Adoptive Cell Therapy for Solid Tumors: Current Status in Melanoma and Next-Generation Therapies.

Lifileucel or TIL has recently been FDA approved for metastatic melanoma patients as first cell therapy for a solid tumor. We discuss roll-out of TIL as new SOC and other upcoming new cell therapies.

Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study.

BACKGROUND: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma. METHODS: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1). RESULTS: The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD

Routine Computer Tomography Imaging for the Detection of Recurrences in High-Risk Melanoma Patients.

BACKGROUND: The use of routine CT imaging for surveillance in asymptomatic patients with cutaneous melanoma is controversial. We report our experience using a surveillance strategy that included CT imaging for a cohort of patients with high-risk melanoma. METHODS: A total of 466 patients with high-risk cutaneous melanoma enrolled in adjuvant immunotherapy trials were followed for tumor progression by physical examination, labs, and CT imaging as defined by protocol. Evaluations were obtained at least every 6 months for year 1, every 6 months for year 2, and then annually for the remainder of the 5-year study. Time to tumor progression, sites of recurrence, and the method of relapse detection were identified. RESULTS: The patient cohort consisted of 115 stage II patients, 328 stage III patients, and 23 patients with resected stage IV melanoma. The medium time to progression for the 225 patients who developed tumor progression was 7 months. Tumor progression was detected by patients, physician examination or routine labs, or by CT imaging alone in 27, 14, and 59% of cases respectively. Melanoma recurrences were noted to be locoregional in 36% of cases and systemic in 64% of cases. Thirty percent of patients with locoregional relapse and 75% of patients with systemic relapse were detected solely by CT imaging. CONCLUSIONS: CT imaging alone detected the majority of sites of disease progression in our patients with high-risk cutaneous melanoma. This disease was not heralded by symptoms, physical examination, or blood work. Although the benefit of the early detection of advanced melanoma is unknown, this experience is relevant because of the rapid development and availability of potentially curative immunotherapies.

Modified breast cancer model for preclinical immunotherapy studies.

BACKGROUND: Interest in immunotherapy for breast cancer is rapidly emerging, and applicable animal models that mimic human cancer are urgently needed for preclinical studies. This study aimed to improve a technique for orthotopic inoculation of syngeneic breast cancer cells to be used as a preclinical animal model for immunotherapy. MATERIALS AND METHODS: We used our previously reported murine model of orthotopic cancer cell inoculation under direct vision and compared the efficiency of tumorigenesis with tumor cells suspended in either phosphate-buffered saline or Matrigel containing varying numbers of cells. As a model for immune rejection, murine BALB/c-derived 4T1-luc2 breast cancer cells were inoculated orthotopically into both BALB/c and C57BL/6 mice. RESULTS: Matrigel-suspended cells formed larger tumors with higher efficiency than phosphate-buffered saline-suspended cells. The maximum volume of Matrigel that could be inoculated without spillage was 20 µL and 30 µL in the #2 and #4 mammary fat pads, respectively. Tumor take rates increased as the injected cell number increased. In this immune rejection model, there were no significant differences in tumor weight between the strains up to day 7, after which tumor weight decreased in C57BL/6 mice. Bioluminescence in C57BL/6 mice was also significantly less than that in BALB/c mice and increased up to day 7, then swiftly decreased thereafter. CONCLUSIONS: This improved technique of innoculating murine breast cancer cells using bioluminescence technology may be useful in evaluating the efficacy of tumor regression mediated by immune responses, as shown by an allogeneic response in C57BL/6 mice.

Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma.

PURPOSE: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. EXPERIMENTAL DESIGN: Thirty-three patients with metastatic melanoma were treated in a cell dose-escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT.IL12). No IL2 was administered. RESULTS: The administration of 0.001 to 0.1 × 10(9) NFAT.IL12-transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 10(9) cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNγ as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. CONCLUSIONS: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100-fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients.

Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor.

PURPOSE: T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies. PATIENTS AND METHODS: We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. RESULTS: Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/µL. CONCLUSION: This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.

Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans.

Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.

Adoptive cell transfer for patients with metastatic melanoma: the potential and promise of cancer immunotherapy.

BACKGROUND: Current FDA-approved therapeutic options for patients with metastatic melanoma include dacarbazine, interleukin 2, ipilimumab, vemurafenib, dabrafenib, and trametinib, but long-term tumor regression using available agents remains out of reach for most patients. Adoptive cell transfer (ACT) with autologous tumor-infiltrating lymphocytes (TILs) has shown encouraging results in clinical trials, with evidence of durable ongoing complete responses in patients with advanced melanoma. Emerging techniques to engineer T-cell receptors (TCRs) or chimeric antigen receptors (CARs) using lymphocytes from peripheral blood may offer new tactics in ACT. METHODS: We reviewed the literature to provide a synopsis on the development and clinical trial results of ACT, as well as the future outlook for using ACT in patients with metastatic melanoma. RESULTS: ACT with TILs as part of a lymphodepleting regimen has been shown in clinical trials to cause objective clinical responses in approximately 40% to 72% of patients with metastatic melanoma, with up to 40% of those patients experiencing complete responses lasting up to 7 years ongoing. Pilot trials using TCR-engineered cells against melanoma-associated antigens MART-1 and gp100 and the cancer-testis antigen NY-ESO-1 have shown clinical responses in patients with melanoma. CAR cells directed against melanoma have been tested only in preclinical models; however, CAR cells targeting other histologies such as lymphoma have elicited antitumor responses in patients. CONCLUSIONS: An example of state-of-the-art personalized medicine, ACT is a potentially curative therapy for patients with metastatic melanoma. Ongoing trials aiming to simplify the regimens may allow a broader range of patients to be treated and enable ACT to be offered by academic cancer centers.

A divergent variant of the eleventh human polyomavirus species, saint louis polyomavirus.

Saint Louis polyomavirus (STLPyV) was recently discovered in human feces. Using random-primed rolling circle amplification combined with deep sequencing, we have found a divergent variant of STLPyV in a sanitized human skin wart specimen. The result strongly suggests that STLPyV directly infects humans and is not simply a dietary contaminant.

Utility of intraoperative parathyroid hormone monitoring in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism undergoing initial parathyroidectomy.

BACKGROUND: Intraoperative parathyroid hormone monitoring (IOPTH) is a widely used adjunct for primary hyperparathyroidism (pHPT). However, the benefit of IOPTH in familial pHPT, such as in multiple endocrine neoplasia type I (MEN1), remains unclear. METHODS: We performed a retrospective analysis of 52 patients with MEN1-associated pHPT undergoing initial parathyroidectomy with IOPTH monitoring at our institution. Parathyroid hormone (PTH) levels were measured before skin incision and 10 min after resection of the last parathyroid gland. Variables analyzed included percent drop of PTH from baseline and the final PTH level compared to the normal reference range (RR). RESULTS: A total of 52 patients underwent initial subtotal parathyroidectomy with IOPTH. An IOPTH decrease cutoff of ≥75 % from baseline had the highest biochemical cure rate (87 %). In the remaining 13 % who met this cutoff, all had persistent pHPT, with ≥90 % drop of PTH from baseline. The remaining patients, who did not meet the ≥75 % cutoff, were cured. Follow-up was available for three of four patients with final IOPTH levels above the RR: one had persistent pHPT, two had hypoparathyroidism (50 %). When a postresection PTH level was within the RR, 88 % of patients were cured. While considered cured from pHPT, 7 % of patients in this group developed permanent hypoparathyroidism. When the final PTH level dropped below the RR, 28 % developed permanent hypoparathyroidism. CONCLUSIONS: A cutoff in IOPTH decrease of ≥75 % from baseline has the highest biochemically cure rate in patients with pHPT associated with MEN1. However, a 75 % cutoff in IOPTH decrease does not exclude persistent pHPT. The absolute IOPTH value does not accurately predict postoperative hypoparathyroidism.

Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma.

PURPOSE: Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. PATIENTS AND METHODS: Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8(+)-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. RESULTS: Thirty-four patients received unselected young TILs with a median of 8.0% CD4(+) lymphocytes, and 35 patients received CD8(+)-enriched TILs with a median of 0.3% CD4(+) lymphocytes. One month after TIL infusion, patients who received CD8(+)-enriched TILs had significantly fewer CD4(+) peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8(+)-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8(+)-enriched TILs responded. CONCLUSION: A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8(+)-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.

Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy.

Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five patients experienced clinical regression of their cancers including 2 on-going responders. Beginning 1-2 days postinfusion, 3 patients (#'s 5, 7, and 8) experienced mental status changes, and 2 patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3(+)/CD8(+) T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.

A novel nomogram for peritoneal mesothelioma predicts survival.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare disease treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Estimation of personalized survival times can potentially guide treatment and surveillance. METHODS: We analyzed 104 patients who underwent CRS and cisplatin-based HIPEC for MPM. By means of 25 demographic, laboratory, operative, and histopathological variables, we developed a novel nomogram using machine-learned Bayesian belief networks with stepwise training, testing, and cross-validation. RESULTS: The mean peritoneal carcinomatosis index (PCI) was 15, and 66 % of patients had a completeness of cytoreduction (CC) score of 0 or 1. Eighty-seven percent of patients had epithelioid histology. The median follow-up time was 49 (1-195) months. The 3- and 5-year overall survivals (OS) were 58 and 46 %, respectively. The histological subtype, pre-CRS PCI, and preoperative serum CA-125 had the greatest impact on OS and were included in the nomogram. The mean areas under the receiver operating characteristic curve for the 10-fold cross-validation of the 3- and 5-year models were 0.77 and 0.74, respectively. The graphical calculator or nomogram uses color coding to assist the clinician in quickly estimating individualized patient-specific survival before surgery. CONCLUSIONS: Machine-learned Bayesian belief network analysis generated a novel nomogram predicting 3- and 5-year OS in patients treated with CRS and HIPEC for MPM. Pre-CRS estimation of survival times may potentially individualize patient care by influencing the use of systemic therapy and frequency of diagnostic imaging, and might prevent CRS in patients unlikely to achieve favorable outcomes despite surgical intervention.

von Hippel-Lindau disease-associated solid microcystic serous adenomas masquerading as pancreatic neuroendocrine neoplasms.

BACKGROUND: Patients with von Hippel-Lindau disease (VHL) commonly develop pancreatic cysts and neuroendocrine neoplasms (PNENs or PNETs). Solid microcystic serous adenoma (SMSA), a rare neoplasm described in VHL patients, can be mistaken for PNEN on imaging. METHODS: Clinical, pathologic, and radiologic data were reviewed on VHL patients who underwent surgery for a preoperative diagnosis of PNEN since 1994 at 1 institution. Blinded to the pathologic diagnoses, radiologists reassessed available imaging. RESULTS: For 55 patients, 79 pancreatectomies were performed for presumed PNENs. Ten (18%) patients underwent 12 (15%) resections for neoplasms diagnosed as SMSA on final pathology. The average size of a SMSA leading to operation was 3.6 ± 0.4 cm. Four out of 11 SMSAs were still mistaken for PNENs when imaging was reassessed. The mean FDG-positron emission tomography (PET) standardized uptake value was greater for 17 PNENs (12.1 ± 1.2) compared with 6 SMSAs (4.2 ± 0.5; P = .002). The mean doubling time of SMSAs and PNENs was similar. Seven (15%) patients with pathologically proven PNENs had malignant disease. CONCLUSION: SMSAs can mimic PNENs on nonfunctional imaging; FDG-PET may help to differentiate them. A high index of suspicion is needed to minimize operations performed for SMSA and to counsel VHL patients of their risks of undergoing operation for a lesion with no known malignant potential.

Complete genome sequence of a tenth human polyomavirus.

Nine polyomavirus (PyV) species are known to productively infect humans. The circular DNA genomes of PyVs are readily detectable using rolling circle amplification (RCA). RCA-based analysis of condyloma specimens from a patient with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome demonstrated the presence of a tenth apparently human-tropic polyomavirus species, which we name HPyV10.

Rate of clinically significant postoperative pancreatic fistula in pancreatic neuroendocrine tumors.

BACKGROUND: In 2005, the International Study Group of Pancreatic Fistula (ISGPF) developed a definition and grading system for postoperative pancreatic fistula (POPF). The authors sought to determine the rate of POPF after enucleation and/or resection of pancreatic neuroendocrine tumors (PNET) and to identify clinical, surgical, or pathologic factors associated with POPF. METHODS: A retrospective analysis of pancreatic enucleations and resections performed from March 1998 to April 2010. We defined a clinically significant POPF as a grade B that required nonoperative intervention and grade C. RESULTS: One hundred twenty-two patients were identified; 62 patients had enucleations and 60 patients had resections of PNET. The rate of clinically significant POPF was 23.7 % (29/122). For pancreatic enucleation, the POPF rate was 27.4 % (17/62, 14 grade B, 3 grade C). The pancreatic resection group had a POPF rate of 20 % (12/60, 10 grade B, 2 grade C). This difference was not significant (p = 0.4). In univariate analyses, patients in the enucleation group with hereditary syndromes (p = 0.02) and non-insulinoma tumors (p = 0.02) had a higher POPF rate. Patients in the resection group with body mass index (BMI) > 25 (p < 0.01), multiple endocrine neoplasia type 1 (MEN-1; p < 0.01) and those who underwent simultaneous multiple procedures (p = 0.02) had a higher POPF rate. Multivariate analyses revealed that hereditary syndromes were able to predict POPF in the enucleation group, while having BMI > 25 and increasing lesion size were also associated with POPF in the group undergoing resection. CONCLUSIONS: We found a clinically significant POPF rate after surgery in PNET to be 23.7 % with no difference by the type of operation. Our POPF rate is comparable to that reported in the literature for pancreatic resection for other types of tumors. Certain inherited genetic diseases-von Hippel-Lindau disease (VHL) and MEN-1-were associated with higher POPF rates.

Sleeping parathyroid tumor: rapid hyperfunction after removal of the dominant tumor.

CONTEXT: Due to frequent multiplicity of tumors in multiple endocrine neoplasia type 1, it may be difficult to decide when to stop a parathyroid exploration. A fall of intraoperative serum PTH by a certain percentage during parathyroid surgery is often used as one criterion for ending the operation. RESULTS: We report two patients with primary hyperparathyroidism due to multiple endocrine neoplasia type 1 who had their first parathyroidectomy at the National Institutes of Health. In both cases, two and a half glands were removed, an extensive search was done for an occult parathyroid tumor, and intraoperative PTH decreased markedly to the lower limits of normal, suggesting a successful operation. Despite this, both patients became hypercalcemic within 3 d after the operation and showed persistent primary hyperparathyroidism. Detailed findings suggest the following course: chronic hypercalcemia had caused near total suppression of PTH secretion by an undiscovered parathyroid tumor (sleeping parathyroid tumor). When the hypercalcemia decreased after surgery due to the removal of the dominant parathyroid tumor(s), the abnormal yet previously suppressed tumor rapidly began to oversecrete PTH and thus caused postoperative hypercalcemia. CONCLUSIONS: Even a fall of the intraoperative PTH to the lower limits of the normal range cannot guarantee that removal of all parathyroid tumors has been complete in cases with multiple tumors. These findings likely reflect strikingly differing PTH secretory functions among distinct tumors in the same patient, with hypercalcemia at least from a dominant tumor suppressing PTH secretion by one or more other parathyroid tumors.

Preoperative localizing studies for initial parathyroidectomy in MEN1 syndrome: is there any benefit?

BACKGROUND: The objective of the present study was to evaluate the utility of preoperative localizing studies in patients with MEN1 undergoing initial bilateral neck exploration (BNE) and parathyroidectomy for pHPT. METHODS: We performed a retrospective analysis of patients diagnosed with MEN1 who underwent initial parathyroidectomy between December 1993 and December 2010. Results of preoperative localizing studies were compared with intraoperative findings and outcome. RESULTS: Sixty patients with MEN1 (32 females and 28 males) underwent initial subtotal parathyroidectomy. The median age at the time of surgery was 33 years (range: 13-78 years). Fifty-three patients had one or more positive localizing study results. Neck ultrasonography, sestamibi scan, parathyroid protocol computed tomography scan, and neck and mediastinum magnetic resonance imaging were performed in 93, 91, 32, and 19% of patients, respectively. Fifty-three patients (88%) had cervical thymectomy. Twenty patients had 24 ectopic parathyroid glands; 18 glands were in the thymus (75%). Preoperative localizing studies identified 9 of 24 ectopic parathyroid glands (38%), including 4 ectopic glands outside the thymus in 4 patients (7%); 3 were detected by ultrasonography. There were no supernumerary glands identified on preoperative localizing studies. CONCLUSIONS: In patients with MEN1, preoperative localizing studies identified a subset of ectopic glands (38%). Preoperative localizing studies may alter the operative approach in 7% of patients. Ultrasonography can detect most ectopic parathyroid glands outside thymus. This suggests that routine preoperative localizing studies to identify ectopic and supernumerary enlarged parathyroid glands is not useful in the majority of patients with MEN1 undergoing bilateral neck exploration and subtotal parathyroidectomy with cervical thymectomy.

CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma.

PURPOSE: Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to evaluate the durability of responses. EXPERIMENTAL DESIGN: Patients with metastatic melanoma were treated in three trials from 2002 to 2005. In protocol 1, 56 patients received ipilimumab with gp100 peptides. In protocol 2, 36 patients received ipilimumab with interleukin-2. In protocol 3, 85 patients received ipilimumab with intrapatient dose-escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data. RESULTS: With median follow-up for protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with 5-year survival rates being 13%, 25%, and 23%, respectively. Patients in protocol 2 had a 17% complete response (CR) rate, compared with 7% in protocol 1 and 6% in protocol 3. These CR rates are higher than previously reported for the same trials because some patients who eventually became complete responders had continual tumor regression months to years after therapy. All but one of the 15 complete responders are ongoing at 54+ to 99+ months. CONCLUSIONS: This report provides the longest follow-up of patients with melanoma treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma. The combination of ipilimumab and interleukin-2 seems to have an increased CR rate, but this needs to be tested in a randomized trial.