathy may regress after reperfusion in a piglet model of chronic (5 weeks) left pulmonary artery obstruction. Methods The ligated left pulmonary artery was reimplanted into the pulmonary arterial trunk. Pulmonary artery blood flow and pressure were measured 2 days and 5 weeks after reperfusion. Pulmonary artery smooth muscle thickness, endothelium-dependent relaxation, and left lung endothelial nitric oxide synthase activity and expression were assessed 5 weeks after ligation (n = 10) and 5 weeks after reperfusion (n = 10), and compared with a sham group (n = 10). Patency of the anastomoses and systemic blood supply to the lung were assessed by pulmonary angiography and nonselective thoracic aortography, respectively. Results Angiography showed that pulmonary artery anastomoses were patent in all animals. Five weeks after reperfusion, left pulmonary blood flows were similar to those in the sham animals, and systemic blood supply to the left lung decreased. Left pulmonary vascular resistance decreased by 50% at 5 weeks after reperfusion compared with 2 days after reperfusion ( P = .0009). Medial muscle thickness of the left pulmonary artery greater than 600 μm increased 5 weeks after ligation and regressed to sham values 5 weeks after reperfusion ( P = .001). Endothelium-dependent relaxation was only partially restored 5 weeks after reperfusion, whereas left lung endothelial nitric oxide synthase expressions and activities returned to sham values. Conclusions This study shows that postobstructive pulmonary vasculopathy induced by ligation of the pulmonary artery for 5 weeks regresses after reperfusion, accounting for the progressive improvement in hemodynamics after thromboendarterectomy.

Over 30 years ago, the Vietnam War established the current standard use of isotonic crystalloid fluids (normal saline [NS] and Ringer’s lactate [RL]) for the resuscitation of hemorrhagic shock. Subsequent studies have demonstrated that crystalloids represent an effective and inexpensive means to restore intravascular volume and additionally offer a survival advantage over colloids in the resuscitation of traumatic hemorrhagic shock. 1 More recently, “small volume resuscitation”2 with 4 mL of 7.5% NaCl per kilogram of body weight of hypertonic saline (HTS) has been proposed in the treatment of hemorrhagic shock. Whereas isotonic fluid administration requires large volumes, hypertonic resuscitation offers the advantages of ease of transport, speed of administration, and almost instantaneous hemodynamic effect. The intravascular administration of 7.5% NaCl rapidly creates a potent transcapillary osmotic gradient causing intravascular movement of water from the interstitium, endothelial cells (ECs), and red blood cells, a process that could reduce third-space fluid sequestration in the lungs of patients with traumatic pulmonary contusions or in the brain following head trauma. 3 Early animal studies showed that HTS resuscitation rapidly restored mean arterial pressure (MAP), peripheral tissue perfusion, cardiac contractility, and oxygen consumption, mainly through vasodilatation of precapillary resistance vessels and increases in cardiac preload. 4–6 Although large multicentric randomized human clinical trials subsequently confirmed that HTS resuscitation was safe and efficacious, they failed to demonstrate a clear survival advantage over standard isotonic resuscitation. 4,7 Nonetheless, one multicentric randomized control trial has demonstrated fewer postresuscitation complications, such as ARDS, renal failure, and coagulopathies, with the use of HTS. 4 Many of the complications following the resuscitation of hemorrhagic shock may be related to alterations in host immunity. In particular, the polymorphonuclear neutrophil (PMN), one of the principal host immune effector cells, has been implicated in the development of organ dysfunction and death following sepsis, burns, and multiple trauma as well as hemorrhagic shock resuscitation. 8–10 Although the PMN is essential in protecting the host from traumatic and infectious insults, it may also turn its potent defenses inappropriately against the host, activated by and contributing to the severity of injury. The sequential events in the passage of PMNs from the vasculature to their sites of action have been well characterized. First marginating to the periphery of the vessel, the PMN rolls on the vessel wall, interacting with ECs through surface selectins (L, E, and P). 11 These weak interactions allow PMN β2-integrins (CD18/CD11) to strongly interact with endothelial receptors of the Ig superfamily (ICAM-1, ICAM-2), 12 resulting in firm adhesion of the two cell types and permitting subsequent PMN diapedesis between ECs to reach the injured site. 13 The inappropriate upregulation of these PMN–EC interactions in the ischemia/reperfusion injury of hemorrhagic shock resuscitation is believed to be an important step in the host’s progression to systemic inflammation and subsequent remote organ injury. There are data suggesting that activated PMNs are then sequestered in end organs, where they unleash a cytotoxic arsenal of proteases and oxygen radicals, causing injury to endothelium and resulting in vascular leakage, tissue edema, and eventually organ damage. 8,10,14 Much evidence now exists demonstrating that HTS resuscitation of hemorrhagic shock alters PMN activity. When human PMNs are incubated in hypertonic media, they display decreased cytotoxicity, cellular activation, superoxide production, and elastase release. 15–19 In vivo studies suggest that both neutrophil and endothelial adhesion molecule expression is reduced in HTS-resuscitated animals as compared to those receiving RL. 15,20–22 These alterations in adhesion molecules suggest that HTS may impart functional changes in PMNs and ECs. More importantly, animal models of hemorrhagic shock resuscitated with HTS have shown reductions in lung and liver injury, diminished bronchioalveolar lavage PMNs, and diminished pulmonary myeloperoxidase (MPO - total PMN content) as well as decreases in mortality. 15,21,23 Models of hemorrhagic shock resuscitation studied with intravital microscopy suggest that the beneficial effects of HTS may be due to altered EC–PMN interactions. 24–26 However, the consequences of such altered EC–PMN interactions following HTS resuscitation of hemorrhagic shock remain elusive, and the links to altered adhesion molecule expression and to subsequent tissue edema are unclear. We thus hypothesized that through diminished endothelial ICAM-1 expression, HTS resuscitation of hemorrhagic shock lessens venular EC–PMN interactions, leading to decreased in vivo vascular leakage in remote organs. We tested this hypothesis in a murine model of resuscitated hemorrhagic shock using intravital microscopy of cremaster muscle.

PURPOSE: Downstaging rectal carcinoma by preoperative radiotherapy decreases local recurrence, and recent phase II studies suggest that, in the lower one-third lesions, sphincter-preserving surgery can be considered. The purpose of the current study was to assess the efficacy and the toxicity of endorectal high dose-rate brachytherapy as a preoperative downstaging treatment modality. METHODS: Patients with newly diagnosed invasive rectal adenocarcinoma, T2 to very early T4, operable tumors were eligible. A dose of 26 Gy was given over four consecutive daily treatments of 6.5 Gy prescribed at the tumor radial margin using endorectal brachytherapy with high dose-rate delivery system. Surgery as planned initially was done four to eight weeks later to allow for tumor downstaging. Patients found to have pathologic positive nodes received postoperative external beam (45 Gy/25 fractions) to the pelvis and systemic 5-fluorouracil-leucovorin chemotherapy. RESULTS: Forty-nine patients entered the study. Tumors were in the lower one-third in 24 patients, middle one-third in 22, and upper one-third in 3. With preoperative endorectal ultrasound and magnetic resonance imaging, the clinical staging of the tumors was: 3 T2, 42 T3, 4 T4, and 16 N1–2. Acute toxicity related to brachytherapy was limited to a moderate proctitis (Radiation Therapy Oncology Group acute toxicity scoring system, Grade 2) in all patients, with two patients with tumors extending into the anal canal having Grade 3 dermatitis. Forty-seven patients underwent surgery. Two patients refused their operation based on a normal endoscopic rectal ultrasound after treatment. A complete clinical response was obtained in 32 of 47 (68 percent) patients with 32 percent pathologically pT0N0–1, and 36 percent had only residual microfoci of carcinoma. The surgical approaches did not yield more complications than expected. CONCLUSION: Preoperative high dose-rate endorectal brachytherapy seems to be safe, because acute toxicity was mainly local, with moderate proctitis (Grade 2) and occasional dermatitis (Grade 3) for very low tumors. Finally, this modality, by providing high rate of tumor downstaging and downsizing especially for patients with lesions in the lower one-third of the rectum, represents a definite potential for sphincter-preserving surgery for investigation in future studies.

A 26-year-old man with a prior history of acute leukemia that was treated with a stem cell transplant (SCT) was referred for an F-18 FDG PET/CT to assess suspicious new gastric mucosal lesions. The lesions were FDG-avid and were histologically proven to be acute lymphoblastic leukemia (ALL). Extramedullary relapse of ALL after SCT is very rare, with only 60 cases reported in the literature, and the role of F-18 FDG PET/CT in monitoring for ALL relapse following SCT has not been previously investigated. This rare case report highlights the use of F-18 FDG PET/CT in staging gastric relapse of ALL following SCT.

BACKGROUND Delayed graft function (DGF) and slow graft function (SGF) are a continuous spectrum of ischemia-reperfusion-related acute kidney injury (AKI) that increases the risk for acute rejection and graft loss after kidney transplantation. Regulatory T cells (Tregs) are critical in transplant tolerance and attenuate murine AKI. In this prospective observational cohort study, we evaluated whether pretransplantation peripheral blood recipient Treg frequency and suppressive function are predictors of DGF and SGF after kidney transplantation. METHODS Deceased donor kidney transplant recipients (n=53) were divided into AKI (n=37; DGF, n=10; SGF, n=27) and immediate graft function (n=16) groups. Pretransplantation peripheral blood CD4CD25FoxP3 Treg frequency was quantified by flow cytometry. Regulatory T-cell suppressive function was measured by suppression of autologous effector T-cell proliferation by Treg in co-culture. RESULTS Pretransplantation Treg suppressive function, but not frequency, was decreased in AKI recipients (P

Chronic ligation of one pulmonary artery results in pulmonary vascular remodeling and bronchial angiogenesis, collectively known as postobstructive pulmonary vasculopathy (POPV). To investigate pulmonary vascular reactivity in POPV, we ligated the left main pulmonary artery of guinea pigs and, after 1-10 mo, prepared explants by inflating lungs with agarose and sectioning them into approximately 1-mm-thick slices; we measured areas of pulmonary vessels and determined contractile responses to histamine and serotonin (5-HT) and relaxant responses to ACh and sodium nitroprusside. We found maximal contractions of arteries to 5-HT (24. 4 +/- 2.6%) and of veins to histamine (53.9 +/- 4.7%) were significantly increased in POPV of 3-mo duration compared with those of controls (16.8 +/- 1.5 and 40.8 +/- 5.0%, respectively). Relaxation of arteries with ACh was enhanced at 10 mo but not at 1 mo after ligation. Relaxation with sodium nitroprusside was increased in veins at 1 mo after ligation but was not altered in arteries. Morphometry revealed reduced diameters of arteries and veins without increased medial thickness. Our data suggest that the enhanced contractile responses of pulmonary vessels to histamine and 5-HT in POPV were not a result of endothelial dysfunction or of structural alterations but might be caused by as-yet-undiscovered mechanisms.

Acute respiratory distress syndrome (ARDS) was first described about 30 years ago. Modern definitions and statements have recently been proposed to describe ARDS accurately, but none is perfect. Diffuse alveolar damage is the basic pathological pattern most commonly observed in ARDS, and the term includes permeability edema. The alveolar epithelium of the alveolar-capillary barrier is clearly a key component requiring repair, given its multipotent functional activity. Lung inflammation and neutrophil accumulation are essential markers of disease in ARDS, and a wide variety of pro- and anti-inflammatory cytokines have been described in the alveolar fluid and blood of patients. These molecules still have to prove their value as diagnostic or prognostic biomarkers of ARDS.Supportive therapy in ARDS improved in the past decade; mechanical ventilation with lung protective strategies and patient positioning are gaining interest, but the indications for corticosteroids for ARDS are still debated. Nitric oxide may have a place in the treatment of one-third of patients. Novel approaches, such as surfactant replacement and liquid ventilation, may further improve supportive therapy. Innovative interventions may be on the horizon in treatments that help to resolve or modulate common pathways of ARDS, such as inflammation (eg, granulocyte-colony stimulating factor) or epithelial repair (eg, keratinocyte growth factor).

1. The mechanisms by which histamine and 5-HT differentially contract pulmonary arteries and veins are unclear. In lung explants from 26 guinea-pigs, we compared responses of pulmonary arteries and vein to histamine, 5-HT and KCI, and examined potential determinants for the differential responses. Lungs were filled with agarose, sectioned into approximately 1 mm thick slices, and vascular luminal areas measured by image analysis. 2. Histamine and 5-HT produced a concentration-dependent constriction in arteries and veins, greater in the latter. KCl constricted arteries and veins equally. 3. The histamine H1 antagonist chlorpheniramine (10(-4) M) abolished contractions to histamine; the H2 antagonist cimetidine enhanced maximal responses and sensitivity of arteries and veins to histamine, and diminished the differences between their maximal responses; the NO synthase inhibitor Nomega-nitro-L-arginine (L-NOARG) increased the maximal responses of arteries and veins, and the differences between their responses; indomethacin had no effect. 4. Contractions to 5-HT were abolished in arteries and markedly reduced in veins by the 5-HT2 antagonist ketanserin (10(-4) M); L-NOARG potentiated the maximal responses of arteries but not of veins; indomethacin increased the maximal responses of arteries but reduced them in veins. 5. By morphometry, arteries had a greater medial thickness and luminal diameter than veins. 6. The data suggest that in guinea-pigs, H2 receptors are responsible for the differential contractile responses of pulmonary arteries and veins to histamine, whereas endothelium-derived vasoactive substances are responsible for their differential contractile responses to 5-HT.

Idiopathic pulmonary fibrosis (IPF) is characterized by an alveolitis with epithelial and endothelial damage progressing to fibrosis. Numerous mediators have been implicated in this complex process. Studies in humans have shown that endothelin-1 (ET-1), a vasoconstrictor and mitogenic peptide, is a mediator in IPF. To determine the role of ET-1 and endothelin-converting enzyme (ECE)-1 and the effect of Bosentan, an ET receptor antagonist, in an animal model of IPF, we studied three groups of rats (n = 6 each): Group 1, control, received saline; Group 2, fibrosis, received 1.5 U bleomycin intratracheally; Group 3, fibrosis-Bosentan treated, received bleomycin and Bosentan daily by gavage. After 28 d, right upper lobes were fixed for immunohistochemistry (IHC) and sections were stained with antisera to ET-1 and ECE-1 and graded semiquantitatively. Sections from left lungs were embedded in paraffin and stained for light microscopic morphometry to quantitate the fibrosis. By IHC, we found increased ET-1 immunoreactivity (ir) in airway epithelium and inflammatory cells, and ECE-1-ir in airway epithelium, type II pneumocytes and endothelial cells (p < 0.05). By morphometry, the volume fraction (Vv) of connective tissue (CT) increased and the Vv of air decreased in the fibrosis group compared with that in the control group. Bosentan reduced the Vv of CT and increased the Vv of air compared with that in the fibrosis group (p < 0.05). These results indicate that ET-1 is involved in the pathogenesis of pulmonary fibrosis in the rodent model and that blockage of its receptors reduces the fibrosis.

Background : Numerous studies of treatment for Hodgkin's disease have demonstrated large increases in the incidence of leukemia in the early years following chemotherapy, although the duration of effect and the specific agents involved are not well understood. Also, some, but not all, studies have indicated that the incidence of certain solid tumors increases following treatment for Hodgkin's disease. Purpose : We studied the association between treatment for Hodgkin's disease and the incidence of second cancers. Methods : We conducted a study within a cohort that included 10 472 patients from 14 cancer centers in the United States and Canada who were first diagnosed as having Hodgkin's disease at some point from 1940 through 1987. Discounting the 1st year after diagnosis, the average length of follow-up was 7.1 years per subject. Results : We observed 122 leukemias and 438 solid tumors. The relative risk (RR) of leukemia following chemotherapy, compared with no chemotherapy, was 14 (95% confidence interval [CI] = 5.6-35). Increased risks of leukemia were observed after treatment with chlorambucil (RR = 2.0 ; 95% CI = 1.1-3.6), procarbazine (RR = 4.9 ; 95% CI = 2.6-9.1), vinblastine (RR = 1.7 ; 95% CI = 1.1-2.8), and a group of rarely used drugs that included methotrexate, vindesine, etoposide, and 22 others (RR = 3.8 ; 95% CI = 1.9-7.4). RRS were also estimated for various combinations of drugs, including MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) (RR = 5.9 ; 95% CI = 2.9-12) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (RR = 1.5 ; 95% CI = 0.7-3.4). The RR of leukemia associated with splenectomy was 1.6 (95% CI = 1.0-2.5). The RR of solid tumors following chemotherapy was 1.4 (95% CI = 1.1-1.8). For the group of rarely used drugs, the RR of solid tumors was 3.1 (95% CI = 1.7-5.8). Chemotherapy was associated with an increased risk of cancers of the bones, joints, articular cartilage, and soft tissues (RR = 6.0 ; 95% CI = 1.7-20), and cancers of the female genital system (RR = 1.8 ; 95% CI = 1.1-3.2). In patients followed for 10 or more years after radiotherapy, increased risks were found for cancers of the respiratory system and intrathoracic organs (RR = 2.7 ; 95% CI = 1.1-6.8) and for cancers of the female genital system (RR = 2.4 ; 95% CI = 1.1-5.4). Conclusions : Procarbazine, chlorambucil, and vinblastine are associated with increased leukemia risk. Combination drug regimens have leukemogenic effects estimated as the product of RRs for individual drugs. Chemotherapy and radiotherapy increase the risk of selected solid tumors, and the effect of chemotherapy on solid tumor risk is weaker than the leukemogenic effect. Implications : Without doubt, the benefits of treatment of Hodgkin's disease outweigh the risk of a subsequent malignancy, but data on the carcinogenic effects of radiation and drugs beyond 10 years after treatment continue to be sparse, and future analyses should be directed at long-term survivors. [J Natl Cancer Inst 87 :732-741, 1995]

The liver is a major site of metastasis for human malignancies, yet the factors that regulate tumor cell survival and growth in this organ remain elusive. Previously, we reported that M-27(IGF-IR) murine lung carcinoma cells with ectopic insulin-like growth factor-1 (IGF-I) receptor overexpression acquired a site-specific, liver-metastasizing potential. Gene expression profiling and subsequent RNA and protein analyses revealed that this was associated with major changes to the expression of extracellular matrix (ECM) protein-encoding genes including type III, IV and XVIII collagen genes, and these changes were also observed in the respective tumors in vivo. Because type IV collagen was the most prominently altered ECM protein in this model, we further analyzed its functional relevance to liver metastasis. M-27 cells stably overexpressing type IV collagen α1 and α2 chains were generated and their growth and metastatic properties investigated. We found that these cells acquired a site-selective growth advantage in the liver and this was associated with cell rescue from anoikis in a collagen IV/α2 integrin/FAK-dependent manner and increased responsiveness to IGF-I. Conversely, collagen IV or focal adhesion kinase (FAK) silencing by small-interfering RNA in highly metastatic tumor cells enhanced anoikis and decreased liver metastases formation. Moreover, analysis of human surgical specimens revealed uniformly high collagen IV expression in 65/65 hepatic metastases analyzed, regardless of tissue of origin, whereas it was variable and generally low in 50/50 primary colorectal carcinoma specimens examined. The results suggest that collagen IV-conveyed signals are essential cues for liver metastasis in diverse tumor types and identify mediators of collagen IV signaling as potential therapeutic targets in the management of hepatic metastases.

Pulmonary hypertension is characterized by an increase in vascular tone or an abnormal proliferation of muscle cells in the walls of small pulmonary arteries. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide with important mitogenic properties. It has therefore been suggested that endothelin-1 may contribute to increases in pulmonary arterial tone or smooth-muscle proliferation in patients with pulmonary hypertension. We studied the sites and magnitude of endothelin-1 production in the lungs of patients with various causes of pulmonary hypertension.We studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridization) in lung specimens from 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6), and 17 patients with secondary pulmonary hypertension and pulmonary arteriopathy of grades 1 through 3.In the controls, endothelin-1-like immunoreactivity was rarely seen in vascular endothelial cells. In the patients with pulmonary hypertension, endothelin-1-like immunoreactivity was abundant, predominantly in endothelial cells of pulmonary arteries with medial thickening and intimal fibrosis. Likewise, endothelin-1 messenger RNA was increased in the patients with pulmonary hypertension and was expressed primarily at sites of endothelin-1-like immunoreactivity. There was a strong correlation between the intensity of endothelin-1-like immunoreactivity and pulmonary vascular resistance in the patients with plexogenic pulmonary arteriopathy, but not in those with secondary pulmonary hypertension.Pulmonary hypertension is associated with the increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endothelin-1 may contribute to the vascular abnormalities associated with this disorder.

Postobstructive pulmonary vasculopathy (POPV) is produced by chronic ligation of one pulmonary artery and results in bronchial collateral vessel proliferation and pulmonary arterial abnormalities. The role of endothelin-1 (ET-1), a potent vasoconstrictor peptide, was investigated in a canine model of POPV using radioimmunoassay and immunohistochemistry. The left main pulmonary artery of 9 dogs was ligated, and 3 months (n = 3) and 15 months (n = 6) later, ET-1 levels were measured by radioimmunoassay of plasma samples from left and right pulmonary arteries and veins. In addition, tissues from control and ligated lungs were fixed in Bouin's solution embedded in paraffin and stained with antiserum to ET-1. Plasma ET-1 levels distal to the ligation were not different from those of the control pulmonary artery (1.7 pg/ml in the ligated lungs vs. 1.4 pg/ml in the controls; NS). ET-1-like immunoreactivity was localized mainly to the epithelium in both control and ligated lungs, but the pulmonary arteries and the new bronchial vessels stained more intensely in the ligated lungs. The sections immunostained with ET-1 antiserum preabsorbed with synthetic ET-1 did not stain. These results suggest that ET-1 may play a role in the bronchial neovascularization and the pulmonary arterial thickening characteristic of POPV.

Patients with hepatocellular carcinoma (HCC) have limited curative therapeutic options. In North America, liver transplantation is one of the most commonly used curative therapies. Many potential transplant patients will be treated with another therapeutic modality to prevent local disease progression while awaiting organ donation. We present the case of 60-years old male diagnosed with HCC and awaiting liver transplantation. Prior to registration on the transplant list, the patient had a significant increase of his serum alpha-fetoprotein level. Due to his vascular anatomy and tumor location, he was not a candidate for more standard local ablative therapies. He was thus offered stereotactic radiotherapy as a bridge to liver transplantation. He received 50 Gy in 5 fractions using respiratory gating. Following this, he had a complete radiological and serological response without worsening of his baseline Child-Pugh class C cirrhosis. Following transplant, 13 months later, pathological examination of the liver explant revealed only scarring at the site of radiation. This case illustrated the fact that hepatic stereotactic radiotherapy is a promising and safe treatment for patients with HCC. In selected patients, it can be a bridge to transplantation and, on its own, has the potential to induce complete pathological response in non-surgical candidates.

Postobstructive pulmonary vasculopathy (POPV) was produced by chronic ligation (120 days) of the left main pulmonary artery of seven dogs. To explain the abnormal physiological changes found using arterial and venous occlusion (AVO) in POPV (J. Appl. Physiol. 69: 1022–1032, 1990), the light-microscopic morphology, morphometry (n = 5), and ultrastructure (n = 6) of ligated left lower lobes were compared with contralateral control right lower lobes. First, there was a proliferation of bronchial vessels around pulmonary vessels and airways to explain bronchial blood flow rates of 330 ml/min in left lower lobes. The walls of the bronchial vessels contained smooth muscle with minimal elastic tissue and prominent myoendothelial junctions. Second, focal bronchopulmonary anastomoses were seen in pulmonary arteries approximately equal to 100 microns diam, which is consistent with our conclusion that the major site of communication is at the precapillary level and suggests that the limit between arterial and middle segments defined by AVO may lie in arteries of approximately equal to 100 microns. Third, to explain the increased arterial resistance in POPV, the pulmonary arteries had an increased percent medial muscle thickness, peripheral muscularization, and focal intimal thickening but had no plexiform lesions. The ultrastructure of the arteries revealed new intimal cells and numerous myoendothelial junctions rarely found in controls. Capillaries and veins were only subtly altered. Fourth, the hyperreactivity of arteries to serotonin and of veins to histamine found using AVO was partially explained by the increased medial thickness and decreased diameter but may also be due to increased receptor concentration or related to the myoendothelial junctions. We conclude that most of the hemodynamic alterations in POPV are related to morphological abnormalities and that this model has clinical and experimental relevance in the study of bronchopulmonary vascular interactions.

Organs involved by Castleman disease (CD) may be investigated by fine-needle aspiration cytology. No specific cytomorphological criteria are currently described for a definitive diagnosis. The cytological features of three fine-needle aspirations from three different lymph nodes of a patient with histologically confirmed CD of the hyaline-vascular type are herein reported, with a review of the literature. The fine-needle aspirations showed branching capillaries associated with fragments of germinal center. Review of the literature yielded 12 other case reports with over half describing similar findings. Because branching hyalinized small blood vessels penetrating follicular germinal center are characteristic of CD of the hyaline-vascular type on histology, this finding in fine-needle aspirates should raise that diagnostic possibility. Diagn. Cytopathol. 2008. © 2008 Wiley-Liss, Inc.

The ability to predict complete pathologic response or sensitivity to radiation before treatment would have a significant impact on the selection of patients for preoperative radiotherapy or chemo-radiation therapy schedules. The aim of this study was to determine the value of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), p53, Bcl-2 and apoptosis protease-activating factor-1 (APAF-1) as predictors of complete pathologic tumour regression in patients undergoing preoperative radiotherapy for advanced rectal cancer. Pretreatment tumour biopsies from predominantly cT3 patients undergoing a preoperative high-dose-rate brachytherapy protocol were immunostained for EGFR, VEGF, p53, Bcl-2 and APAF-1. Immunoreactivity was evaluated by three pathologists. Cut-off scores for tumour marker positivity were obtained by receiver-operating characteristic (ROC) curve analysis. The association of marker expression with complete pathologic response was analysed in univariate and multivariable analysis. Multi-marker phenotypes of the independent protein markers were evaluated. In multivariable analysis, loss of VEGF (P-value=0.009; odds ratio (OR) (95% CI)=0.24 (0.08–0.69)) and positive EGFR (P-value=0.01; OR (95% CI)=3.82 (1.37–10.6)) both demonstrated independent predictive value for complete pathologic response. The odds of complete response were 12.8 for the multi-marker combination of VEGF-negative and EGFR-positive tumours. Of the 34 EGFR-negative- and VEGF-positive cases, 32 (94.1%) had no complete pathologic response. The combined analysis of VEGF and EGFR is predictive of complete pathologic response in patients undergoing preoperative radiotherapy. In addition, the findings of this study have identified a subgroup of simultaneous EGFR-negative and VEGF-positive patients who are highly resistant to radiotherapy and should perhaps be considered candidates for innovative neoadjuvant combined modalities.