Melanoma brain metastases: Biological basis and novel therapeutic strategies

The development of brain metastases is the deadliest complication of advanced melanoma and has long been associated with a dismal prognosis. The recent years have seen incredible progress in the development of therapies for melanoma brain metastases (MBM), with both targeted therapies (the BRAF-MEK inhibitor combination) and immune checkpoint inhibitors (the anti-CTLA-4, anti-PD-1 combination) showing impressive levels of activity. Despite this, durations of response for these therapies remain lower at intracranial sites of metastasis compared to extracranial metastases and it has been suggested that there are unique features of the brain microenvironment that contribute to therapeutic escape. In this review, we outline the latest research into the biology and pathophysiology of melanoma brain metastasis development and progression. We then discuss the current status of clinical trial that are open to patients with MBM and end by describing the ongoing challenges for the field.     

Open liver resection for colorectal metastases: better short- and long-term outcomes in patients potentially suitable for laparoscopic liver resection

Background:

There is no prospective randomized data comparing laparoscopic to open hepatectomy. This study compared short- and long-term outcomes in patients undergoing hepatectomy for colorectal metastases (CRM), who were suitable for either laparoscopic or open surgery.

Methods:

Data were prospectively collected from consecutive patients undergoing hepatic resection of CRM at a single centre (1987–2007). Patients who were suitable for laparoscopic resection (Group 1) were compared with patients whose tumour characteristics would best be considered for open resection (Group 2).

Results:

Out of 1152 hepatectomies, 266 (23.1%) were deemed suitable for a laparoscopic approach. The median (IQR) number of metastases was greater in Group 2 [2(1–20) vs. 1(1–10), P < 0.001], as was the mean (SD) tumour size [5.3(3.6) cm vs. 3.3(1.2) cm, P < 0.001]. The median (IQR) operation time [210 (70) min vs. 240 (90) min, P < 0.001] and blood loss [270 (265) ml vs. 355 (320) ml, P < 0.001] were less in Group 1. There was no difference in length of stay, morbidity or mortality. Patients in Group 2 had a higher R1 resection rate (14.9%) compared with Group 1 (4.5%, P < 0.001) and lower 5-year survival (37.8% vs. 44.2%, P= 0.005).

Discussion:

Current criteria for laparoscopic hepatectomy selects patients who have more straight-forward surgery, with less risk of an involved resection margin and better long-term survival, compared with patients unsuited to a laparoscopic approach. Clearly defined criteria for laparoscopic hepatectomy are essential to allow meaningful analysis of outcomes and the results of unrandomized series of laparoscopic hepatectomies must be interpreted with caution.     

Using lean techniques to define the platelet (PLT) transfusion process and cost-effectiveness to evaluate PLT dose transfusion strategies

BACKGROUND: Platelet (PLT) doses of 1.1 × 10¹¹, 2.2 × 10¹¹, and 4.4 × 10¹¹/m² body surface area are equally effective in preventing bleeding. These different dose strategies involve different numbers of transfusions. We conducted a cost analysis of three separate PLT dose therapies. STUDY DESIGN AND METHODS: A process map of preparation and administration of a PLT transfusion identified 46 steps (23 steps in the blood bank and 23 steps on the care unit). Time studies were conducted for these 46 steps. Supply costs and personnel costs were estimated based on time studies. We conducted a cost analysis of three separate treatment regimes involving 16 transfusions per patient for the low‐dose, 12 transfusions for medium‐dose, and eight transfusions for high‐dose regimes. RESULTS: The time and the cost of the transfusion process for the blood bank were 32.41 minutes and $21.93 per unit, and for the patient care unit, 58.36 minutes and $57.71 per unit. The total cost for a course of PLT therapy per patient ranged from $4503.77 to $7014.59 for three different PLT doses. For a simulated bone marrow transplantation unit with 259 patients annually, there would be approximately a $700,000 difference among the clinically equivalent low‐, medium‐, and high‐dose treatment options. CONCLUSIONS: The overall cost of transfusion therapy is more influenced by the cost of the product than the cost of providing the transfusion. Depending on the cost adjustment by the supplier for different doses of PLTs, a low‐dose transfusion strategy can be less costly.     

Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway

Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate <5%. From an initial drug screen, we identified bortezomib as having robust activity in ESCC lines. Mechanistically, bortezomib induced a G2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens.     

The effect of adherence to ACLS protocols on survival of event in the setting of in-hospital cardiac arrest

Aim

Advanced Cardiac Life Support (ACLS) algorithms are the default standard of care for in-hospital cardiac arrest (IHCA) management. However, adherence to published guidelines is relatively poor. The records of 149 patients who experienced IHCA were examined to begin to understand the association between overall adherence to ACLS protocols and successful return of spontaneous circulation (ROSC).

Methods

A retrospective chart review of medical records and code team worksheets was conducted for 75 patients who had ROSC after an IHCA event (SE group) and 74 who did not survive an IHCA event (DNS group). Protocol adherence was assessed using a detailed checklist based on the 2005 ACLS Update protocols. Several additional patient characteristics and circumstances were also examined as potential predictors of ROSC.

Results

In unadjusted analyses, the percentage of correct steps performed was positively correlated with ROSC from an IHCA (p < 0.01), and the number of errors of commission and omission were both negatively correlated with ROSC from an IHCA (p < 0.01). In multivariable models, the percentage of correct steps performed and the number of errors of commission and omission remained significantly predictive of ROSC (p < 0.01 and p < 0.0001, respectively) even after accounting for confounders such as the difference in age and location of the IHCAs.

Conclusions

Our results show that adherence to ACLS protocols throughout an event is correlated with increased ROSC in the setting of cardiac arrest. Furthermore, the results suggest that, in addition to correct actions, both wrong actions and omissions of indicated actions lead to decreased ROSC after IHCA.     

Cervical lymph node metastasis in squamous cell carcinoma of the buccal mucosa: a retrospective study on pattern of involvement and clinical analysis

Background The study was performed with an aim to map the pattern of metastasis of squamous cell carcinomas of buccal mucosa to various cervical lymph node levels and analyze its correlation with primary tumor size and histo-pathological grading. Material and Methods 254 patients with squamous cell carcinoma of the buccal mucosa treated with surgery first approach were analyzed retrospectively. The tumor size was noted from pre-operative CT Scans and were divided into early and advanced tumors. The resected specimen was studied to note the histo-pathological grading of the squamous cell carcinoma and the metastatic deposits at various lymph node levels. Results Out of 254 patients (149 females, 105 males), 145 patients showed histo-pathologically proven metastatic deposits in one or more lymph nodes out of which there were 56 patients showing occult metastasis. 78/145 patients showed metastatic involvement of level IB and/or IA lymph nodes, 31 showed involvement of level II and/or I lymph nodes, 27 showed involvement of level III with or without involvement of level I and II and 9 showed metastasis to level IV and V lymph nodes with or without level I, II or III lymph nodes. Cervical lymph node metastasis had statistically significant association with tumor size with advanced tumors showing worse pattern of metastatic spread beyond level I and II lymph nodes. As the degree of differentiation of squamous cell carcinoma reduced, they were more prone for cervical metastasis with moderately and poorly differentiated squamous cell carcinoma showing higher involvement of level III, IV and V lymph nodes. Conclusions The majority of buccal mucosa cases showed metastasis to level I, II and III lymph nodes out of which level IB and/or IA was most frequently involved. Metastasis to level IV and V lymph nodes was rare and was seen especially in patients with advanced primary tumor and poor histo-pathologic differentiation. Key words:Oral squamous cell carcinoma (OSCC), cervical lymph node metastasis, histologic differentiation, locally advanced disease.     

Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with Kaposi's sarcoma

Twenty-eight HIV patients either naive or failing highly active antiretroviral therapy (HAART)with moderate-advanced Kaposi's sarcoma (KS)were randomly chosen to initiate a new HAART regimen plus pegylated liposomal doxorubicin(PLD) or the new HAART regimen alone. After 48 weeks, better response rates were observed in the HAART plus PLD group (76% versus 20%).In HIV-infected patients with moderate-advanced KS, HAART alone may not be enough for KS response.