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Nanoliposomal irinotecan (nal-IRI) is a promising novel hyperthermic intraperitoneal chemotherapy (HIPEC) agent given its enhanced efficacy against gastrointestinal tumors, safety profile, thermo-synergy, and heat stability. This report describes the first in-human phase 1 clinical trial of nal-IRI during cytoreductive surgery (CRS) and HIPEC.Patients with peritoneal surface disease (PSD) from appendiceal and colorectal neoplasms were enrolled in a 3 + 3 dose-escalation trial using nal-IRI (70-280 mg/mThe study enrolled 18 patients, who received nal-IRI during HIPEC at 70 mg/mIn this phase 1 HIPEC trial (NCT04088786), nal-IRI was observed to be safe, and PK profiling showed low systemic absorption overall. These data support future studies testing the efficacy of nal-IRI in CRS/HIPEC.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of desmoplastic small round cell tumor, breast, and gastrointestinal stromal tumor specifically related to peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for palliative care specifically related to peritoneal surface malignancies. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of neuroendocrine tumors specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Organoids are three-dimensional in vitro models of human disease developed from benign and malignant gastrointestinal tissues with tremendous potential for personalized medicine applications. We sought to determine whether gastric cancer patient-derived organoids (PDOs) could be safely established from endoscopic biopsies for rapid drug screening. Patients underwent esophagogastroduodenoscopy (EGD) for surveillance or staging and had additional forceps biopsies taken for PDO creation. Cancer tissues from operative specimens were also used to create PDOs. To address potential tumor heterogeneity, we performed low-coverage whole-genome sequencing of endoscopic-derived PDOs with paired surgical PDOs and whole-tumor lysates. The stability of genomic alterations in endoscopic organoids was assessed by next-generation sequencing and nested polymerase chain reaction (PCR) assay. The feasibility and potential accuracy of drug sensitivity screening with endoscopic-derived PDOs were also evaluated. Gastric cancer PDOs (n = 15) were successfully established from EGD forceps biopsies (n = 8) and surgical tissues (n = 7) from five patients with gastric adenocarcinoma. Low-coverage whole-genomic profiling of paired EGD and surgical PDOs along with whole-tumor lysates demonstrated absence of tumor heterogeneity. Nested PCR assay identified similar KRAS alterations in primary tumor and paired organoids. Drug sensitivity testing of endoscopic-derived PDOs displayed standard dose–response curves to current gastric cancer cytotoxic therapies. Our study results demonstrate the feasibility of developing gastric cancer PDOs from EGD biopsies. These results also indicate that endoscopic-derived PDOs are accurate surrogates of the primary tumor and have the potential for drug sensitivity screening and personalized medicine applications.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of peritoneal mesothelioma. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness of the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides the following multidisciplinary recommendations for the care of patients with peritoneal surface malignancies. This article focuses on the standards of a peritoneal surface malignancy center, standards of billing and coding, standards of operative reports for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, standards of cytoreductive surgery training, and standards of intraoperative chemotherapy preparation. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of ovarian neoplasms specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Background Pancreatic cancer (PC) hijacks innate cellular processes to promote cancer growth. We hypothesized that PC exploits PD-1/PD-L1 not only to avoid immune responses, but to directly enhance growth. We also hypothesized that immune checkpoint inhibitors (ICIs) have direct cytotoxicity in PC. We sought to elucidate therapeutic targeting of PD-1/PD-L1. Methods PD-1 was assessed in PC cells, patient-derived organoids (PDOs), and clinical tissues. Then, PC cells were exposed to PD-L1 to evaluate proliferation. To test PD-1/PD-L1 signaling, cells were exposed to PD-L1 and MAPK was examined. Radio-immunoconjugates with anti-PD-1 drugs were developed to test uptake in patient-derived tumor xenografts (PDTXs). Next, PD-1 function was assessed by xenografting PD-1-knockdown cells. Finally, PC models were exposed to ICIs. Results PD-1 expression was demonstrated in PCs. PD-L1 exposure increased proliferation and activated MAPK. Imaging PDTXs revealed uptake of radio-immunoconjugates. PD-1 knockdown in vivo revealed 67% smaller volumes than controls. Finally, ICI treatment of both PDOs/PDTXs demonstrated cytotoxicity and anti-MEK1/2 combined with anti-PD-1 drugs produced highest cytotoxicity in PDOs/PDTXs. Conclusions Our data reveal PCs innately express PD-1 and activate druggable oncogenic pathways supporting PDAC growth. Strategies directly targeting PC with novel ICI regimens may work with adaptive immune responses for optimal cytotoxicity.

Rationale: Heterotaxy with polysplenia is an extremely rare congenital condition resulting from abnormal arrangement of organs in the abdominal and thoracic cavities during embryologic development. When a malignancy such as pancreatic cancer develops under these conditions, surgical resection becomes particularly complex. This case report demonstrates successful pancreatic cancer resection despite the patient's complicated anatomy. Patient concerns: An 82-year-old female presented to our institution with complaints of mild right upper quadrant pain radiating to the mid-epigastric region. Diagnoses: Physical examination revealed jaundice with scleral icterus consistent with obstructive jaundice. Radiographic imaging revealed hepatic duct dilation with several anatomic anomalies including small bowel location in the right upper abdomen, cecum, and appendix in the left lower quadrant, reversed superior mesenteric artery and superior mesenteric vein positions, and right-sided duodenal-jejunal flexture as well as an entirely right-sided pancreas, and left lower pelvis with ≥6 separate splenules. These findings resulted in a diagnosis of heterotaxy syndrome with polysplenia. Interventions: Careful preoperative planning and total pancreatectomy was performed without complication. Outcomes: The patient recovered well. Pathologic examination of the pancreatic mass revealed moderately/poorly differentiated invasive pancreatic duct adenocarcinoma. The patient remains alive and well without signs of recurrent disease at the 2-year follow-up. Lessons: Given the wide range of anatomical variants observed in patients with heterotaxy syndrome, a thorough radiologic assessment is necessary before engaging in any surgical procedure. In our case, preoperative identification of the various anatomic anomalies, such as the short and vertically oriented pancreas, the porta hepatis position anterior to the duodenum, the nonrotation of the intestines and the anomalous origin of the right hepatic artery allowed us to perform a safe and uncomplicated total pancreatectomy.

Epigenetic changes have been implicated in silencing several B-cell genes in Hodgkin and Reed-Sternberg cells (HRS) of Hodgkin lymphoma (HL), and this mechanism has been proposed to promote HRS survival and escape from immunosurveillance. However, the molecular and functional consequences of histone deacetylase (HDAC) inhibition in HL have not been previously described. In this study, we report that the HDAC inhibitor vorinostat induced p21 expression and decreased Bcl-xL levels causing cell-cycle arrest and apoptosis. Furthermore, vorinostat inhibited STAT6 phosphorylation and decreased its mRNA levels in a dose- and time-dependent manner, which was associated with a decrease in the expression and secretion of Thymus and Activation-Regulated Chemokine (TARC/CCL17) and interleukin (IL)–5 and an increase in IP-10 levels. Moreover, vorino-stat inhibited TARC secretion by dendritic cells that were activated by the thymic stromal lymphopoietin (TSLP). Collectively, these data suggest that pharmacologic HDAC inhibition in HL may induce favorable antitumor activity by a direct antiproliferative effect on HRS cells, and possibly by an immune mediated effect by altering cytokine and chemokines secretion in the microenvironment.

Mantle cell lymphoma (MCL), a distinct type of non-Hodgkin lymphoma, is characterised by the overexpression of cyclin D1. Heat shock protein 90 (HSP90) is a molecular chaperon to proteins that regulate cell cycle and survival. 17-allylamino-17-demethoxy-geldanamycin (17-AAG), a HSP90 small molecule inhibitor, induced G(0/1) cell cycle arrest and cell death in a dose- and time-dependent manner in MCL cell lines. This effect was associated with the downregulation of cyclin D1, cdk4 and Akt, depletion of Bid, and activation of the intrinsic/mitochondrial caspase pathway. These data suggest that 17-AAG may have a potential therapeutic value in patients with MCL.

One of the most prominent pathways explored in the area of targeted therapy is the PI3K/Akt/mTOR pathway, which plays a central role in cell survival and proliferation. Deregulation of this pathway has been implicated in the promotion of cancer cell growth and survival. Inhibition of several steps of this pathway has been shown to confer favorable antitumor activity in a variety of cancer types. This article provides a brief analysis of the PI3K/Akt/mTOR pathway, its importance in tumor pathogenesis and the current status of preclinical and clinical studies targeting signaling components of this pathway.

Heat-shock protein-90 (HSP90) inhibitors are currently being used in phase I clinical trials for treating patients with a variety of neoplasms including lymphomas. Using immunohistochemical methods, we assessed for HSP90 expression in 412 cases of non-Hodgkin's lymphoma. In B-cell lymphomas, HSP90 was moderately to strongly expressed in all cases of Burkitt's lymphoma (5/5, 100%), and in subsets of follicular lymphoma (17/28, 61%), diffuse large B-cell lymphoma (27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%), small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell lymphoma (12/38, 32%) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (3/10, 30%). HSP90 was weakly expressed in six of 14 (43%) cases of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. In T-cell lymphomas, HSP90 was moderately to strongly expressed in subsets of anaplastic large-cell lymphoma (14/24, 58%; 9/12 ALK+ and 5/12 ALK-), precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified peripheral T-cell lymphoma (8/43, 23%) and angioimmunoblastic T-cell lymphoma (2/17, 12%). HSP90 was weakly expressed in seven of 58 (12%) cases of mycosis fungoides. We conclude that HSP90 is commonly expressed in a subset of many types of B- and T-cell lymphoma. These data suggest that many lymphoma types are suitable targets for modulation of HSP90 activity, and that HSP90 inhibitors are a potential investigational therapy for lymphoma patients.

Purpose: The malignant Hodgkin and Reed-Sternberg cells of Hodgkin disease (HD) are known to constitutively express high levels of activated nuclear factor κB (NF-κB), which plays an important role in their survival. The proteasome inhibitor PS-341 has been recently shown to modulate tumor cell proliferation and survival by inhibiting NF-κB and modulating critical cellular regulatory proteins, but its activity in cells carrying IκBα gene mutations has not been reported previously. Experimental Design: The activity of PS-341 in four well-characterized, HD-derived cell lines. Cell proliferation and apoptosis were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium (MTS) and Annexin-V binding methods, respectively. Cell cycle analysis was determined by flow cytometry. Intracellular protein levels were determined by Western blot. Results: PS-341 demonstrated a strong antiproliferative activity, which was irrespective of the status of mutations in IκBα and even the presence of CD30, CD40, or RANK receptor activation. This effect was attributable to the induction of apoptosis and cell cycle arrest at the G2-M phase. PS-341 not only inhibited nuclear localization of NF-κB but also activated the caspase cascade, increased p21 and Bax levels, and decreased Bcl-2 levels. Furthermore, PS-341 enhanced the effect of gemcitabine chemotherapy and potentiated the effect of tumor necrosis factor-related apoptosis-inducing ligand/APO2L and two agonistic antibodies to tumor necrosis factor-related apoptosis-inducing ligand death receptors R1 and R2. Conclusions: The in vitro activity of PS-341 against HD-derived cell lines suggests that PS-341 may have a therapeutic value for the treatment of HD.

The mitogen-activated protein kinase (MAPK) (also called extracellular signal–regulated kinase [ERK]) pathway has been implicated in malignant transformation and in the regulation of cellular growth and proliferation of several tumor types, but its expression and function in Hodgkin disease (HD) are unknown. We report here that the active phosphorylated form of MAPK/ERK is aberrantly expressed in cultured and primary HD cells. Inhibition of the upstream MAPK kinase (also called MEK) by the small molecule UO126 inhibited the phosphorylation of ERK and demonstrated a dose- and time-dependent antiproliferative activity in HD cell lines. UO126 modulated the levels of several intracellular proteins including B-cell lymphoma protein 2 (Bcl-2), myeloid cell leukemia–1 (Mcl-1) and caspase 8 homolog FLICE-inhibitory protein (cFLIP), and induced G2M cell-cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of apoliprotein 2/tumor necrosis factor–related apoptosis-inducing ligand (APO2L/TRAIL) and chemotherapy-induced cell death. Activation of CD30, CD40, and receptor activator of nuclear kappaβ (RANK) receptors in HD cells by their respective ligands increased ERK phosphorylation above the basal level and promoted HD cell survival. UO126 inhibited basal and ligand-induced ERK phosphorylation, and inhibited ligand-induced cell survival of HD cell lines. These findings provide a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD.

We previously demonstrated that pancreatic transection with a reinforced staple line results in significantly lower fistula rates than when stapling without reinforcement. (J Gastrointest Surg. 2007;11:345-349). Criticism of this initial study focused on the small size of the treated group (N = 13). We report four more years of experience with this technique with a larger sample size.This was a before-after trial. Patients included had distal pancreatectomies with stapled stump closure. The main intervention analyzed was staple-line reinforcement with Seamguard. The experimental group consisted of a consecutive series of stapled pancreatectomies with reinforcement performed from 2005 to 2010. The control group was a consecutive series of stapled pancreatectomies without reinforcement performed between 2003 and 2005 (previously published). The main outcome measure was pancreatic fistula.54 patients were included; 36 in the experimental group and 18 in the control group. Mean age was 62; 50% were males. The most common diagnoses were adenocarcinoma (31%), cystic neoplasm (24%), and neuroendocrine tumor (22%). There were no mortalities. Postoperative pancreatic leak rate was 39% in the control group, and 8% in the experimental group (P = 0.01). Seven of ten patients with leak required additional drain placement. Development of pancreatic leak resulted in prolonged hospital stays (12 vs eight days, P0.007).We demonstrate sustained success of reinforced stapling for pancreatic stump closure. Our technique is straightforward and results in reduced morbidity and cost. Our results suggest that surgical drains may not be needed when this technique is applied.

Hypothesis Grade 4 and grade 5 blunt liver injuries can be safely treated by nonoperative management (NOM). Design Retrospective case series. Setting Eleven level I and level II trauma centers in New England. Patients Three hundred ninety-three adult patients with grade 4 or grade 5 blunt liver injury who were admitted between January 1, 2000, and January 31, 2010. Main Outcome Measure Failure of NOM (f-NOM), defined as the need for a delayed operation. Results One hundred thirty-one patients (33.3%) were operated on immediately, typically because of hemodynamic instability. Among 262 patients (66.7%) who were offered a trial of NOM, treatment failed in 23 patients (8.8%) (attributed to the liver in 17, with recurrent liver bleeding in 7 patients and biliary peritonitis in 10 patients). Multivariate analysis identified the following 2 independent predictors of f-NOM: systolic blood pressure on admission of 100 mm Hg or less and the presence of other abdominal organ injury. Failure of NOM was observed in 23% of patients with both independent predictors and in 4% of those with neither of the 2 independent predictors. No patients in the f-NOM group experienced life-threatening events because of f-NOM, and mortality was similar between patients with successful NOM (5.4%) and patients with f-NOM (8.7%) (P = .52). Among patients with successful NOM, liver-specific complications developed in 10.0% and were managed definitively without major sequelae. Conclusions Nonoperative management was offered safely in two-thirds of grade 4 and grade 5 blunt liver injuries, with a 91.3% success rate. Only 6.5% of patients with NOM required a delayed operation because of liver-specific issues, and none experienced life-threatening complications because of the delay.

Morbidity after pancreaticoduodenectomy (PD) is nearly 50%. In this study we analyzed if early enteral nutrition via feeding tube (FT) contributes to better patient outcomes.Patients undergoing PD from 2003-2010. FTs were placed routinely before August 2006, and omitted thereafter. Short-term outcome measures included: time to start of oral diet, need for total parenteral nutrition (TPN), morbidity and mortality, pancreatic fistula, complications from FT, hospital length of stay, and disposition. Long-term outcome measures included time to start adjuvant therapy, and survival.N = 59 (25 had FT, 34 did not). Adenocarcinoma was found in 88%. Early institution of tube feeding had no positive impact on any of the outcome measures. There were three FT-related complications.Our results demonstrate that FT placement does not improve short-term or long-term outcomes after PD. Moreover, major complications can result from FT placement. We do not advocate the routine use of FT after PD.

Unselective histone deacetylase (HDAC) inhibitors are a promising novel therapy for lymphoid malignancies. However, these treatments remain empiric as the pattern of HDAC enzymes in different types of cancer, including lymphoid malignancies, remains unknown. We examined the expression of class I and class II HDACs in a panel of cell lines and tissue sections from primary lymphoid tumours. Class I enzymes were highly expressed in all cell lines and primary tumours studied, including the non-malignant reactive cells in the Hodgkin lymphoma (HL) microenvironment. The most frequently altered HDAC expression was HDAC6, as it was either weakly expressed or undetected in 9/14 (64%) of lymphoid cell lines and in 83/89 (93%) of primary lymphoma tissue specimens, including 50/52 (96%) cases of diffuse large B-cell lymphoma, and 18/22 (82%) cases of classical HL. Cell lines that had low expression level of HDAC6 demonstrated aberrant expression of hyper-acetylated tubulin, and were found to be more sensitive to the growth inhibitory effects of the class I HDAC inhibitor MGCD0103. Collectively, our data demonstrate that HDAC6 is rarely expressed in primary lymphoma cases, suggesting that it may not be an important therapeutic target in these lymphoid malignancies.

B-cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder characterized by the surface expression of CD20, CD5 antigens, as well as the receptor CD40. Activation of CD40 by its ligand (CD40L) induces proliferation and rescues the cells from spontaneous and chemotherapy-induced apoptosis. CD40 activation also induces secretion of cytokines, such as IL-6, IL-10, TNF-α, IL-8, and GM-CSF, which are involved in tumor cell survival, migration, and interaction with cells in the tumor microenvironment. Here we demonstrate that in primary B-CLL tumor cells, the novel antagonist anti-CD40 monoclonal antibody, HCD122, inhibits CD40L-induced activation of signaling pathways, proliferation and survival, and secretion of cytokines. Furthermore, HCD122 is also a potent mediator of antibody-dependent cellular cytotoxicity (ADCC), lysing B-CLL cells more efficiently than rituximab in vitro, despite a significantly higher number of cell surface CD20 binding sites compared with CD40. Unlike rituximab, however, HCD122 (formerly CHIR-12.12) does not internalize upon binding to the cells. Our data suggest that HCD122 may inhibit B-CLL growth by blocking CD40 signaling and by ADCC-mediated cell lysis.

Objective To investigate the mechanisms of antiproliferative effect induced by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus in mantle cell lymphoma (MCL). Materials and Methods The antiproliferative effect of temsirolimus on three well-defined MCL cell lines was examined by the MTS assay. Induction of cell-cycle arrest, autophagy, and apoptosis were determined by fluorescence-activated cell sorting analysis. The molecular mechanisms underlining these effects were determined by Western blot. Synergy between temsirolimus and vorinostat were examined by MTS assay and the combination index was calculated. Results Temsirolimus has antiproliferative activity in three MCL cell lines in a dose- and time-dependent manner. Mechanistically, temsirolimus inhibited mTOR, as evidenced by inhibition of ribosomal S6 phosphorylation, and induced cell-cycle arrest in the G 0 /G 1 phase and a decrease in p21 expression without altering p27 or cyclin D1 levels. Furthermore, temsirolimus increased the number of acidic vesicular organelles and the amount of microtubule-associated protein 1 light-chain 3 processing, which are characteristic of autophagy, without induction of apoptosis. These changes were not associated with alteration in phosphorylated extracellular signal-regulated kinase (ERK), beclin-1, Bax, or Bak levels. In contrast, treatment of these cell lines with the histone deacetylase inhibitor vorinostat decreased ERK phosphorylation, activated caspase 3, and induced apoptosis. Moreover, temsirolimus synergized with submaximal concentrations of vorinostat in all MCL cell lines. Conclusion This is the first report of temsirolimus-induced autophagy in MCL, and of vorinostat inhibition of ERK phosphorylation in MCL. Collectively, these data suggest that the combination of temsirolimus and vorinostat have synergistic antiproliferative activity in MCL cells by distinctively targeting apoptosis and autophagy.

Multiple survival factors have shown to play important roles in development and growth of non-Hodgkin lymphoma (NHL) [1]. B-lymphocyte stimulator (BLyS), a transmembrane protein that belongs to the...

The treatment of Hodgkin lymphoma continues to be based on combination chemotherapy and radiation therapy. Although this treatment strategy produces a high cure rate, short- and long-term toxic effects continue to be problematic for young cured patients. In this review we focus on emerging novel therapies using small molecules that target specific survival pathways in the cancer cells. This approach is aimed at improving the cure rate while reducing treatment-related toxicity.

Objective Heat shock protein 90 (HSP90) chaperones and maintains the molecular integrity of a variety of signal transduction proteins, including the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogenic protein, a genetic abnormality that is frequently observed in anaplastic large cell lymphoma (ALCL) cells. Here we demonstrate that HSP90 is overexpressed in primary and cultured ALK-positive and ALK-negative ALCL cells, and we evaluate the potential role of the small molecule inhibitor of HSP90, 17-allylamino-17-demethoxygeldanamycin (17-AAG) in treating ALCL. Methods The antiproliferative effect of 17-AAG–cultured cells was determined by MTS assay. Apoptosis and cell-cycle arrest were determined by Annexin-V/propidium iodide and propidium iodide staining, respectively, and fluorescein-activated cell sorting analysis. Expression of HSP90 was evaluated by immunohistochemistry, and molecular changes were determined by Western blot. Results Treatment of cultured ALCL cells with 17-AAG induced cell-cycle arrest and apoptosis, irrespective of ALK expression. At the molecular level, 17-AAG induced degradation of ALK and Akt proteins, dephosphorylated extracellular signal-regulated kinase, and degraded the cell-cycle regulatory protein cyclin D1 and its cyclin-dependent kinases, CDK4 and CDK6, but had a differential effect on p27 and p53 proteins. Inhibition of extracellular signal-regulated kinase phosphorylation by the mitogen activated protein kinase inhibitor U0126 induced cell death in all ALCL cell lines, and sublethal concentration 17-AAG showed synergistic antiproliferative effects when combined with U0126 or doxorubicin. Conclusion Our data demonstrate that targeting HSP90 function by 17-AAG may offer a novel therapeutic strategy for ALCL, either as single-agent activity or by combining 17-AAG with conventional or targeted therapeutic schemes.

Heat-shock protein 90 (HSP90) has diverse functions in mammalian cells. It acts as molecular chaperone, together with several co-chaperone molecules (such as Hop, Hip, p23, cdc37, Aha, and immunophilins). HSP90 binds to its client proteins (such as steroid receptors, AKT, Bcr-Abl, Apaf-1, survivin, cyclin dependent kinases which are involved in signal transduction that regulate cell cycle, survival, and death, and promote their proper protein folding, assembly, and transportation across different cellular compartments. Failure of Hsp90 chaperone activity leads to misfolding of client proteins, which leads to ubiquitination and proteasome degradation, and this deregulating cellular homeostasis. Since tumor cells frequently overexpress the active form of HSP90, which is more susceptible to inhibition by small molecules such as geldanamycin and its analogs, HSP90 became an attractive target for cancer therapy. This paper will review the recent advances in HSP90-biology and will discuss the emerging role of the HSP90 inhibitors such as 17-allylamino-17 demethoxy-geldanamycin and other HSP-90-directed small molecules in cancer therapy.

Purpose: Heat shock protein 90 (HSP90) is a chaperone for several client proteins involved in transcriptional regulation, signal transduction, and cell cycle control. HSP90 is abundantly expressed by a variety of tumor types and has been recently targeted for cancer therapy. The objective of this study was to determine the role of HSP90 in promoting growth and survival of Hodgkin's lymphoma and to determine the molecular consequences of inhibiting HSP90 function by the small-molecule 17-allylamino-17-demethoxy-geldanamycin (17-AAG) in Hodgkin's lymphoma. Experimental Design: HSP90 expression in Hodgkin's lymphoma cell lines was determined by Western blot and in primary lymph node sections from patients with Hodgkin's lymphoma by immunohistochemistry. Cell viability was determined by the 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Apoptosis and cell cycle fractions were determined by flow cytometry. Expression of intracellular proteins was determined by Western blot. Results: HSP90 is overexpressed in primary and cultured Hodgkin's lymphoma cells. Inhibition of HSP90 function by 17-AAG showed a time- and dose-dependent growth inhibition of Hodgkin's lymphoma cell lines. 17-AAG induced cell cycle arrest and apoptosis, which were associated with a decrease in cyclin-dependent kinase (CDK) 4, CDK 6, and polo-like kinase 1 (PLK1), and induced apoptosis by caspase-dependent and caspase-independent mechanisms. Furthermore, 17-AAG depleted cellular contents of Akt, decreased extracellular signal–regulated kinase (ERK) phosphorylation, and reduced cellular FLICE-like inhibitory protein levels (FLIP), and thus enhanced the cytotoxic effect of doxorubicin and agonistic anti–tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) death receptor antibodies. Conclusion: Inhibition of HSP90 function induces cell death and enhances the activity of chemotherapy and anti–tumor necrosis factor–related apoptosis-inducing ligand death receptor antibodies, suggesting that targeting HSP90 function might be of therapeutic value in Hodgkin's lymphoma.

Activation of the phosphatidylinositol 3-kinase (PI(3)K) pathway has been linked with tumour cell growth, survival and resistance to therapy in several cancer types. The active, phosphorylated form of Akt (pAkt) was found to be aberrantly expressed in Hodgkin lymphoma (HL)-derived cell lines and in Hodgkin-Reed-Sternberg (HRS) cells in 27 of 42 (64.3%) of primary lymph node sections of HL, indicative of PI(3)K activity. Akt phosphorylation was not associated with loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression, but with its phosphorylation in HL-cell lines, suggesting that its biological function is impaired. Akt phosphorylation was further induced by CD30 ligand (CD30L), CD40L and receptor activator of nuclear factor kappa B (RANK) ligand. The PI(3)K inhibitor LY294002 demonstrated antiproliferative effects in a dose- and time-dependent manner, which was associated with Akt dephosphorylation on Thr308 and Ser473 sites and dephosphorylation of the downstream ribosomal protein S6. LY209002 induced cell cycle arrest in the G0/G1 phase and apoptosis, which were associated with upregulation of MDM2, downregulation of cyclin D1, activation of caspase 9 and poly-ADP-ribose polymerase cleavage. The Akt inhibitor QLT394 also demonstrated antiproliferative effects in a dose- and time-dependent manner, dephosphorylated ribosomal S6 and cleaved caspase 9. Collectively, these data suggest that the aberrant activation of the PI(3)K/Akt survival pathway in HRS cells is not because of loss of PTEN expression. Our data suggest that PTEN phosphorylation and activation of CD30, CD40 and RANK may play a role in activating Akt in HRS cells.

Summary Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a death protein that preferentially kills tumour cells while sparing normal cells. TRAIL has four exclusive receptors, two of which (TRAIL-R1, TRAIL-R2) are death receptors. Both TRAIL/Apo2L and agonistic antibodies to the TRAIL death receptors are currently being explored for cancer therapy. Although the activity of TRAIL/Apo2L in a variety of haematological malignancies has been examined, the activity of anti-TRAIL receptor agonistic antibodies in primary and cultured lymphoma cells has not. Using two fully human selective agonistic monoclonal antibodies to the TRAIL death receptors TRAIL-R1 (HGS-ETR1) and TRAIL-R2 (HGS-ETR2) this study demonstrated that both monoclonal antibodies activated caspase-8 and induced cell death in five of nine human lymphoma cell lines, and induced >10% cell death in 67% and 70%, respectively, of 27 primary lymphoma cells, and >20% cell death in at least one-thirds of the samples. HGS-ETR1 and HGS-ETR2 demonstrated comparable activity in the fresh tumour samples, which was independent of TRAIL receptor surface expression, Bax, cFLIP, or procaspase-8 expression, or exposure to prior therapy. Furthermore, both antibodies enhanced the killing effect of doxorubicin and bortezomib. Our data demonstrate that HGS-ETR1 and HGS-ETR2 monoclonal antibodies can induce cell death in a variety of cultured and primary lymphoma cells, and may have therapeutic value in lymphoma.

The tumour necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL/Apo2L) is a member of the TNF superfamily that preferentially induces apoptosis in cancer cells, while sparing normal cells. TRAIL induces apoptosis by interacting with its receptors TRAIL-R1 and TRAIL-R2. Recently, new humanized agonistic anti-TRAIL-R1 and anti-TRAIL-R2 antibodies have been developed, and are undergoing phase I/II clinical trails. Esophageal adenocarcinoma (EA) is associated with significantly poor outcome and is rapidly increasing in incidence in the United States and Western Europe, with virtually no effective non-surgical treatment. The aim of this study was to determine whether human EA tissue express TRAIL-R1 and/or TRAIL-R2, and whether EA cell lines Bic-1 and Seg-1 expresses functional TRAIL-R1 and/or TRAIL-R2. The expression of TRAIL-R1 and TRAIL-R2 was determined in sections from 18 human EA by immunohistochemistry (IHC). Sixteen (89%) of the EA expressed TRAIL-R1 and 17 (94%) expressed TRAIL-R2. Both cell lines were found to express TRAIL-R1 and TRAIL-R2 by western blot analysis, IHC, and flow cytometry. The fully human agonistic TRAIL-R1 (HGS-ETR1) and TRAIL-R2 (HGS-ETR2) antibodies induced apoptosis in Bic-1 and Seg-1 cells in a time and dose dependent manner. Our results show that the vast majority of primary human EA express TRAIL-R1 and TRAIL-R2 and that EA cells lines express functional TRAIL-R1 and TRAIL-R2. Targeting of these receptors by agonist monoclonal antibodies may be of therapeutic value in patients with EA.

c-Kit receptor (CD117) is expressed by erythroid, megakaryocytic, and myeloid precursors and mature mast cells and has been reported to be expressed in CD30+ lymphomas such as Hodgkin's disease and anaplastic large-cell lymphoma. Imatinib mesylate, a well-established inhibitor of bcr-abl tyrosine kinase, and currently used for the treatment of patients with chronic myeloid leukemia, also inhibits c-kit receptor kinase activity. In view of the possible use of imatinib as experimental therapy for patients with c-kit-positive tumors, we assessed c-kit expression in CD30+ cell lines and lymphomas. The cell lines were assessed using multiple methods (RT-PCR, flow cytometry, and Western blot). c-Kit expression was also immunohistochemically assessed in 168 CD30+ lymphomas including 87 classical Hodgkin's disease, 63 anaplastic large-cell lymphoma, and 15 cutaneous anaplastic large-cell lymphoma. We also studied 18 cases of lymphomatoid papulosis, a CD30+ lesion closely related to cutaneous anaplastic large-cell lymphoma. Neither c-kit mRNA nor protein was detected in any of the cell lines assessed. Furthermore, treatment with imatinib did not inhibit proliferation of cell lines in vitro. Using immunohistochemistry, only one of 183 (0.5%) lesions was positive for c-kit, the positive case being an ALK-negative anaplastic large-cell lymphoma. Our data demonstrate that expression of c-kit receptor is exceedingly rare among CD30+ lymphomas and lymphomatoid papulosis, suggesting that c-kit receptor is unlikely to be an appropriate target for therapeutic options such as imatinib in patients with these tumors.

c-kit receptor (CD117) is expressed by erythroid, megakaryocytic, and myeloid precursors and mature mast cells.[1][1] Imatinib mesylate (STI571), a well-established inhibitor of bcr-abl protein tyrosine kinase and currently used for the treatment of chronic myeloid leukemia,[2][2] also inhibits c

B-lymphocyte stimulator (BLyS) plays a critical role in the survival of B-lymphocytes. In 50 patients with Hodgkin's lymphoma BLyS levels were higher in newly diagnosed patients (median 2.0 ng/mL, range0.3-56.0) and relapsed patients (8.7 ng/mL, range 1.5-71.5) than in 93 healthy donors (0.3 ng/mL, range0.3-0.5). High serum BLyS levels (or =2.0 ng/mL) in newly diagnosed patients were associated with resistance to therapy (p=0.01) and shorter progression-free survival (log-rank p=0.029, 2-year rate 64% vs 100%). Serum BLyS levels may have prognostic significance in Hodgkin's lymphoma.