Successful emergency pancreatoduodenectomy in a non-trauma patient

In the past decades considerable improvements in diagnostic imaging procedures, surgical technique and perioperative intensive care treatment have lead to a significant decrease in perioperative mortality and morbidity after pancreatic resection. This lead to an expansion of the indications for pancreatoduodenectomy. Little data exist in the literature on emergency pancreatoduodenectomy in non-trauma patients. We present a 43-year-old woman with extensive bleeding from papilla of Vater after endoscopic retrograde cholangiopancreatography (ERCP) with papillosphincterotomy. During the surgical exploration a tumor mass on the head of the pancreas was observed and a pancreatoduodenectomy was performed. On day 7 after the operation pancreatic leakage was observed and conservative therapy was administrated. Two weeks later the patient was released from the hospital in good health. Emergency pancreatoduodenectomy may be considered in institutions with extensive experience in these procedures, where cooperation of the invasive gastroenterologists and the abdominal surgeons, long experience of the surgeon and intensive reanimation care are present.     

Good vibrations: cross-frequency coupling in the human nucleus accumbens during reward processing

The nucleus accumbens is critical for reward-guided learning and decision-making. It is thought to "gate" the flow of a diverse range of information (e.g., rewarding, aversive, and novel events) from limbic afferents to basal ganglia outputs. Gating and information encoding may be achieved via cross-frequency coupling, in which bursts of high-frequency activity occur preferentially during specific phases of slower oscillations. We examined whether the human nucleus accumbens engages such a mechanism by recording electrophysiological activity directly from the accumbens of human patients undergoing deep brain stimulation surgery. Oscillatory activity in the gamma (40-80 Hz) frequency range was synchronized with the phase of simultaneous alpha (8-12 Hz) waves. Further, losing and winning small amounts of money elicited relatively increased gamma oscillation power prior to and following alpha troughs, respectively. Gamma-alpha synchronization may reflect an electrophysiological gating mechanism in the human nucleus accumbens, and the phase differences in gamma-alpha coupling may reflect a reward information coding scheme similar to phase coding.     

Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model

Objective

An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor α (TNFα)–neutralizing agents. In murine models, impaired signaling by TNF causes exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. This study was undertaken to investigate immune modulation in the setting of TNF neutralization in primary and latent tuberculosis in a non‐human primate model.

Methods

Cynomolgus macaques 4 years of age or older were infected with Mycobacterium tuberculosis and subjected to clinical, microbiologic, immunologic, and radiographic examinations. Monkeys were classified as having active or latent disease 6–8 months after infection, based on clinical criteria. Monkeys used in acute infection studies were randomized to receive either adalimumab (prior to and during infection) or no treatment. Monkeys with latent infection that were randomized to receive TNF‐neutralizing agent were given either an inhibitor of soluble TNF, recombinant methionyl human soluble TNF receptor I (p55‐TNFRI), or adalimumab. Control monkeys with latent infection were given no treatment or saline. Data from previously studied monkeys with active or latent disease were also used for comparison.

Results

Administration of TNF‐neutralizing agents prior to M tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks after infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathologic examination and bacterial burden. A spectrum of dissemination was noted, including extrapulmonary disease. Surprisingly, monkeys that developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition to that of control monkeys with active disease. TNF neutralization was associated with increased levels of interleukin‐12, decreased levels of CCL4, increased chemokine receptor expression, and reduced mycobacteria‐induced interferon‐γ production in blood but not in the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes.

Conclusion

These findings have important clinical implications for determining the mechanism of TNF neutralization–related tuberculosis.

     

Differential Effect of Imatinib and Synergism of Combination Treatment with Chemotherapeutic Agents in Malignant Glioma Cells

Abstract: Imatinib mesylate (STI571, Gleevec^®) is a signal transduction inhibitor and novel anti‐cancer agent. It selectively inhibits aberrantly activated tyrosine kinases in malignant cells, for example, bcr‐abl in leukaemia, platelet‐derived growth factor receptor and stem cell factor receptor (c‐Kit) in solid cancers including malignant glioma. However, recently published clinical studies with imatinib monotherapy in patients with malignant glioma demonstrated only very modest anti‐tumour activity. The aim of this study was to investigate the biological activity of imatinib, its cellular mechanisms of action and its synergism with other chemotherapeutic agents in human malignant glioma cells in culture. Expression of PDGF/R and c‐Kit was analyzed by RT‐PCR. Proliferation was measured by MTT assays and drug synergy was assessed by the Chou–Talalay method. Cell cycle and apoptosis were analyzed by flow cytometry and migration by monolayer migration assays. Multi‐immunoblot was performed on imatinib‐treated and control malignant glioma cells. Results indicate that imatinib is more effective in inhibiting cell colony formation and migration rather than proliferation. Imatinib treatment caused cell cycle arrest of glioma cells in G0–G1 or G2/M, with significant elevation of a few cyclin‐dependent kinases. Furthermore, imatinib acted synergistically with chemotherapy agents, such as the DNA alkylating agent, temozolomide, and riboneucleotide reductase inhibitors, for example, hydroxyurea at varied effective dose levels. In conclusion, imatinib exerts varied biological effects on malignant glioma cells in culture. Synergistic interaction of imatinib with chemotherapy agents may be related to cell cycle control mechanisms and could be potentially important in a clinical setting.     

Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4-6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.