Feasibility of pancreatectomy following high-dose proton therapy for unresectable pancreatic cancer.

AIM: To review surgical outcomes for patients undergoing pancreatectomy after proton therapy with concomitant capecitabine for initially unresectable pancreatic adenocarcinoma. METHODS: From April 2010 to September 2013, 15 patients with initially unresectable pancreatic cancer were treated with proton therapy with concomitant capecitabine at 1000 mg orally twice daily. All patients received 59.40 Gy (RBE) to the gross disease and 1 patient received 50.40 Gy (RBE) to high-risk nodal targets. There were no treatment interruptions and no chemotherapy dose reductions. Six patients achieved a radiographic response sufficient to justify surgical exploration, of whom 1 was identified as having intraperitoneal dissemination at the time of surgery and the planned pancreatectomy was aborted. Five patients underwent resection. Procedures included: Laparoscopic standard pancreaticoduodenectomy (n = 3), open pyloris-sparing pancreaticoduodenectomy (n = 1), and open distal pancreatectomy with irreversible electroporation (IRE) of a pancreatic head mass (n = 1). RESULTS: The median patient age was 60 years (range, 51-67). The median duration of surgery was 419 min (range, 290-484), with a median estimated blood loss of 850 cm3 (range, 300-2000), median ICU stay of 1 d (range, 0-2), and median hospital stay of 10 d (range, 5-14). Three patients were re-admitted to a hospital within 30 d after discharge for wound infection (n = 1), delayed gastric emptying (n = 1), and ischemic gastritis (n = 1). Two patients underwent R0 resections and demonstrated minimal residual disease in the final pathology specimen. One patient, after negative pancreatic head biopsies, underwent IRE followed by distal pancreatectomy with no tumor seen in the specimen. Two patients underwent R2 resections. Only 1 patient demonstrated ultimate local progression at the primary site. Median survival for the 5 resected patients was 24 mo (range, 10-30). CONCLUSION: Pancreatic resection for patients with initially unresectable cancers is feasible after high-dose [59.4 Gy (RBE)] proton radiotherapy with a high rate of local control, acceptable surgical morbidity, and a median survival of 24 mo.

Involved-node proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2 study.

PURPOSE: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. METHODS AND MATERIALS: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on (18)F-Fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. RESULTS: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. CONCLUSIONS: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes were similar to those of conventional photon therapy.

Male Breast Cancer and Hyperestrogenemia: A Thirteen-Year Review.

BACKGROUND: Male breast cancer (MBC) is a very rare malignancy and accounts for 0.1% of all male cancers. MBC has not been studied as extensively as its female counterpart. Certain clinical and pathological risk factors like smoking history, age at onset, family history of cancer, obesity, ethnicity, estrogen/progesterone receptor status and BRCA gene mutation status have all been studied well in the female breast cancer (FBC) patients and the clinical trial evidence from these studies is then extrapolated to treat and manage patients with MBC. One such area of interest is high levels of estrogen and its relationship with MBC. In our retrospect research study we aim to find an association between MBC and high levels of circulating estrogen at the time of diagnosis. METHODS: A 13-year retrospective review of the male breast cases at University of Florida College of Medicine's Tumor Registry was conducted. Data regarding certain clinic-pathological risk factors and MBC were collected and reviewed. Main surrogate indicators for elevated estrogen were examined, namely, low HDL (< 40 mg/dL), low albumin (< 4 g/dL) and high BMI (> 25). Presence of any one of these surrogates was seen as an indirect marker for high estrogen level. For cancer staging, the American Joint Committee on Cancer (AJCC) staging system was used. Stages 0-2 were grouped together as they are less extensive compared to stages 3-4 (also grouped together) which represent extensive disease. Univariate analysis was conducted using STATA 13 to do Fischer's exact test as cross-tables showed cell counts of five or less. The main comparison was that between extensive MBC (stages 3-4) and non-extensive breast cancer (stages 0-2). RESULTS: Between January 2000 and November 2013, we found a total of 2,129 cases of breast cancer patients at our institute. Out of these 2,113 (99.24%) were female and 16 (0.75%) were men. Four MBC patients were excluded because their complete charts could not be found in the medical records department. Six (50%) patients had one indicator, four (33%) patients had two indicators and one (8.3%) patient had all three. Eleven (91.6%) patients had precursors suggestive of hyperestrogenemia. Only one (8.33%) patient did not have any surrogate marker indicator of high estrogen levels. Two (16%) were black and 10 (83.33%) were white. Mean age was 61.75. Five (41%) had a first degree relative with a malignancy. Laterality was nine (75%) in the left breast, three (35%) in right breast. Eight (66.6%) found a mass on physical exam. Five (41.6%) had a positive smoking history. One patient had no data in the chart. Remaining all 11 (91.6%) had non-TNBC. One patient did not have complete documentation. Five (41.6%) had mastectomy, six (50%) received RT, four (33.3%) received chemotherapy and another four received hormone therapy. In terms of stage, four (33.3%) had stage 4, two (16.6%) stage 3B, two (16.6%) stage 2B, two (16.6%) stage 2A, one (8.33%) had stage 1C and one had stage 0. HDL data were available in seven (58.3%) with mean of 37, albumin in 10 (83.3%) with mean of 3.61, BMI in 11 (91.66%) patients with a mean of 33.30. Within subgroups, two patients were black and 10 white. Both black patients had LE disease (stage 0-2). Of the white patients, four (40%) had limited disease while six (60%) had extensive breast cancer. Family history assumed a similar distribution as three (60%) of patients with negative family history for cancer had limited disease and two (40%) had extensive one, same numbers applied for family-history-positive population. Three (60%) of patients with limited disease smoker and two (40%) did not. As for laterality, a total of nine patients had left-sided breast cancer, of whom five had had limited disease and four fell into the extensive disease category. The hormonal status for most patients were HER/NEU negative (seven out of 10 patients, two patients did not have this information on file), ER positive (11 out of 12) and PR positive (8 out of 12). Estrogen status: Low HDL was seen in three out of seven patients, low albumin in four out of 10 and obese BMI in nine out of 11. Finally, 11 out of 12 patients had at least one indicator of high estrogen. No significant change in prevalence of these markers was seen when comparing patients with limited and extensive disease. CONCLUSION: None of the aforementioned variables assumed statistical significance between the two subgroups. Results, however, show that as a whole, 11 out of the 12 patients had at least one indicator of high estrogen. Our results point in the direction that elevated estrogen is probably associated with MBC. Further meta-analysis of similar studies can be helpful to explain the dynamics of this association. Our statistical analysis was limited due to the small sample size, which is due to the extreme rarity of the disease.

Relationship of Gender and Smoking History in the Development of Hypothyroidism From Exposure to External Beam Radiation for Head and Neck Cancers.

BACKGROUND: Patients with head and neck cancers (HNCs) are often treated with external beam radiation therapy (XRT). Unfortunately this therapy is not without its unintended consequences. One of these side effects includes the development of radiation-induced hypothyroidism. Our study is designed to pay special attention to variables like gender and smoking history and analyze their relationship with the development of hypothyroidism. METHODS: Patients' charts were reviewed over a period of 13 years from January 1, 2000 to November 30, 2013 to gather information on patients who had previously received XRTs for HNCs. We used the Tumor Registry Database at the University of Florida, College of Medicine in Jacksonville for this retrospective review. Patient characteristics were examined including age, gender, race/ethnicity and smoking history. Special attention was paid to the development of hypothyroidism (thyroid stimulating hormones > 5.0 with appropriate decrease in free serum T4) levels after exposure to XRT for HNCs. Results were then analyzed using the univariate statistical analysis which was done using the SAS software using a 0.05 alpha level of significance expressed in terms of odds ratio (OR) with 95% confidence intervals (CIs). RESULTS: We found a total of 1,116 patients in our database who have received XRTs for HNCs. Out of these 72 (6.45%) patients developed hypothyroidism. Out of 263 African American patients 20 (7.6%) had hypothyroidism, whereas 49 (6%) out of 819 white people had this outcome. As for gender 32 out of 341 females (9.4%) and 40 out of 775 males had hypothyroidism. Thirty-five out of 544 (6.4%) with no family history and 19 (2.4%) out of 205 (9.3%) with positive family history for cancer had the outcome too. Finally 43 (6.5%) out of 664 smokers and 17 (8.3%) out of 206 non-smokers were found to develop hypothyroid as well. Both groups were found to have homogenous average age at diagnosis. When the univariate analysis was conducted, the strongest predicting variable was gender as hypothyroid patients were 1.90 (95% CI 1.17 - 3.09) times more likely to be females, and these results were statistically significant with P value of 0.008. More patients tended to be African Americans with OR 1.21 (CI 0.822 - 1.78), had positive family history of cancer (negative family history had OR 0.67 (CI 0.38 - 1.21), and less likely to be smokers (OR 0.77 (0.43 - 1.38). However, race, family history of cancer and smoking history did not achieve any statistical significance as evident by the P values. CONCLUSION: In our patient population, females were more likely to develop radiation-induced hypothyroidism.

Proton therapy may allow for comprehensive elective nodal coverage for patients receiving neoadjuvant radiotherapy for localized pancreatic head cancers.

BACKGROUND: Neoadjuvant radiotherapy has the potential to improve local disease control for patients with localized pancreatic cancers. Concern about an increased risk of surgical complications due to small bowel and gastric exposure, however, has limited enthusiasm for this approach. Dosimetric studies have demonstrated the potential for proton therapy to reduce intestinal exposure compared with X-ray-based therapy. We sought to determine if neoadjuvant proton therapy allowed for field expansions to cover high-risk nodal stations in addition to the primary tumor. METHODS: Twelve consecutive patients with nonmetastatic cancers of the pancreatic head underwent proton-based planning for neoadjuvant radiotherapy. Gross tumor volume was contoured using diagnostic computed tomography (CT) scans with oral and intravenous contrast. Four-dimensional planning scans were utilized to define an internal clinical target volume (ICTV). Five-mm planning target volume (PTV) expansions on the ICTV were generated to establish an initial PTV (PTV1). A second PTV was created using the initial PTV but was expanded to include the high-risk nodal targets as defined by the RTOG contouring atlas (PTV2). Optimized proton plans were generated for both PTVs for each patient. All PTVs received a dose of 50.4 cobalt gray equivalent (CGE). Normal-tissue exposures to the small bowel space, stomach, right kidney, left kidney and liver were recorded. Point spinal cord dose was limited to 45 CGE. RESULTS: Median PTV1 volume was 308.75 cm(3) (range, 133.33-495.61 cm(3)). Median PTV2 volume was 541.75 cm(3) (range, 399.44-691.14 cm(3)). In spite of the substantial enlargement of the PTV when high-risk lymph nodes were included in the treatment volume, normal-tissue exposures (stomach, bowel space, liver, and kidneys) were only minimally increased relative to the exposures seen when only the gross tumor target was treated. CONCLUSIONS: Proton therapy appears to allow for field expansions to cover high-risk lymph nodes without significantly increasing critical normal-tissue exposure in the neoadjuvant setting.

Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity.

BACKGROUND: To review treatment toxicity for patients with pancreatic and ampullary cancer treated with proton therapy at our institution. MATERIAL AND METHODS: From March 2009 through April 2012, 22 patients were treated with proton therapy and concomitant capecitabine (1000 mg PO twice daily) for resected (n = 5); marginally resectable (n = 5); and unresectable/inoperable (n = 12) biopsy-proven pancreatic and ampullary adenocarcinoma. Two patients with unresectable disease were excluded from the analysis for reasons unrelated to treatment. Proton doses ranged from 50.40 cobalt gray equivalent (CGE) to 59.40 CGE. RESULTS: Median follow-up for all patients was 11 (range 5-36) months. No patient demonstrated any grade 3 toxicity during treatment or during the follow-up period. Grade 2 gastrointestinal toxicities occurred in three patients, consisting of vomiting (n = 3); and diarrhea (n = 2). Median weight loss during treatment was 1.3 kg (1.75% of body weight). Chemotherapy was well-tolerated with a median 99% of the prescribed doses delivered. Percentage weight loss was reduced (p = 0.0390) and grade 2 gastrointestinal toxicity was eliminated (p = 0.0009) in patients treated with plans that avoided anterior and left lateral fields which were associated with reduced small bowel and gastric exposure. DISCUSSION: Proton therapy may allow for significant sparing of the small bowel and stomach and is associated with a low rate of gastrointestinal toxicity. Although long-term follow-up will be needed to assess efficacy, we believe that the favorable toxicity profile associated with proton therapy may allow for radiotherapy dose escalation, chemotherapy intensification, and possibly increased acceptance of preoperative radiotherapy for patients with resectable or marginally resectable disease.

Breast cancer and racial disparity between Caucasian and African American women, part 1 (BRCA-1).

Breast cancer is a commonly diagnosed malignancy and the second leading cause of cancer-related death among American women today. Despite the lower incidence of breast cancer among African American women, they are more likely to die from the disease each year than their white counterparts. We present a retrospective cohort study of the tumor registry data from electronic medical records of patients diagnosed with breast cancer at the University of Florida Health, Jacksonville from 2000 to 2005. A total of 907 patients were diagnosed with breast cancer; 445 patients with invasive breast cancer had complete medical records and were selected for this review. Much like previously published research, we found that African American patients presented with a more advanced stage and aggressive subtype of breast cancer than white patients, and were less likely to have health insurance. However, we have yet to determine if universal health care insurance can lead to improved health care access, better breast cancer awareness, and an enhanced attitude toward breast cancer screenings. Such factors would ultimately lead to an earlier diagnosis and better outcomes in both African American and white patients. We plan to investigate this critical issue in a follow-up study (BRCA-2; Breast Cancer and Racial Disparity Between Caucasian and African American Women, Part 2), which will begin a few years after the complete implementation of the universal health care law enacted by President Obama in 2010. The higher frequency of aggressive tumor subtypes in African American women warrants more attention. We suggest further research to determine whether decreasing the initial age for screening or increasing the frequency of mammograms in African American women would improve breast cancer outcomes. This study underscores the importance of identifying and preventing obstacles in routine breast cancer screening, as well as increasing breast cancer awareness.

Plasmablastic lymphoma of the stomach: an unusual presentation.

Plasmablastic lymphoma (PBL) is listed in the World Health Organization (WHO) classification as a subtype of diffuse large B-cell lymphoma (DLBCL). Some morphologic features of PBL are similar to DLBCL; however, PBL has minimal or no expression of CD20 and leukocyte common antigen. Instead, PBL has been characterized by the plasmablastic morphology of the cancer cells, with high mitotic figures. It is believed to be an aggressive lymphoma. We describe a case of a patient who seemed to pose a diagnostic dilemma, and who was later found to have PBL.

Improving the therapeutic ratio in Hodgkin lymphoma through the use of proton therapy.

The risk of serious late complications in Hodgkin lymphoma (HL) survivors has led to a variety of strategies for reducing late treatment effects from both chemotherapy and radiation therapy. With radiation therapy, efforts have included reductions in dose, reductions in the size of the target volume, and most recently, significant reductions in the dose to nontargeted normal tissues at risk for radiation damage, achieved by using the emerging technologies of intensity-modulated radiation therapy and proton therapy (PT). PT is associated with a substantial reduction in radiation dose to critical organs, such as the heart and lungs, and has the potential to improve not only the therapeutic ratio, but also both event-free and overall survival. This review addresses the rationale and evidence for--and the challenges, cost implications, and future development of--PT as an important part of the treatment strategy in HL.

Heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a growing complication of a common medication used to prevent deep vein thrombosis (DVT) in hospitalized patients. The purpose of this article is to review the mechanism that causes paradoxical thrombus formation in HIT and ways to recognize this important complication with various testing modalities and to discuss the approaches to treatment once a diagnosis has been made. HIT is a clinical diagnosis that can be further supported by utilizing the "4 Ts": thrombocytopenia, timing of platelet count fall, thrombosis or other complications, and other causes for thrombocytopenia. Diagnosis of HIT can be established using an HIT antibody test. Once a drop in platelet count is observed in a patient, it is important to rule out HIT. When HIT is first suspected, it is important to discontinue all heparin products. The gold standard in diagnosing HIT is the 14C-serotonin release assay (14C-SRA) assay, which has high sensitivity and specificity but is technically demanding and more time consuming than other antibody-detecting immunoassays. Anticoagulation in HIT patients is essential due to the increased risk of thrombosis. Treatment consists of utilizing alternative, nonheparin anticoagulants like lepirudin, argatroban, bivalirudin, or fondaparinux (although fondaparinux is not formally approved by the US Food and Drug Administration for this condition). Each of these agents should be individually formulated based on the patient and the presence/absence of liver or renal failure. Treatment duration has yet to be determined. However, in patients requiring long-term anticoagulation (pulmonary embolism, DVT, stroke), the transition to warfarin can be made once the platelet count recovers and there has been at least 5 days of overlap with a nonheparin anticoagulant.

Improving frontline treatment for chronic myeloid leukemia: emerging evidence for use of nilotinib and dasatinib.

The approval of imatinib in 2001 changed the landscape of chronic myeloid leukemia (CML) management, becoming the standard of care and improving the survival rates of patients. With the prevalent use of imatinib worldwide, it was observed that up to one-third of patients are resistant to or intolerant of imatinib therapy, fueling the search for safer and more effective agents. The newer and more potent tyrosine kinase inhibitors nilotinib and dasatinib were first indicated for the treatment of imatinib-resistant/-intolerant patients, for whom these agents are both safe and efficacious. More recent clinical studies have examined nilotinib and dasatinib in the frontline setting in newly diagnosed patients. Data reported from the phase III ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) study and the DASISION (Dasatinib versus Imatinib in Patients with Newly Diagnosed Chronic-phase CML) trial support the use of nilotinib and dasatinib as potential new standards for frontline care of newly diagnosed patients with CML in chronic phase. Furthermore, both agents have received regulatory approval for use as frontline agents. These agents have demonstrated significantly superior efficacy compared with imatinib, as measured by complete cytogenetic response and major molecular response rates. In addition, progression to advanced disease was significantly lower for nilotinib, and a trend toward lower progression was observed with dasatinib. Although both nilotinib and dasatinib are generally well tolerated in the frontline setting, they have different safety profiles that may affect their selection as treatment. Understanding the efficacy, safety profiles, and patterns of resistance to various BCR-ABL1 mutations of these newer agents, as well as implementing management strategies to treat adverse events, will help physicians to provide the best therapy options for their patients with CML.

Hepatitis C infection and the risk of bacteremia in hemodialysis patients with tunneled vascular access catheters.

BACKGROUND: The major complication of tunneled vascular catheters in dialysis patients is infection. In preliminary work, an association was noted between hepatitis C virus (HCV) infection and bacteremia in these patients. On this basis, we theorized that HCV infection may be associated with bacteremia in dialysis patients with tunneled catheters. METHODS: We conducted a two-phase clinical study to define the association between HCV infection and bacteremia in hemodialysis patients with catheters. Phase 1 was a cross-sectional study designed to assess the association between HCV serologic status and bacteremia. Phase 2 was a prospective study that examined the relationship between HCV viral load and bacteremia. RESULTS: In Phase 1, HCV (+) patients had a significantly greater prevalence of bacteremia than HCV (-) patients (61 vs 7.7% respectively, P < 0.05). In Phase 2, the presence of detectable virus was associated with a numerical trend toward an increase in the incidence of bacteremia (40 vs 0% for patients with and without detectable virus, respectively, P = 0.09). CONCLUSION: These studies suggest that HCV infection may be associated with the development of bacteremia in hemodialysis patients with tunneled catheters.

Blood culture isolates in hemodialysis vascular catheter-related bacteremia.

Hemodialysis requires reliable and recurrent access to the central circulation and arteriovenous fistulas or grafts are the preferred modes of vascular access. However, in many patients the use of external tunneled vascular catheters may be necessary. The major complication of tunneled catheters is infection. Understanding local epidemiologic patterns of dialysis catheter-related bacteremia may help in the management of these patients. To address this issue, we reviewed the 5-year microbiologic culture results from all bacteremic hemodialysis patients with tunneled catheters at our institution. During this period, there were 203 organisms isolated from 153 positive blood cultures. Gram-positive, Gram-negative, and fungal species represented 55.7%, 43.3%, and 1% of isolates, respectively. Positive blood cultures classified according to the presence of a single Gram-positive or single Gram-negative organism, single fungus, or polymicrobial organisms, accounted for 41.8%, 29.4%, 0.6% and 28.1% of infectious events. From 2000-2004, there was a numerical trend toward a decrease in Gram-positive infection (64.3% versus 34.8% respectively, P = 0.12) and a numerical trend toward an increase in Gram-negative and polymicrobial bacteremias (17.9 versus 21.7, P = 0.07 and 17.9 versus 43.5, P = 0.09, respectively). These data indicate that bacteremic events in hemodialysis patients with vascular catheters are commonly due to a single Gram-positive organism, but the incidence of Gram-negative and polymicrobial bacteremia may be increasing. If confirmed in a prospective trial, adjustment of empiric antibiotic regimens for suspected catheter-associated bacteremia may be indicated.