Polypectomy versus surgery in early colon cancer: size and location of colon cancer affect long-term survival.

BACKGROUND AND AIMS: The colon cancer survival rate is significantly affected by location, stage, and size of the cancer. Polypectomy was shown be as equally effective as surgery in early-stage colon cancer, but there have been no established clinical guidelines in the management of colon cancer based on the size of the polyp or the tumor location. The aim of our study was to assess the early-stage colon cancer-specific survival rate in patients who underwent endoscopic polypectomy versus surgery, based on size and location of tumor in early-stage colon cancer. METHODS: This is a population-based nationwide study in the USA. RESULTS: Of 13,157 patients, 15.5% underwent endoscopic treatment and 84.5% underwent surgical therapy. For early cancer tumors located in the left colon, polypectomy yielded comparable 5-year survivals to surgery irrespective of size of the tumors. Five-year early cancer-specific survivals were similar for tumors located in the right colon that were < 20 mm in size (94.5 vs 94.3%, p value = 0.94). However, tumors > 20 mm in size that were located in the right colon had better survivals when treated surgically compared to those treated with polypectomy (20-39 mm: 91.8 vs 74.2%; ≥ 40 mm: 92.4 vs 60%, both p values < 0.01). Similar results were obtained on propensity score analysis. CONCLUSIONS: Polypectomy was as effective as surgical therapy for small tumors. For larger tumors, surgical therapy is better than polypectomy for right-sided tumors, but both are equally effective for left-sided tumors.

A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors.

PURPOSE: The first-in-human phase 1 trial examined the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and antitumor activity of TLC388, a novel camptothecin with a unique lactone ring modification, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: TLC388 was administered intravenously to patients with metastatic chemotherapy refractory solid tumors on days 1, 8, and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8, and 15 of cycles 1 and 2. RESULTS: Fifty-four patients were enrolled at doses ranging from 1.5 to 60.0 mg/m(2) over 12 cohorts. Treatment was generally well-tolerated and no cumulative toxicity observed. Two of six patients treated at 60.0 mg/m(2) developed DLTs of grade 3 neutropenia causing dose delay and grade 3 febrile neutropenia. The next lower dose, 50.0 mg/m(2), was declared as MTD. Treatment-related grade 3-4 hematologic toxicities included neutropenia (19 %), leukopenia (15 %), anemia (9 %), and thrombocytopenia (7 %). Grade 3-4 nonhematologic toxicities included diarrhea (2 %) and hyponatremia (4 %). Pharmacokinetics of both diastereomers (S,R and S,S) of TLC388, a mixture of two diastereomers, was dose independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m(2) for S,R and 996 (1333) L/m(2) for S,S, and 2174 (2526) L/h-m(2) for S,R and 2670 (2988) L/h-m(2) for S,S, respectively. The half-life values averaged 0.67 (1.15) hours for S,R and 0.64 (1.11) hours for S,S. The best overall response was stable disease in 21 (39 %) patients. Prolonged (≥ 6 months) stable disease was noted in eight patients. CONCLUSIONS: TLC388 at 50 mg/m(2) on the current treatment schedule is generally safe and well tolerated.

Radiologic Responses in Cynomolgus Macaques for Assessing Tuberculosis Chemotherapy Regimens.

Trials to test new drugs currently in development against tuberculosis in humans are impractical. All animal models to prioritize new regimens are imperfect, but nonhuman primates (NHPs) infected with Mycobacterium tuberculosis develop active tuberculosis (TB) disease with a full spectrum of lesion types seen in humans. Serial 2-deoxy-2-[18F]-fluoro-d-glucose (FDG) positron emission tomography (PET) with computed tomography (CT) imaging was performed on cynomolgus macaques during infection and chemotherapy with individual agents or the four-drug combination therapy most widely used globally. The size and metabolic activity of lung granulomas varied among animals and even within a single animal during development of disease. Individual granulomas within untreated animals had highly local and independent outcomes, some progressing in size and FDG uptake, while others waned, illustrating the highly dynamic nature of active TB. At necropsy, even untreated animals were found to have a proportion of sterile lesions consistent with the dynamics of this infection. A more marked reduction in overall metabolic activity in the lungs (decreased FDG uptake) was associated with effective treatment. A reduction in the size of individual lesions correlated with a lower bacterial burden at necropsy. Isoniazid treatment was associated with a transient increase in metabolic activity in individual lesions, whereas a net reduction occurred in most lesions from rifampin-treated animals. Quadruple-drug therapy resulted in the highest decrease in FDG uptake. The findings of PET-CT imaging may provide an important early correlate of the efficacy of novel combinations of new drugs that can be directly translated to human clinical trials.

Cefepime neurotoxicity despite renal adjusted dosing.

Neurotoxicity is a rare side-effect of cefepime. There are previous reports of cefepime neurotoxicity in patients whose dosages were not adjusted for their kidney disease. We report a toxic case of non-convulsive status epilepticus in a patient receiving renally-dosed cefepime. A 70-y-old woman was admitted with febrile neutropenia for which renally-dosed cefepime was started. On day 4 she developed altered mental status with orofacial myokymia. Blood and urine cultures were negative. Cerebrospinal fluid analysis was normal. Head computed tomography and magnetic resonance imaging showed no acute intracranial process. An electroencephalogram showed non-convulsive status epilepticus. Anticonvulsants were started, but she continued to have seizures. At this time, careful review of her medication list with temporal association of symptoms suggested cefepime as a probable cause and the drug was stopped. Within 24 h of discontinuation, her mental status began to improve and returned to baseline in 3 days. Our case illustrates that cefepime toxicity may still occur in patients who are dose-adjusted for renal insufficiency. It also underscores the importance of assessing for additional risk factors like history of stroke and seizures. Because cefepime-induced status epilepticus is completely reversible, prompt recognition and medication discontinuance can prevent further morbidity and mortality.

Identification of distant metastases with positron-emission tomography-computed tomography in patients with previously untreated head and neck cancer.

OBJECTIVES: To investigate the utility of positron-emission tomography-computed tomography (PET-CT) in identifying distant metastatic disease in patients with previously untreated head and neck squamous cell cancer (HNSCC) prior to definitive treatment. MATERIALS AND METHODS: Retrospective analysis of 27 consecutive patients with previously untreated HNSCC who underwent PET-CT imaging in addition to chest radiography (CXR) as part of their metastatic workup. RESULTS: The majority of patients (89%) had TNM stage III or IV disease. PET-CT was suspicious for pulmonary malignancy in four (15%) patients and indeterminate in one (4%) patient. CXR was suspicious for pulmonary malignancy in two (7%) patients. Pulmonary metastases or a new lung primary was present in 3 (11%) patients: 3 of 4 (75%) patients with positive PET-CT scans and 0 of 23 (0%) patients with negative or indeterminate PET-CT scans compared with 2 of 2 (100%) patients with positive CXR and 1 of 25 (4%) patients with negative CXR. The sensitivity and specificity of PET-CT in predicting pulmonary malignancy was 100% and 96%, respectively, with a positive predictive value of 75% and a negative predictive value of 100%. The sensitivity and specificity of CXR in predicting pulmonary malignancy was 67% and 100%, respectively, with a positive predictive value of 100% and a negative predictive value of 96%. Including nonpulmonary sites, the overall incidence of distant metastatic disease was 19% (5/27) with 11% (3/27) unsuspected prior to PET-CT. CONCLUSIONS: PET-CT improves detection of metastatic disease in the high-risk patient and should be performed as part of the routine pretreatment evaluation of patients with advanced stage HNSCC.

In vivo imaging in an ABSL-3 regional biocontainment laboratory.

The Regional Biocontainment Laboratory (RBL) at the University of Pittsburgh is a state-of-the-art ABSL-3 facility that supports research on highly pathogenic viruses and bacteria. Recent advances in radiologic imaging provide several noninvasive, in vivo imaging modalities that can be used to longitudinally monitor animals following experimental infection or vaccination. The University of Pittsburgh RBL provides digital radiography, bioluminescence imaging, and PET/CT. Operating these platforms in an ABSL-3 poses unique challenges. This review will discuss the development and refinement of these imaging platforms in high containment, emphasizing specific challenges and how they were overcome.

Utility of ¹8F-FDG PET/CT in identifying penile squamous cell carcinoma metastatic lymph nodes.

OBJECTIVES: Due to the significant potential morbidity of inguinal and pelvic lymphadenectomy, the search for an imaging modality that can accurately identify penile squamous cell carcinoma (SCCA) lymphatic metastases continues. Initial (18)F-FDG PET/CT studies have reported 80% sensitivity and 100% specificity in the detection of inguinal and obturator lymph node metastasis. We review a single institutional experience of (18)F-FDG PET/CT imaging of SCCA of the penis to assess for accuracy and potential impact on clinical management. METHODS: Three patients diagnosed with penile SCCA at a single institution underwent staging (18)F-FDG PET/CT and went on to subsequent inguinal lymph node dissection. The (18)F-FDG PET machine was a Philips Gemini Time-of-Flight PET with LYSO crystals with 4.7 mm spatial resolution. The CT was a 16-slice helical CT with 5 mm slice widths. (18)F-FDG PET/CT findings were compared with the histologic findings of these procedures. Decision to proceed with lymphadenectomy was based on clinical judgment of a single urologist and all fused (18)F-FDG PET/CT imaging was assessed by a single experienced radiologist. RESULTS: No patient received chemotherapy or radiation before the (18)F-FDG PET/CT or surgery. The first patient was obese (BMI > 30), clinically node negative, and the (18)F-FDG PET/CT showed inflammation. Histologic examination showed a positive 2 cm right inguinal metastatic node. The second patient's (18)F-FDG PET/CT showed a suspicious 1 cm left inguinal node. Histologically, the suspicious lymph node was positive for SCCA as was a second positive 2 cm lymph node not identified on preoperative (18)F-FDG PET/CT. Clinical exam of this patient was negative. The third patient was (18)F-FDG PET/CT and clinically negative but subsequently developed a palpable lymph node approximately 1 month later, which was suspicious on repeat (18)F-FDG PET/CT and positive for SCCA on histological examination. CONCLUSIONS: (18)F-FDG PET/CT has shown initial promise in the staging of penile SCCA. However, our review shows that false negative studies occur at alarmingly high rates, and (18)F-FDG PET/CT is poor in detection of micro-metastasis. Thus, close follow-up in these patients is imperative.

Frequent dose interruptions are required for patients receiving oral kinase inhibitor therapy for advanced renal cell carcinoma.

OBJECTIVE: Recent advances for patients with advanced or metastatic renal cell carcinoma (RCC) have been shown to improve progression-free survival with both response rates and disease stabilizing activity. Sorafenib, a multikinase inhibitor, and sunitinib, an inhibitor of vascular endothelial growth factor-r and platelet-derived growth factor-r, have been approved by the Food and Drug Administration since 2005/2006. This retrospective analysis of patients treated with both aforementioned kinase inhibitors for advanced RCC presents data related to their antitumor effects as well as safety profile with particular attention to dose interruption and modification requirements. METHODS: This was a retrospective review of patients diagnosed with RCC either with advanced disease at initial presentation or after first-line therapy, who received either continuous sorafenib 400 mg bid or sunitinib 50 mg Qday for 4 weeks on and 2 weeks off until disease progression or untoward drug reaction. Tumor response was evaluated by response evaluation criteria in solid tumors criteria, and adverse events were graded by National Cancer Institute-Common Toxicity Criteria. RESULTS: From December 2005 to May 2008, 34 patients were followed. Twenty-two patients received sorafenib first line, 10 received sunitinib first line, and 2 patients received sorafenib as third-line therapy. Twenty-nine were evaluable for response rates. There were 10 patients (34%) who had stabilization of disease, 8 patients (28%) who had a partial response, and 11 patients (38%) who had progression of disease. The progression-free survival median was 8 months. Of the 34 patients evaluable for toxicities, grade 3 or 4 adverse event occurred in 19 patients (56%). These patients required either dose modifications and/or treatment interruptions within an average of the first 2 weeks of treatment. Eight patients (24%) required drug discontinuation. Eleven patients (32%) required dose reductions, but were able to resume the targeted dose after slow dose escalation. Three patients (9%) remain dose reduced for greater than 12 weeks. CONCLUSIONS: Sorafenib and sunitinib have extended patients' disease-free survival by several months; however, the initial grade 3 or 4 adverse event presented in the literature appear to have been under-reported. Our experience suggests that the first 4 weeks of treatment is the most likely timeframe within which drug reactions occur. Therefore, careful monitoring and possibly additional clinical visits are warranted during this time period. Although a significant percentage of patients require dose modification, many can be restarted and titrated up to the targeted dose.

Temsirolimus in the treatment of renal cell carcinoma associated with Xp11.2 translocation/TFE gene fusion proteins: a case report and review of literature.

Xp11.2 translocation renal cell carcinomas (TRCCs) are a rare family of tumors newly recognized by the World Health Organization (WHO) in 2004. These tumors result in the fusion of partner genes to the TFE3 gene located on Xp11.2. They are most common in the pediatric population, but have been recently implicated in adult renal cell carcinoma (RCC) presenting at an early age. TFE3-mediated direct transcriptional upregulation of the Met tyrosine kinase receptor triggers dramatic activation of downstream signaling pathways including the protein kinase B (Akt)/phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. Temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR) kinase, a component of intracellular signaling pathways involved in the growth and proliferation of malignant cells. Here we present a case of a 22-year old female who has been treated with temsirolimus for her Xp11.2/TFE3 gene fusion RCC.

Hepatic failure caused by plasma cell infiltration in multiple myeloma.

Although plasma cell infiltration is not rare in autopsy of patients with multiple myeloma (MM), it is very rarely detected in living patients. This is because MM rarely causes significant liver dysfunction that requires further evaluation. A 49-year-old man presented with acute renal failure and was diagnosed with kappa light chain MM stage IIB. Thalidomide and dexamethasone were initiated. The patient developed a continuous increase in bilirubin that led to severe cholestasis. A liver biopsy revealed plasma cell infiltration. He then rapidly progressed to liver failure and died. Treatment options are limited in MM with significant liver dysfunction. Despite new drug therapies in MM, those patients with rapidly progressive liver failure appear to have a dismal outcome.

Identification of distant metastases with PET-CT in patients with suspected recurrent head and neck cancer.

OBJECTIVES: To investigate the utility of positron-emission tomography/computed tomography (PET-CT) in identifying distant metastatic disease in patients with suspected recurrent head and neck squamous cell cancer (HNSCC). STUDY DESIGN: Retrospective analysis. METHODS: Retrospective analysis of 64 consecutive patients with suspected recurrent HNSCC following definitive treatment who underwent PET-CT imaging were eligible for inclusion. Patients with previous known distant metastatic disease were excluded. RESULTS: The majority of patients (81%) had TNM stage III or IV disease. PET-CT was suspicious for pulmonary malignancy in 14 patients (22%) and indeterminate in 6 patients (9%). Pulmonary metastases or a new lung primary were present in 10 patients (16%): 7 of 14 patients with positive PET-CT scans (50%) and 3 of 50 patients with negative or indeterminate PET-CT scans (6%). Including nonpulmonary sites, the overall incidence of distant disease was 23% (15/64) with 20% (13/64) unsuspected prior to PET-CT. The sensitivity and specificity of PET-CT in predicting distant malignancy was 86% and 84%, respectively, with a positive predictive value of 60% and a negative predictive value of 95%. There was a significant correlation between standardized uptake value (SUV) on PET-CT and positive histology, with a mean SUV of 8.5 (range, 4.7-16.2) in patients with distant metastases compared with a mean SUV of 2.9 (range, 1.9-4.2) in patients with benign pathology (r = 0.87, P < .0001). CONCLUSIONS: A significant number of patients with recurrent HNSCC have distant metastases at the time of recurrence. These data suggest that PET-CT improves detection of metastatic disease in the high-risk patient and should be performed as part of the routine evaluation of patients with suspected recurrence prior to salvage surgery.

The effect of treatment on survival in patients with advanced laryngeal carcinoma.

OBJECTIVES/HYPOTHESIS: Over the last 2 decades, survival from laryngeal cancer has decreased. We sought to identify factors associated with decreased survival in laryngeal cancer. METHODS: Patients diagnosed with laryngeal squamous cell carcinoma from 1985 to 2002 were retrospectively reviewed. RESULTS: A total of 451 patients met study criteria. Five-year survival rates were 85% for stage I, 77% for stage II, 51% for stage III, and 35% for stage IV disease. Survival for patients with stage I-III disease was similar for patients treated operatively or nonoperatively (P = .4). However, patients with stage III disease treated nonoperatively had worse survival with radiation alone (XRT) compared to chemoradiation (CR) (P = .006). Patients with stage IV disease had significantly better survival with surgery (49%) than CR (21%) or XRT alone (14%) (P < .0001). Analysis by primary tumor stage demonstrated that survival for T1-T3 disease was independent of treatment modality (P = .2); however, for T4 patients, operative treatment was associated with significantly better survival (55%) than CR (25%) or XRT (0%) (P < .0001). Proportional hazards models confirmed significantly worse survival for stage IV, T4, N2 or N3 disease, and nonoperative treatment. For T4 disease, after controlling for nodal status, nonoperative treatment was the only significant predictor of worse survival. CONCLUSIONS: Primary surgical treatment is associated with improved survival for patients with stage IV disease and specifically T4 primary tumors. These data suggest that the observed national decrease in survival from laryngeal cancer may be due to a shift toward nonoperative treatment in that subset of patients with advanced primary disease.

Revisiting the role of positron-emission tomography/computed tomography in determining the need for planned neck dissection following chemoradiation for advanced head and neck cancer.

OBJECTIVES/HYPOTHESIS: Planned neck dissection following chemoradiation (CR) has been advocated in patients with head and neck squamous cell cancer (HNSCC) with advanced nodal disease and a clinical complete response to CR because of the potential for residual occult nodal disease. The utility of positron-emission tomography/computed tomography (PET-CT) in identifying occult nodal disease in this scenario is controversial. METHODS: The medical records of all patients treated with CR for advanced HNSCC with N2 or N3 disease from December 2003 to June 2007 were reviewed. Patients with a complete clinical response were included if PET-CT performed 8 to 11 weeks after CR showed no distant disease and they underwent planned neck dissection. RESULTS: Thirty-two patients met study criteria. PET-CT was positive for residual nodal disease in 20 patients (63%). Pathology revealed carcinoma in 10 patients (31%): six of 20 patients with positive PET-CT scans (30%) and four of 12 patients with negative PET-CT scans (33%). The sensitivity and specificity of PET-CT was 60% and 36%. Regional recurrence developed in two patients (6%) who were not successfully salvaged. CONCLUSIONS: PET-CT performed 8 to 11 weeks after CR does not reliably predict the need for planned post-treatment neck dissection in patients with a complete clinical response following CR. Regional recurrence rates are comparable to those reported for patients observed with PET-CT, suggesting no advantage for planned neck dissection, and salvage rates were poor. These data suggest that delaying the timing of PET-CT, with surgery reserved for positive findings, is a reasonable alternative to planned neck dissection to avoid unnecessary surgery.

The effect of occult nodal metastases on survival and regional control in patients with head and neck squamous cell carcinoma.

OBJECTIVES: To determine factors associated with disease-free survival (DFS) and regional control in clinically node-negative head and neck squamous cell cancer (HNSCC) patients with occult metastasis. STUDY DESIGN: Non-randomized retrospective analysis. MATERIALS AND METHODS: Patients who underwent elective neck dissection (END) from 1985 to 2002 were analyzed. RESULTS: A total of 337 patients underwent END. The majority of patients (67%) had advanced stage disease (T3/T4). Occult metastases were present (pN+) in 168 patients (50%), with extracapsular spread (ECS) present in 72 patients (43%). Five-year DFS for patients with histologically node negative necks was 62% versus 36% for pN+ patients (P < .0001). Postoperative radiation (XRT) did not significantly influence DFS for pN+ patients with less than three nodes involved, but had a significant association with DFS with three or more nodes involved (P < .0001). XRT showed a trend toward improved regional control rates in patients with less than three positive nodes (86% vs. 78%; P = .7579) and patients with three or more positive nodes (62% vs. 50%; P = .0014). When ECS was present, XRT did not affect DFS in patients with less than three nodes (36%), but had a significant effect on DFS in patients with three or more nodes (20% vs. 0%; P = .0075). Regional control rates were not improved with XRT in ECS-positive patients with less than three nodes (62% vs. 75%) or with three or more nodes involved (43% vs. 50%; P = .0678). CONCLUSIONS: There is a high incidence of occult metastases in clinically node-negative patients which adversely affects survival, regardless of the use of adjuvant XRT. Postoperative XRT did not significantly affect regional control or survival rates in patients with <3 positive nodes. When ECS was present, survival was poor regardless of the number of nodes. These data emphasize the prognostic and therapeutic role of END and highlight the need for the development of novel therapeutic regimens to improve disease control and survival in HNSCC patients with nodal metastases.

Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia.

Intravenous immunoglobulin (IVIG) therapy is associated with rare reports of thromboembolic events and severe hyponatremia. We hypothesized that IVIG therapy may result in hyperproteinemia, increased serum viscosity, and pseudohyponatremia. We conducted a prospective observational study to evaluate the incidence of hyperproteinemia occurring after IVIG therapy and its relationship to serum sodium, viscosity, osmolality, and the serum osmolar gap. Eighteen IVIG infusions at a standard dose of 2 g/kg administered over 2-5 days were evaluated. Serum glucose, sodium, protein, viscosity, osmolality, and a calculated osmolar gap were obtained prior to therapy, 6 hr after the initiation of therapy, 24 hr after the conclusion of therapy, and on post-treatment day 10. Paired t-testing revealed a statistically significant increase in serum protein and viscosity and decrease in serum sodium and calculated osmolality 24 hr after the completion of IVIG therapy. The calculated serum osmolar gap increased insignificantly. In multivariate analysis, hyperproteinemia at the 6-hr time point predicted hyponatremia (P < 0.000), and hyperproteinemia at the 24-hr time point predicted both hyponatremia and increased serum viscosity (P = 0.024). These data demonstrate that increased serum viscosity occurs following IVIG therapy due to hyperproteinemia, and the rare hyponatremia reported is a pseudohyponatremia also due to hyperproteinemia.