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Supplementary Figure Legends from Combination Therapy with Anti–CTL Antigen-4 and Anti-4-1BB Antibodies Enhances Cancer Immunity and Reduces Autoimmunity

Supplementary Figures S1 & S2 from Combination Therapy with Anti–CTL Antigen-4 and Anti-4-1BB Antibodies Enhances Cancer Immunity and Reduces Autoimmunity

The majority of cancer antigens identified thus far have limited expression in normal tissues. It has been suggested that autoimmune disease is a necessary price for cancer immunity. This notion is supported by a recent clinical trial involving an anti–CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients. To selectively modulate cancer immunity and autoimmunity, we used anti-CTLA-4 and anti-4-1BB antibodies to treat mice with a preexisting cancer, MC38. The combination of the two antibodies led to CD8 T-cell-mediated rejection of large established MC38 tumors and long-lasting immunity to the same tumor cells, although the same regimen was not effective for B16 melanoma. More importantly, whereas individual antibodies induced inflammation and autoimmune manifestations, combination therapy increased cancer immunity while reducing autoimmunity. The reduction of autoimmune effects correlates with an increased function of regulatory T cells. Our results suggest a novel approach to simultaneously enhance cancer immunity and reduce autoimmunity. (Cancer Res 2006; 66(14): 7276-84)

This article reviews of the current evidence-based treatment standards for children with Wilms tumor. In this article, a summary of recently completed clinical trials by the Children’s Oncology Group are provided, the current diagnostic evaluation and surgical standards are discussed, and the surgical impact on current risk stratification for patients with Wilms tumor is highlighted. LEVEL OF EVIDENCE: This is a review article of previously published and referenced LEVEL 1 studies, but also includes expert opinion LEVEL V, represented by the American Pediatric Surgical Association Cancer Committee.

An extremely preterm neonate developed a progressively worsening right axillary ulcerative lesion at the previous site of a temperature probe. Despite treatment with broad-spectrum antibiotic and antifungal therapy, the lesion worsened and required extensive surgical debridement. Histologic examination of the debrided tissue demonstrated the presence of invasive mucormycosis. With prompt surgical intervention and proper antifungal therapy, the patient survived. Here we present a unique case of invasive cutaneous mucormycosis in a preterm neonate, along with a review of the current literature on this rare infection. Keywords: Preterm neonate, Cutaneous mucormycosis, Surgical resection

Neuroblastoma is an embryonic cancer arising from neural crest stem cells. This cancer is the most common malignancy in infants and the most common extracranial solid tumor in children. The clinical course may be highly variable with the possibility of spontaneous regression in the youngest patients and increased risk of aggressive disease in older children. Clinical heterogeneity is a consequence of the diverse biologic characteristics that determine patient risk and survival. This review will focus on current progress in neuroblastoma staging, risk stratification, and treatment strategies based on advancing knowledge in tumor biology and genetic characterization. TYPE OF STUDY: Review article. LEVEL OF EVIDENCE: Level II.

Purpose We have noted an increasing frequency of diagnosed urachal anomalies. The purpose of this study is to evaluate this increase, as well as the outcomes of management at our institution over 10 years. Methods A retrospective analysis of urachal anomalies at our institution was performed. Inclusion criteria were Anomalies of Urachus (ICD 753.7) or Urinary Anomaly NOS (ICD 753.9) between January 2000 and December 2010. Exclusion criteria were having an asymptomatic urachal remnant incidentally excised. Results Eighty-five patients (49 male, 36 female) presented between 0 and 17 years of age (mean 1.5 years). Diagnoses increased from 0 in 2000 to 21 in 2010. Zero was surgically managed in 2000 while 21 were managed in 2010 (p = 0.0145). Fifteen patients (17.6%) were observed with 13 (13/15, or 15.3%) resolving without complication while 2 were operated on. Average time to resolution (clinical or radiologic) was 4.9 months (Range: 0.4–12.6). A total of seventy-two patients (84.7%) underwent excision. Thirty-nine (54%) surgical cases were outpatient while 33 (46%) were admitted. Thirteen (18%) had post-operative complications. Ten (77%) of the complications were wound infections. Patients under 6 months of age accounted for 60% (6 of 10) of all wound infections and 52% (17 of 33) of hospitalizations. Conclusions Our experience and review of the literature suggest a high complication rate with surgical management in young patients, mostly from infections and support non-operative management of all non-infected urachal remnants in children.

Minimally invasive repairs of pediatric diaphragm eventration have been well described via a thoracoscopic approach, oftentimes requiring single-lung ventilation and tube thoracostomy, with the disadvantage of not being able to clearly visualize what lies beneath the diaphragm. We describe a novel pediatric diaphragm eventration repair using a laparoscopic transperitoneal approach and an endostapler device. We also describe our initial experience with this technique.Four pediatric diaphragmatic eventration patients underwent laparoscopic transperitoneal repair using an endostapler device. Repairs were performed in both male and female patients with right-sided eventrations. We approach the repair in a transperitoneal fashion using inverting sutures at the apex of the diaphragm to create tension toward the pelvis. Subsequently, an endostapler is used to remove the redundant portion of diaphragm, leaving a repaired, taut diaphragm.The median age at operation was 10.5 months. The median operative time was 70 minutes. There was no mortality, surgical complications, or recurrence at a median follow-up of 17 months.This laparoscopic approach allows for clear visualization of the intraabdominal organs and, at least in our early experience, a very simple, straightforward operation. Additionally, with the use of the endostapler, the redundant, often weakened diaphragm is removed, leaving the native, healthy diaphragm behind, resulting in a reliable and reproducible repair. This repair should be considered as a feasible alternative approach to the more traditional open and thoracoscopic repairs.

Castleman disease is a rare disorder characterized by lymphoid hyperplasia which rarely manifests in children. We present 2 cases which highlight both histologic variants of this disease, and provide suggestions regarding workup and treatment with the goal of making practitioners aware of Castleman disease in the differential diagnosis of a child presenting with vague symptoms.

Purpose The purpose of this study was to perform a retrospective review of tracheoesophageal fistula (TEF) patients who followed up in a state-sponsored program to assess neurodevelopmental outcomes. Methods Records were reviewed retrospectively of children who underwent TEF repair between August 2001 and June 2014. Children discharged from the neonatal intensive care unit were referred to the state-sponsored Developmental Tracking Infant Progress Statewide (TIPS) program. We reviewed TIPS assessments performed before age 24months and noted referral for early school intervention services. Poor outcomes were defined as scores of "failure" on the screening assessment or referral for enrollment in early intervention services by 24months. Children with TEF were compared with case-matched nonsyndromic children of similar gestational age and birth weight. Results Seventy-eight children underwent TEF repair. Thirty-eight followed up with TIPS. Survival was 93.6%. Predictors of hospital survival were Waterston classification (p=0.001), birth weight (p=0.027), and ventilator days (p=0.013). LOS was the only significant predictor of referral for early intervention services (p=0.0092) in multivariate analysis. There was a borderline significant difference in referral rate between children with TEF and controls. 52.6% of TEF patients were referred, while 34.2% of controls were referred (p=0.071). Conclusion More than half of TEF patients experience neurodevelopmental delays requiring referral for early intervention (53%).

Purpose: To determine if routine bridling of nasoenteric feeding tubes is a low-morbidity method of decreasing unintended tube dislodgement in pediatric patients. Methods: From November 2012 to June 2015, bridle systems were implemented in 30 pediatric patients with nasoenteric feeding tubes in place for an extended period of time, and data was prospectively collected. Historical cohort controls were 33 tracheoesophageal fistula (TEF) repair patients with taped nasoenteric tubes from 2001 to 2012. A second control group was 20 patients with nasoenteric tubes placed under fluoroscopy from February 2012 to July 2013. Analysis compared bridled children with these 2 groups to look at differences in total number tube dislodgements and tube dislodgements per 100 days. Complications related to bridle use were noted. Results: Among the 30 bridled patients, only 4 tube dislodgements were recorded in 1553 total days a tube was in place. During each of these instances, the bridle remained in place. There was a significant association between experimental group and total number tube dislodgements: only 3 of 30 bridled patients experienced tube dislodgements, compared to 18 of 33 TEF patients (p=0.0006) and 9 of 20 patients with fluoroscopically placed tubes (p=0.021). Children with bridled tubes experienced a lower rate of tube dislodgements per 100 days than TEF children with taped tubes (p

Real-time intraoperative image guidance has been successfully applied to malignancies of the head, neck and central nervous system. Few attempts have been made to apply this technology to gastrointestinal cancers. Our purpose was to determine if a computer-assisted navigation system could be accurately used at the time of abdominal exploration. Fourteen patients with resectable recurrent colorectal cancer underwent computer tomography (CT) imaging of the abdomen and pelvis. The CT images were uploaded to a StealthStation (Medtronic, Inc., Minneapolis, MN), a device that tracks the motion of a handheld probe in the operating field and displays its position, in real time, on the uploaded images. Various anatomic points were utilized to match, or register, the patient to the images in the navigation system. After four or more anatomic points were registered, the accuracy of the registration process was computed by the navigation system and reported as the global error. A total of 23 different anatomic structures were used for registration. The median number of points used for registration per patient was 6.5 (range 5–9). The anatomic sites most commonly used were the anterior superior iliac spines, aortic bifurcation, sacral promontory, symphysis pubis, and iliac artery bifurcation. The median global error was 10.0 mm (range 6.7 mm–27.0 mm). Computer-assisted navigation systems can be used to accurately deliver image guidance at the time of abdominal exploration. Future work will be directed at determining the value of this technology in the localization and resection of tumors.

The impact of timing of antigen introduction into fetus and neonates leads to the suggestion that pre-existing antigens are tolerogenic to immunocompetent cells generated thereafter. This hypothesis predicts that in patients with cancer who are undergoing bone marrow transplantation, newly produced T cells with specificity for pre-existing tumor cells will be inactivated by the tumor antigens in the host. Because the effect of tumor cells on developing cancer-reactive T cells has not been investigated, we set out to systematically analyze the impact of tumor cells in the periphery on the development of tumor-reactive T cells in the thymus and their immunocompetence in the periphery. Our data demonstrate that in the host in which a tumor is established in the periphery, the cancer-reactive T cells develop normally, remain fully immunocompetent, become activated in the periphery, and cause regression of large established tumors. The immunocompetence of T cells generated in an antigen-bearing host is also confirmed in a skin graft transplantation model.

Background. Chylous ascites is a rare complication following abdominal radiation or para-aortic lymph node dissection in the management of gynecologic malignancies. Treatment options include dietary restriction with addition of medium-chain triglycerides, serial paracenteses, total parenteral nutrition, and somatostatin. Current opinion advocates that surgical exploration and peritoneo-venous shunts be reserved for refractory cases. Cases. Two patients developed chylous ascites, one after completion of surgical staging and chemoradiation for stage IIB squamous carcinoma of the cervix and one following para-aortic lymph node dissection for recurrent malignant mixed mullerian tumor of the endometrium. In both cases resolution of the chylous ascites followed placement of a peritoneo-venous shunt. Conclusions. Chylous ascites should be considered in the differential diagnosis of ascites in patients with gynecologic malignancy treated with radiation or para-aortic lymph node dissection.

Objectives:We reviewed the surgical management of chronic cervical esophageal foreign bodies (CCEFBs) in a pediatric population after failed endoscopic retrieval.Methods:A descriptive analysis via a retrospective chart review of patients with CCEFBs who failed initial endoscopic management was performed between 2008 and 2013. Details were recorded regarding presenting symptoms, time from symptom onset to diagnosis of the CCEFB, surgical approach, and complications.Results:Three patients with CCEFBs unsuccessfully managed with endoscopy were identified. The range of ages at diagnosis was 14 months to 4.5 years. The foreign bodies (FBs) were present for at least 1 month before diagnosis (range, 1 to 10 months). Respiratory symptoms were predominant in all cases. Neck exploration with removal of the FB was performed in each case. Complications included esophageal stricture necessitating serial dilations (patient 1), left true vocal fold paresis that resolved spontaneously (patient 3), and tracheoesophageal fistula with successful endoscopic closure (patient 3). No long-term sequelae were experienced.Conclusions:A high index of suspicion is required to recognize CCEFBs in children with respiratory distress. Although endoscopic management remains the first-line treatment, it may fail or may not be possible because of transmural FB migration. In this setting, neck exploration with FB removal is a safe and effective alternative.

The optimal age at which to perform orchiopexy for cryptorchidism has long been debated. The aim of this study was to determine if age at orchiopexy affected testicular atrophy.A retrospective review of patients undergoing orchiopexy from 2000 to 2010 was conducted. An individual testis, rather than patient, was used as the dependent variable. A total of 349 testicles from 1126 charts (ICD-9=752.51) were identified. Primary study outcome was testicular survival without atrophy.Mean follow up for the study was 25 months. There was postoperative atrophy in 27 testes (7.7%). Intraabdominal testicle was independently associated with increased postsurgical atrophy (p0.0001). The odds of postsurgical atrophy were 15.66 times higher for an abdominal vs. inguinal location (95% CI: 5.5-44.6). Testicular atrophy was highest for orchiopexy at ages 13-24 months (n=16 of 133, 12%) vs. those less than 13 months (n=3 of 64, 5%), and those greater than 24 months (n=8 of 152, 5%) (p=0.0024). After adjusting for location, age was not statistically significant with postsurgical atrophy (p=0.055).From this study we conclude that there is no increase in testicular atrophy in patients less than 13 months.

We present a case of a 3-year-old male originally diagnosed with a CD30+ anaplastic cutaneous T-cell lymphoma with no evidence of systemic disease after CT scan, PET scan, and bone marrow aspiration. Sentinel lymph node biopsy (SLNB) was performed as an additional step in the workup and showed microscopic disease. Current management/recommendations for cutaneous T-cell lymphoma do not include SLNB. Medical and surgical management of cutaneous malignancies is dramatically different for local versus advanced disease. Therefore adequate evaluation is necessary to properly stage patients for specific treatment. Such distinction in extent of disease suggests more extensive therapy including locoregional radiation and systemic chemotherapy versus local excision only. Two international case reports have described SLNB in cutaneous T-cell lymphoma with one demonstrating evidence of node positive microscopic disease despite a negative metastatic disease workup. This case is being presented as a novel case in a child with implications including lymphoscintigraphy and SLNB as a routine procedure for evaluation and staging of cutaneous T-cell lymphoma if the patient does not demonstrate evidence of metastatic disease on routine workup.

Volvulus of the appendix is an uncommon phenomenon in children ( J Can Med Assoc .1966;95:926-927). Only a few reports exist in the literature concerning this subject. We describe a 2-year-old child who presented with right lower quadrant abdominal pain and was initially diagnosed as ruptured appendicitis with abscess. Attempt at computed tomography–guided drainage failed to produce purulent drainage, and the child was taken to the operating room for diagnostic laparoscopy. Operative findings revealed a volvulus of the appendix, and a laparoscopic appendectomy was performed.

Background Ataxia-Telangiectasia syndrome is characterized by progressive cerebellar dysfunction, conjuctival and cutaneous telangiectasias, severe immune deficiencies, premature aging and predisposition to cancer. Clinical and radiographic evaluation for malignancy in ataxia-telangiectasia patients is usually atypical, leading to delays in diagnosis. Case presentation We report the case of a 20 year old ataxia-telangiectasia patient with gastric adenocarcinoma that presented as complete gastric outlet obstruction. Conclusion A literature search of adenocarcinoma associated with ataxia-telangiectasia revealed 6 cases. All patients presented with non-specific gastrointestinal complaints suggestive of ulcer disease. Although there was no correlation between immunoglobulin levels and development of gastric adenocarcinoma, the presence of chronic gastritis and intestinal metaplasia seem to lead to the development of gastric adenocarcinoma. One should consider adenocarcinoma in any patient with ataxia-telangiectasia who presents with non-specific gastrointestinal complaints, since this can lead to earlier diagnosis.

The majority of cancer antigens identified thus far have limited expression in normal tissues. It has been suggested that autoimmune disease is a necessary price for cancer immunity. This notion is supported by a recent clinical trial involving an anti–CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients. To selectively modulate cancer immunity and autoimmunity, we used anti-CTLA-4 and anti-4-1BB antibodies to treat mice with a preexisting cancer, MC38. The combination of the two antibodies led to CD8 T-cell-mediated rejection of large established MC38 tumors and long-lasting immunity to the same tumor cells, although the same regimen was not effective for B16 melanoma. More importantly, whereas individual antibodies induced inflammation and autoimmune manifestations, combination therapy increased cancer immunity while reducing autoimmunity. The reduction of autoimmune effects correlates with an increased function of regulatory T cells. Our results suggest a novel approach to simultaneously enhance cancer immunity and reduce autoimmunity. (Cancer Res 2006; 66(14): 7276-84)

Background: CC49 is a monoclonal antibody directed against a pancarcinoma antigen (TAG-72) expressed by colorectal cancers. The use of murine CC49 in radioimmunoguided surgery (RIGS) was problematic because of the human anti-mouse antibodies (HAMA) generated. This study was designed to assess the clearance, safety, and effectiveness of localization of a complimentarity determining region (CDR)-grafted humanized domain-deleted antitumor CC49 antibody (HuCC49°CH2). Methods: After thyroid blockade, 1 mg of HuCC49°CH2 radiolabeled with 2 mCi of iodine-125 was administered. All patients subsequently underwent traditional exploration followed by a survey with the gamma-detecting probe. In five patients, exploration was performed 10 to 24 days after injection, when precordial counts were sufficiently low (

The purpose of this study was to compare outcomes of pediatric trauma patients transported by helicopter from the injury scene (IS group) to a trauma center and those transported by air after hospital stabilization (HS group).A retrospective analysis of pediatric trauma patients (19 years of age) transported by air ambulance and admitted to a pediatric trauma center was conducted. Outcomes compared were mortality and length of stay. Patients were subdivided into minor (Injury Severity Score [ISS]15) and major (ISS15) trauma. TRISS analysis was performed to verify the overall quality of the care.Eight hundred forty-two HS and 379 IS patients were included. The mean age, median ISS, and distribution of penetrating and blunt injuries did not differ significantly between the groups. The overall death rate was significantly lower for the interfacility transfer patients (HS group, 5.5%; IS group, 8.7%; p0.05). Mean intensive care unit (ICU) and hospital length of stay did not differ significantly. HS patients with major trauma had significantly less mortality (HS group, 15.5%; IS group, 26.7%; p0.05) and shorter mean ICU stays (HS group, 118.3 hours; IS group, 149.1 hours; p0.05) than IS major trauma patients. No differences were seen in patients with minor trauma. TRISS analysis showed improved survival for all patients compared with Major Trauma Outcome Study norms.Retrospective analysis was not able to demonstrate any benefit to direct transport from the scene to a trauma center. Hospital stabilization before transfer by air ambulance may improve survival and shorten ICU stays for patients with major trauma.

Consideration of sentinel lymph node biopsy (SLNB) is recommended for thin melanomas with poor prognostic features; however, few metastases are identified. The purpose of this study was to assess the cost effectiveness of SLNB in this population.The prospective melanoma database was reviewed to identify patients with melanomas1.2 mm thick who had undergone SLNB. Physician and hospital charges were collected from the appropriate billing department.A total of 138 patients were identified over an 8-year period (1994-2002). Two patients with positive SLNs were identified (1.4%), one with a melanoma1 mm thick. Patient charges for SLNB ranged from $10,096 to $15,223 US dollars, compared with $1000 to $1740 US dollars for wide excision as an outpatient. Using these charges, the cost to identify a single positive SLN would be between $696,600 and $1,051,100 US dollars. The cost for wide excision would be between $69,000 and $120,100 US dollars. Assuming that all patients with a positive SLN would die of melanoma, the cost per life saved would be $627,000 to $931,000 US dollars.The cost of performing SLNB in this population is great and only a small number will have disease identified that will alter treatment. These data call into question the appropriateness of SLNB for thin melanomas.

Sentinel lymph node biopsy (SLNB) is gaining acceptance as an alternative to axillary lymph node dissection. The purpose of this study was to determine the frequency and pattern of disease recurrence after SLNB.Two-hundred twenty-two consecutive patients undergoing SLNB from April 6, 1998, to October 27, 1999, and who wereor=24 months out from their procedure were identified from a prospectively maintained database. Retrospective chart review and data analysis were performed to identify variables predictive of recurrence.The median patient follow-up was 32 months (range, 24-43 months). A total of 159 patients (72%) were sentinel lymph node (SLN) negative and had no further axillary treatment. Five of these patients (3.1%) developed a recurrence (one local and four distant), with no isolated regional (axillary) recurrences. Sixty-three patients (28%) were SLN positive and underwent a subsequent axillary lymph node dissection. Six of these patients (9.5%) developed a recurrence (three local, one regional, and two distant). Pathologic tumor size (P.001), lymphovascular invasion (P =.018), and a positive SLN (P =.048) were all statistically significantly associated with disease recurrence.With a minimum follow-up of 24 months, patients with a negative SLN and no subsequent axillary treatment demonstrate a low frequency of disease recurrence. This supports the use of SLNB as the sole axillary staging procedure in SLN-negative patients.

The purpose of this study was to determine the factors that predict the presence of metastasis in nonsentinel lymph nodes (SLN) when the SLN is positive.A prospective database was analyzed and included patients who underwent SLN biopsy for invasive breast cancer from July 1997 to August 2000 (n = 442). One hundred (22.6%) patients had one or more positive SLNs, and were analyzed to determine factors that predicted additional positive axillary nodes.Of the 100 patients with a positive SLN, 40 patients (40%) had additional metastasis in non-SLNs. The only significant variables that predicted non-SLN metastasis were tumor lymphovascular invasion (P = 0.004), extranodal extension (P0.001), and increasing size of the metastasis within the SLN (P = 0.011). In analyzing just those patients who had lymphovascular invasion, extranodal extension, and a SLN metastasis2mm, 92% were found to have additional positive nodes.In patients with invasive breast cancer and a positive sentinel lymph node, lymphovascular invasion, extranodal extension, and increasing size of the metastasis all significantly increase the frequency of additional positive nodes.

Background: This study was designed to determine the minimum number of sentinel nodes necessary to accurately stage patients with breast cancer. Methods: Between August 1997 and February 2001, 509 consecutive patients were enrolled in a prospective sentinel node database. Nodes were characterized as either blue or hot (>2 times background), or both, and ranked based on the order harvested. Predictive value of the sentinel node based on these characteristics was evaluated to determine the minimum number necessary to stage the basin. Results: In all, 990 sentinel nodes were harvested from 465 basins. Pathologic stage in 126 of 128 positive basins was predicted by the first or second node harvested. The remaining 2 patients were positive by immunohistochemistry only. The hottest node predicted the status in 114 of 128 basins. Conclusions: Although all nodes should be examined, these data suggest that limiting frozen section analysis to the first two sentinel nodes identified will not compromise the accuracy of staging and may provide a vehicle for resource savings.

Introduction: Preliminary data have shown that two signals, both MHC class I and the costimulatory molecule B7–1, are required for NK cell-mediated rejection of allogeneic tumors and for activation of NK cells in vivo. In view of the fact that B7–1 and B7–2 interact with the receptor CD28 on T cells, this study investigates the role of CD28 in B7-mediated proliferation of NK cells. Methods: C57BL/6 mice deficient for RAG-1 or both RAG-1 and CD28 were injected intravenously with either 10 6 B7-expressing plasmacytoma cells (J558-B7) or B7-deficient plasmacytoma cells (J558-Neo) followed by intraperitoneal injections of bromodeoxyuridine (BrdU) every 12 hours. Mice were sacrificed 48 hours after tumor cell challenge for analysis. Mononuclear leukocytes from the spleen were stained with NK cell surface markers, and intracellularly with anti-BrdU mAb or isotype control. Cells were then analyzed by flow cytometry. There were twelve mice per experiment. Similar methods were employed to compare NK cell proliferation in C57BL/6 wild type versus C57BL/6 mice deficient only for CD28. Results: Consistent with previous studies, in RAG-1 deficient mice, there was a significantly increased proliferation of NK cells in response to B7-expressing tumor cell challenge compared to non-B7 expressing tumor (5.7% vs 12.3%). In RAG-1 knockout mice challenged with B7-expressing tumors, the proliferation of NK cells was increased in the absence of CD28 (12.3% vs 17.4%). This contradicts the result that would be expected if B7/CD28 interaction had played a role in B7-mediated proliferation. Similarly, in C57BL/6 wild type mice compared with C56BL/6 mice deficient for CD28, the proliferation of NK cells was not significantly different (14.2% vs 13.8%), further supporting that the B7/CD28 interaction does not play a role in proliferation. Conclusion: These findings indicate that CD28 is not required for B7-mediated costimulation of NK cell proliferation in response to tumor challenge. Future studies will investigate the potential role of alternative B7 family receptors, such as CTLA-4, in NK cell costimulation.