Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma.

BACKGROUND: Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC. EXPERIMENTAL DESIGN: Treatment consisted of cetuximab load at 400 mg/m(2) followed by cetuximab 250 mg/m(2) weekly and gemcitabine 50 mg/m(2) twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection. RESULTS: Thirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status. CONCLUSIONS: Neoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.

Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes.

We have investigated the mechanisms whereby adoptively transferred murine CD8+ lymphocytes mediate tumor regressions. Noncytolytic, CD8+ tumor-infiltrating lymphocytes (TIL) eradicated established lung tumors in irradiated mice. Many cytolytic and noncytolytic CD8+ TIL cultures specifically secreted interferon gamma (IFN-gamma) and tumor necrosis factor when stimulated with tumor cells in vitro. The effectiveness of TIL when adoptively transferred to mice bearing micrometastases correlated better with their ability to specifically secrete lymphokines than with their cytotoxicity in vitro. In 14 of 15 tests, therapeutically effective TIL specifically secreted IFN-gamma in vitro, whereas only 1 of 11 ineffective TIL specifically secreted IFN-gamma. In contrast, only 8 of 15 therapeutically effective TIL were cytolytic. Antibodies to TNF inhibited the effectiveness of two adoptively transferred TIL cultures. In five experiments, antibodies to IFN-gamma abrogated the ability of four different CD8+ TIL cultures to mediate tumor regressions, indicating that secretion of IFN-gamma is an essential part of the mechanism of action of TIL.

Intranodal immunization with tumor lysate-pulsed dendritic cells enhances protective antitumor immunity.

We developed a technique for direct inguinal lymph node injection in mice to compare various routes of immunization with tumor lysate-pulsed dendritic cell (DC) vaccines. Syngeneic, bone marrow-derived, tumor lysate-pulsed DCs administered intranodally generated more potent protective antitumor immunity than s.c. or i.v. DC immunizations. Intranodal immunization with ovalbumin peptide-pulsed DCs induced significantly greater antigen-specific T-lymphocyte expansion in the spleen than either s.c. or i.v. immunization. Furthermore, a significantly more potent, antigen-specific TH1-type response to the ovalbumin peptide was induced by intranodal, compared with s.c. or i.v., immunization. Intranodal immunization, designed to enhance DC-T cell interaction in a lymphoid environment, optimizes induction of T lymphocyte-mediated protective antitumor immunity. These results support the use of intranodal immunization as a feasible and effective route of DC vaccine administration.

Protective immunity induced by tumor vaccines requires interaction between CD40 and its ligand, CD154.

Interactions between CD40 and its ligand, CD154 (CD40L, gp39), have been shown to play a central role in the regulation of humoral immunity. Recent evidence suggests that this ligand-receptor pair also plays an important role in the induction of cell-mediated immune responses, including those directed against viral pathogens, intracellular parasites, and alloantigens. The contribution of this ligand-receptor pair to the development of protective immunity against syngeneic tumors was evaluated by blocking the in vivo function of CD154 or by studying tumor resistance in mice genetically deficient in CD40 expression (CD40-/-). In the former case, anti-CD154 monoclonal antibody treatment inhibited the generation of protective immune responses after the administration of three potent tumor vaccines: irradiated MCA 105, MCA 105 admixed with Corynebacterium parvum adjuvant, and irradiated B16 melanoma cells transduced with the gene for granulocyte macrophage colony-stimulating factor. Confirmation of the role of CD40/CD154 interactions in tumor immunity was provided by the overt tumor susceptibility in CD40-deficient mice as compared to that in CD40+/+ mice. In this case, wild-type but not CD40-deficient mice could be readily protected against live TS/A tumor challenge by preimmunization with TS/A admixed with C. parvum. These findings suggest a critical role for CD40/CD154 interactions in the induction of cellular immunity by tumor vaccines and may have important implications for future approaches to cell-based cancer therapies.

The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells.

This review focuses on the emerging body of literature suggesting a critical role for CD40/CD154 interactions in antigen-presenting cell (APC) activation, CD4+ and CD8+ T cell priming, and effector T cell maturation. In this context effective antigen presentation involves not only T cell expansion and long-term survival but also the ability of the APC to guide the T cell response toward the Th1 (interferon-gamma producing) or the Th2 (interleukin-4 producing) phenotype. We suggest a model to explain why CD40/CD154 interactions are critical for some helper and cytotoxic T cell responses, whereas others occur independently of this receptor/ligand pair. In addition, we will discuss the potential role for CD40/CD154 interactions in effector T cell maturation and cytokine production.

Identification of unique murine tumor associated antigens by tumor infiltrating lymphocytes using tumor specific secretion of interferon-gamma and tumor necrosis factor.

Stimulation of multiple CD8+ murine tumor infiltrating lymphocyte (TIL) lines and one TIL clone with the tumor of origin of the TIL induced at least three-fold more secretion of TNF and/or INF-gamma than was elicited by other syngeneic, methylcholanthrene (MCA) induced sarcomas. TIL which specifically secreted lymphokines were generated from three different sarcomas. Specific lymphokine secretion was a stable characteristic of the lines over time. IL-2 was necessary for maximal lymphokine secretion by TIL. These investigations demonstrate that lymphokine secretion by CD8+ lymphocytes derived from tumor bearing mice can be used to define unique tumor associated antigens on at least three different sarcomas and may be valuable in studies of the biologic nature of these antigens and of the adoptive immunotherapy of cancer.

Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas.

PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity associated with twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. METHODS AND MATERIALS: Twenty-one patients with biopsy-proven adenocarcinoma of the pancreas were treated with external-beam radiotherapy to a dose of 50.4 Gy in 28 fractions, concurrent with gemcitabine, infused over 30 min before irradiation on a Monday and Thursday schedule. The dose of gemcitabine was escalated in 5 cohorts of 3--6 patients each. Initial gemcitabine dose was 10 mg/m(2), with dose escalation until dose-limiting toxicity was observed. RESULTS: The maximum tolerated dose of gemcitabine was 50 mg/m(2), when given in a twice-weekly schedule with radiation. Dose-limiting toxicity was seen in 2 patients at 60 mg/m(2), and consisted of severe upper gastrointestinal bleeding approximately 1 month after completion of treatment. Six patients had radiographic evidence of response to treatment, and 5 of these underwent complete surgical resection. Three patients who underwent complete resection had been deemed to have unresectable tumors before enrollment on trial. Four patients are alive, including 2 without evidence of disease more than 1 year after resection. CONCLUSION: The combination of external-beam radiation and twice-weekly gemcitabine at a dose of 50 mg/m(2) is well tolerated and shows promising activity for the treatment of pancreatic cancer. Our data suggest a higher maximum tolerated dose and different dose-limiting toxicity than previously reported. Further investigation of this regimen is warranted.

A prospective study of the value of core needle biopsy and fine needle aspiration in the diagnosis of soft tissue masses.

We prospectively sampled 38 large soft tissue masses in 37 patients with both core needle biopsy (CNBX) and fine-needle aspiration (FNA) to determine the diagnostic utility of these biopsy methods. In 27 cases the histologic diagnosis made from the resected specimen was compared with the diagnosis based on the biopsy. CNBX correctly identified 16 of 16 malignant sarcomas and 10 of 11 benign masses (one was indeterminate). The grade of the sarcoma was determined correctly in every case. There were no false malignant or false benign CNBX diagnoses. FNA correctly classified 12 of 14 malignant sarcomas and four of 11 benign lesions. Diagnoses based on FNA were limited by a high proportion of samples, especially from benign lesions, that were inadequate for definitive diagnosis and by an inability to grade many malignant sarcomas. There were no significant complications resulting from the biopsies. We conclude that CNBX is a highly accurate, easily performed method for the diagnosis of large soft tissue masses that can be accomplished with minimal morbidity.

Short-term outcome after mesh or shouldice herniorrhaphy: a randomized, prospective study.

BACKGROUND: Retrospective analyses have shown that long-term recurrence rates after Lichtenstein mesh and Shouldice herniorrhaphies are low. Therefore differences in short-term outcome may be important determinants of one's choice of repair. Although proponents of the mesh repair claim that their methods is less morbid, to our knowledge no prospective comparative studies of short-term morbidity have been reported. METHODS: One hundred five adult patients were randomized to undergo either a mesh or Shouldice inguinal hernia repair. Postoperative pain, narcotic use, and time to resumption of usual activities and employment were recorded. Patients were blinded to the type of repair received until all data were collected. RESULTS: There was no difference between the herniorrhaphy methods with respect to postoperative pain, duration of narcotic use, and time to resumption of usual activity and employment. Recovery was rapid for both groups of patients. By 3 days after operation, 50% of patients rated their pain as very mild or less and no longer required narcotic analgesics. Patients in both groups returned to usual activity and work by a median of 9 days after operation. CONCLUSION: Both of these well-established methods can be used to repair inguinal hernias with local anesthetics in an outpatient setting with minimal morbidity. Despite the "tension-free" design of the mesh repair, short-term outcomes of mesh and Shouldice repairs of inguinal hernias do not differ.

Interval hepatic resection of colorectal metastases improves patient selection.

HYPOTHESIS: Interval reevaluation for resectability of hepatic colorectal metastases aids patient selection. DESIGN: A retrospective review. SETTING: A tertiary care medical center. PATIENTS AND METHODS: From January 1, 1985, to July 1, 1998, 318 patients with colorectal hepatic metastases were identified. Resectable lesions (N = 73) were divided into synchronous (n = 36) or metachronous (n = 37) and retrospectively reviewed for immediate resection or interval reevaluation. Kaplan-Meier survival curves of treatment groups were compared by the log-rank test. RESULTS: Survival curves of patients with synchronous and metachronous lesions undergoing interval reevaluation vs. immediate resection were not significantly different (P = .74 and P = .65, respectively). No lesions from patients who underwent interval reevaluation became unresectable due to growth of the initial metastases. After interval reevaluation, 8 (29%) of 28 patients with synchronous metastases were spared the morbidity of laparotomy because of distant or an increased number of metastases and 10 (36%) of 28 patients were spared the morbidity of hepatic resection at the time of interval laparotomy. Actuarial median and 5-year survival of patients after delayed hepatic resection (51 months and 45%, respectively) were significantly improved compared with those of all other patients with resectable metastases (23 months and 7%, respectively) (P = .02). For patients with metachronous lesions who underwent interval reevaluation, 4 (29%) of 14 patients were spared the morbidity of laparotomy because of an increased number of hepatic or distant metastases. CONCLUSIONS: Delaying hepatic resection for metastatic colorectal cancer does not impair survival. Potentially, two thirds of patients can avoid maj or hepatic surgery. For synchronous metastases, delaying hepatic resection appears to select patients who will benefit from hepatic resection.

Hypoprothrombinemia and hemorrhage in a surgical patient treated with cefotetan.

For 4 days before surgical repair of a diverticulitic colovesical fistula and for 6 days after, a 63-year-old man was treated with 2 g of intravenous cefotetan disodium every 12 hours for associated urosepsis with bacteremia. Postoperatively, the patient followed a diet of intravenous nutrition only. Uneventful convalescence was interrupted by signs of sudden major blood loss, accompanied by prolonged prothrombin time. After stabilization with packed red blood cells, fresh plasma, crystalloids, and parenteral vitamin K, laparotomy revealed a huge intra-abdominal clot, which was evacuated. This case illustrates the risk of unexpected hypoprothrombinemia and hemorrhage in a cefotetan-treated surgical patient who demonstrated none of the usual comorbid conditions generally described in patients with antibiotic-induced hypoprothrombinemia. Like cefamandole nafate, cefoperazone sodium, moxalactam disodium, and other cephalosporins containing the methylthiotetrazole side chain, cefotetan appears to pose an unusual risk of major bleeding.

Level of axillary involvement by lymph node metastases from breast cancer is not an independent predictor of survival.

We examined the relationship of axillary level of lymph node metastases from clinical stage I and II breast cancer to overall survival and disease-free survival rates in 135 patients who underwent complete axillary lymph node dissection to determine if anatomic level of axillary involvement (I vs II vs III) is an independent prognostic factor. All patients underwent either modified radical mastectomy or lumpectomy with axillary dissection and whole breast radiotherapy for breast cancer. Median follow-up was 6.9 years. We found no difference in overall survival or disease-free survival between patients whose highest or only level of axillary involvement was level I compared with patients whose highest or only level was II. Although patients whose highest level of nodal involvement was III had significantly worse overall survival and disease-free survival rates than patients whose highest nodal involvement was I or II, when patients were stratified by the total number of positive nodes (one to three vs four or more), there was no difference in overall survival or disease-free survival rates between levels I, II, and III. These findings indicate that the level of axillary involvement for stage II breast cancer is not of independent prognostic significance.

Communication effectiveness training improves surgical resident teaching ability.

BACKGROUND: An important educational objective of academic surgical programs is to train surgical teachers. Whether formal instruction of surgery residents in general principles of teaching has a role in the achievement of this objective is unproven. STUDY DESIGN: We tested whether the teaching ability of surgery residents could be improved by two different interventions: (A) a lecture on communication effectiveness plus home study of their own videotaped lectures and (B) a critical review of their own videotaped lectures with a teaching consultant. Each resident taught four sessions. There was no intervention between sessions 1 and 2; intervention A occurred between sessions 2 and 3; and intervention B, between sessions 3 and 4. Each of the four videotaped sessions was graded for communication effectiveness using a standardized scoring form. RESULTS: There were no significant differences between scores from lectures 1 and 2 (no intervention) or lectures 2 and 3 (intervention A). Intervention B (individualized feedback) resulted in significant improvement in all scores from session 4 compared with sessions 1 and 2: content 3.40 versus 2.98 (p = 0.01), language 3.43 versus 3.22 (p = 0.03), delivery 3.25 versus 2.87 (p = 0.002), and overall 3.43 versus 2.88 (p = 0.002). CONCLUSIONS: Surgical resident teaching ability can be improved by communication effectiveness teaching. Individualized feedback is more effective than a lecture combined with self-study.

Preoperative diagnosis of acromegaly by growth hormone-releasing factor radioimmunoassay.

Acromegaly was diagnosed in a 37-year-old woman with classical physical and biochemical findings; an enlarged sella on computed tomography suggested the presence of a pituitary macroadenoma. Radiologic evidence of a lung mass prompted radioimmunoassay of plasma growth hormone-releasing factor (7,500 pg/ml; normal less than 100 pg/ml). After resection of a bronchial carcinoid, which stained positive for growth hormone-releasing factor, circulating growth hormone-releasing factor levels normalized. Subsequently, her clinical, biochemical, and radiologic evidence for acromegaly resolved. This case represents the first reported use of the human pancreatic growth hormone-releasing factor 1-40 radioimmunoassay to preoperatively diagnose this rare etiology of acromegaly.

Histologic features predict local recurrence after breast conserving therapy of phyllodes tumors.

BACKGROUND: Pathologists can distinguish benign phyllodes tumors, which very rarely metastasize, from malignant phyllodes tumors, which metastasize in approximately one fourth of patients. However, whether these same histologic criteria can be used to predict the likelihood that a phyllodes tumor will locally recur after breast conserving therapy remains controversial. STUDY DESIGN: Since few patients with malignant phyllodes tumors have been treated with breast conserving surgery in any individual series, the literature was reviewed using a Medline search. RESULTS: After local excision, 21% (111/540), 46% (18/39), and 65% (26/40) of patients with benign, borderline, and malignant phyllodes tumors, respectively, recurred in the breast. Following wide local excision, 8% (17/212), 29% (20/68), and 36% (16/45) of patients with benign, borderline, and malignant phyllodes tumors recurred in the breast. CONCLUSIONS: Malignant phyllodes tumors are much more likely than benign phyllodes tumors to recur in the breast after breast conserving surgery. This high rate of local recurrence of borderline and malignant phyllodes tumors suggests that wide local excision is less than optimal therapy, and challenges us to look for methods to improve local tumor control.

The mislabeling of sexual impulsivity.

Several authors have discussed a pattern of behavior that has been called Compulsive Sexual Behavior, Sexual Addiction, or Hypersexuality. The literature concerning this disorder is reviewed. It is suggested that the various labels applied to this disorder are inaccurate descriptions that are not reflective of the true nature of the condition. It is further suggested that this behavioral pattern is best viewed as a manifestation of an Atypical Impulse Control Disorder.

The use of art therapy in marital and sex therapy.

The literature pertaining to the use of art therapy in marital and sex counseling of couples is reviewed. All articles in this area are based on case study reports; therefore, their conclusions must be considered with caution. Art therapy techniques which have been developed for use in marriage counseling are identified, and several advantages to the use of these procedures are cited. Suggestions for research to validate these procedures are discussed.

The prognosis of melanoma patients with metastases to two or more lymph node areas.

The prognosis of melanoma patients who present with metastatic involvement of two or more noncontiguous lymph node regions before the detection of extranodal metastases has not been previously reported. We identified 21 patients with metastatic melanoma in at least two nodal basins in a review of 175 patients with melanoma undergoing lymphadenectomy at the National Cancer Institute. The median survival time of these patients was 46 months, with 55%, 27%, and 17% of the patients alive 2, 5, and 10 years, respectively, after the second lymphadenectomy. Because the prognosis of melanoma patients with metastases to two or more regional nodal areas appears equivalent to that of patients with metastatic involvement of only one regional node site, lymphadenectomy of the involved groups should be performed with therapeutically curative intent.

Cutaneous fibrous histiocytoma with osteoclast-like giant cells.

We report a case of a rare variant of benign fibrous histiocytoma composed of abundant, multinucleated, osteoclast-like giant cells. Local excision with negative margins is the treatment of choice.

In vivo effects of locally secreted IL-10 on the murine antitumor immune response.

BACKGROUND: Interleukin-10 (IL-10) is a cytokine secreted by the TH2 class of murine lymphocytes that suppresses the secretion of interferon-gamma (IFN-gamma) by TH1 lymphocytes and inhibits macrophage-mediated T-cell stimulation and cytotoxicity. The observation that IL-10 is produced by human carcinomas in vitro and in vivo led to the hypothesis that this cytokine plays a role in the suppression of the human anti-tumor immune response. We tested this hypothesis in a murine model. METHODS: To evaluate the effect of IL-10 on the induction of an anti-tumor immune response, mice were immunized with tumor cells transfected with the IL-10 gene and then challenged with parental tumor. The effect of the local secretion of IL-10 on an established immune response was tested by immunizing mice with parental tumor and then challenging with IL-10-secreting tumors. RESULTS: IL-10-secreting tumors were as effective immunogens as control tumors. Immune mice rejected IL-10-secreting tumors as readily as control challenge tumors. In an in vitro assay, IL-10 did not inhibit CD8 lymphocyte secretion of IFN-gamma in response to tumor stimulation. One IL-10-secreting tumor clone regressed when injected into naive mice and induced an antigen-specific immune response capable of protecting mice from subsequent tumor challenge. CONCLUSIONS: The local secretion of IL-10 did not inhibit either the induction of an antitumor immune response or the ability of established effector cells to reject challenge tumors. In contrast to its effect on TH1 lymphocytes, IL-10 does not inhibit IFN-gamma secretion by CD8 lymphocytes.