E. George Elias

Natural history of adrenal cortical carcinoma: A clinicopathologic study of 42 patients

To study the biologic behavior and natural history of this rare but challenging tumor faced by oncologists, a clinicopathologic study of 42 patients with histologically proven adrenal cortical carcinoma from Roswell Park Memorial Institute (1929–1977) was done. These constituted .04% of all cancer cases and 0.2% of all autopsy cases. Age range was 3–74 years with median of 53 years; female to male ratio was 1.5 to 1. Clinical manifestations were: abdominal mass (36%), metastatic disease (30%), hormonal excess (17%) and weakness with lethargy (17%). Nine of ten functioning tumors were seen in female patients. Tumors arose in left adrenal in 26 patients, right adrenal in 12, and in four the site could not be determined because of bilateral presence of cancer. Median duration of symptoms was six months. At diagnosis, 52% had distant metastases, 41% had locally advanced tumor and 7% had tumor confined to adrenal. Sixteen patients underwent “curative” resection. Tumor diameter ranged from 1–30 cm with median of 10 cm. Of 28 patients who received different chemotherapeutic regimens, three (11%) had objective response; four of ten patients had objective response to radiation therapy. Overall median and five‐year survival rates were 14 months and 24%. Prolonged survival (P < .05) was noted in women, patients who had “curative” resection, a disease‐free interval of more than 12 months, and tumor size > 10 cm diameter. Patients with functional tumors had longer median survival than those with nonfunctional ones (28 vs. 12), but P value was > .05. A second primary cancer was noted in 22.4% of cases, breast and lymphoma being the most common. At autopsy in 31 patients, the most common metastatic sites were retroperitoneal lymph nodes 68%, lung 71%, liver 42%, and bone 26%. To improve survival, an aggressive surgical approach is recommended to extirpate the tumor with involved organs and retroperitoneal lymph nodes. Adrenal carcinoma should be suspected in patients with metastatic cancer with an occult primary.

Wnt5A activates the calpain-mediated cleavage of filamin A

We have previously shown that Wnt5A and ROR2, an orphan tyrosine kinase receptor, interact to mediate melanoma cell motility. In other cell types, this can occur through the interaction of ROR2 with the cytoskeletal protein filamin A. Here, we found that filamin A protein levels correlated with Wnt5A levels in melanoma cells. Small interfering RNA (siRNA) knockdown of WNT5A decreased filamin A expression. Knockdown of filamin A also corresponded to a decrease in melanoma cell motility. In metastatic cells, filamin A expression was predominant in the cytoplasm, which western analysis indicated was due to the cleavage of filamin A in these cells. Treatment of nonmetastatic melanoma cells with recombinant Wnt5A increased filamin A cleavage, and this could be prevented by the knockdown of ROR2 expression. Further, BAPTA-AM chelation of intracellular calcium also inhibited filamin A cleavage, leading to the hypothesis that Wnt5A/ROR2 signaling could cleave filamin A through activation of calcium-activated proteases, such as calpains. Indeed, WNT5A knockdown decreased calpain 1 expression, and by inhibiting calpain 1 either pharmacologically or using siRNA, it decreased cell motility. Our results indicate that Wnt5A activates calpain-1, leading to the cleavage of filamin A, which results in a remodeling of the cytoskeleton and an increase in melanoma cell motility.

Serum glycoproteins in head and neck squamous carcinoma: Correlations with tumor extent, clinical tumor stage, and T-cell levels during chemotherapy

Abstract In patients with solid malignancies, serum levels of specific acute phase proteins (haptoglobin, α 1 -acid glycoprotein, and α 1 -antitrypsin) have been correlated with parameters of both tumor extent and cellular immunity, while α 2 HS-glycoprotein and prealbumin have been correlated with parameters of cellular immunity. To determine the relation of the glycoproteins to these parameters in head and neck squamous carcinoma, serum levels were measured in 90 untreated patients, 51 cured patients, 11 patients with recurrent carcinoma, and 20 patients during preoperative chemotherapy. The control patients were 139 chronic cigarette smokers. Haptoglobin levels were significantly increased in patients with stage I through IV tumors (AJC-1977), but levels were similar for each stage. Serum levels of α 1 -antitrypsin and α 1 -acid glycoprotein increased progressively with increasing tumor stage. Serum α 2 HS-glycoprotein, prealbumin, and albumin levels were decreased in all patients, and α 1 HS-glycoprotein levels decreased progressively with increasing tumor stage. When patients were classified into those with local tumors only and those with regional metastases, and further subclassified by extent of local or regional tumor, the acute phase proteins generally increased with increasing local or regional tumor extent and α 2 HS-glycoprotein levels tended to decrease in the same groups. In cured patients, haptoglobin and α 1 -acid glycoprotein levels were significantly lower and α 2 HS-glycoprotein and prealbumin significantly higher than in untreated patients. Protein levels in patients with recurrent tumors were similar to levels in untreated patients. During acute immunosuppressive chemotherapy, levels of T-cells and α 2 HS-glycoprotein decreased significantly and similarly, and after completion of chemotherapy, rebounded to pretreatment levels, while α 1 -antitrypsin levels increased and haptoglobin and α 1 -acid glycoprotein levels did not change. The data show that α 1 -antitrypsin and α 1 -acid glycoprotein correlate better with AJC tumor stage than cellular immune parameters previously studied and that α 2 HS-glycoprotein levels may be as useful as T-cell levels for monitoring immune reactivity in patients with squamous cancer of the head and neck. These results suggest the potential of these biologic parameters as adjuncts in the derivation of improved staging systems and as indicators of tumor status and immune reactivity in patients with squamous carcinoma of the head and neck.

Immuno-Expression of Human Melanoma Stem Cell Markers in Tissues at Different Stages of the Disease

BACKGROUND Human cutaneous melanoma can be one of the most aggressive tumors and is extremely resistant to all current therapeutic modalities. Immunohistochemistry (IHC) studies were undertaken to assess independent relative frequency on preferential overexpression and simultaneous expression of four stem cell markers; CD133+, ABCB5+, CD166, and Nestin, at different stages of the disease. MATERIAL AND METHODS Five-micron sections from paraffin blocks from primary melanoma, lymph node (LN) metastases, distant metastases, benign nevi from non-melanoma patients (NMP), and patients with past history of melanoma (MP) were IHC stained with monoclonal antibodies (mAb) to the four stem cell markers. RESULTS Overexpression of CD133+ was noted in tissues from LN and distant metastases compared to benign nevi (P < 0.0022, P < 0.013, respectively). Overexpression of ABCB5+ was observed comparing primary melanoma, LN, and distant metastases to benign nevi from NMP (P < 0.0063, P < 0.001, P < 0.00058, respectively). Significant overexpression of ABCB5+ was noted in tissues from LN and distant metastases compared with benign nevi from MP (P < 0.0003, P < 0.0068). None of the benign nevi of NMP demonstrated ABCB5+. CONCLUSIONS This study clearly shows the existence of a distinct hyperpolarized population of stem cells and may implicate genetic factors in human cutaneous melanoma. Simultaneous overexpression of CD133+ and Nestin could reflect on their origin or lineage association with a neural stem cell. These findings may open new perspectives for therapeutic implication of a melanoma stem cell in specific cancer therapy.

Infection among 210 patients with surgically staged Hodgkin's disease

To determine the incidence and types of infections in Hodgkins disease, particularly those related to the overwhelming pneumococcal sepsis syndrome, 210 consecutive patients with previously untreated Hodgkins disease who underwent staging laparotomy with splenectomy from March 1968 to October 1979 were reviewed. For 178 patients (85 percent) alive at the end of the study, the mean follow-up time was 68.1 months. Eighty-two serious infections occurred among 59 (28 percent) of the patients; 47 (57 percent) serious infections were microbiologically documented and 35 (43 percent) were clinically documented. Forty-seven microbiologically documented serious infections occurred in 34 patients and consisted of 23 episodes of pneumonia, 10 cases of bacteremia, seven wound infections, two cases of disseminated herpes zoster, one subphrenic abscess, and four miscellaneous infections. Microbiologically documented serious infections occurring during initial treatment or remission had lower incidences of leukopenia (29 versus 58 percent) (p = 0.09) and death (11 versus 53 percent) (p = 0.005) than those occurring after relapse of Hodgkins disease. Of the microbiologically documented serious infections, 76 percent were associated with a predisposing factor(s) (leukopenia, postoperative state, steroids, peripheral neuropathy, leukemia), of which 34 percent were fatal. Microbiologically documented serious infections unassociated with a predisposing factor were never fatal, including the only episode of pneumococcal sepsis in the series. In contrast to microbiologically documented serious infections, only 14 percent of clinically documented serious infections (versus 38 percent) were fatal. The overwhelming pneumococcal sepsis syndrome and other infections thought to be associated with the asplenic state are uncommon problems in patients with Hodgkins disease after splenectomy.

The risk of regional lymph node metastases in patients with melanoma less than 1.0 mm thick: recommendations for sentinel lymph node biopsy

BACKGROUND Lymphatic mapping and sentinel lymph node biopsy can upstage patients with intermediate thickness (1.0 to 4.0 mm) melanoma. Currently, there are no strict guidelines for sentinel lymph node biopsy in patients with melanoma <1.0 mm thick. STUDY DESIGN A retrospective review of our patient database (598 patients treated at two institutions in Baltimore, MD, between January 1970 and June 2002) was performed to identify patients with primary cutaneous melanoma <1.0 mm thick who developed recurrent disease. This cohort of patients with > or =5 years of followup from the date of diagnosis was compared with patients with primary melanoma of similar thickness and similar followup intervals without recurrent disease. RESULTS A total of 114 patients with primary cutaneous melanoma <1.0 mm thick were identified, 17 of whom developed disease recurrence. In 13 patients, the site of first recurrence was the regional lymph nodes and in 4 patients disease recurred with distant metastases. The median time to lymph node recurrence was 55 months (range 2 to 112) months. Patients with regional lymph node recurrences had a significant (p = 0.02) difference in median primary tumor thickness of 0.80 mm versus 0.45 mm in patients without recurrent disease; there was no association of Clark level of invasion to recurrence (p = 0.42). In all, 35% of patients (7 of 20) presenting with melanoma 0.80 to 0.99 mm thick developed lymph node recurrence a median of 41 months (range 8 to 112 months) after surgical treatment. CONCLUSIONS Sentinel lymph node biopsy can be justified for patients with melanoma > or =0.8 mm thick provided that the technique would detect metastatic disease years before it becomes clinically evident.

Specific active immunotherapy in patients with adenocarcinoma of the colon utilizing tumor‐associated antigens (TAA). A phase I clinical trial

Twenty‐two patients received specific active immunotherapy (TAA vaccine once per month for 3 months), with the duration of follow‐up, as of July 1984, ranging from 3 months to 36 months (median, 21 months). Of these, seven had Dukes B2, seven had Dukes C, and eight had Dukes D lesions. All received surgical resection, and those with Dukes D disease underwent resection of all metastases where possible, with six clinically disease‐free at the time of initiation of therapy. The age range of the 22 patients was 40 to 73 years (median, 60 years); sex distribution was 12 males and 10 females. All patients were monitored by physical examination and by laboratory parameters including complete blood count, liver and renal function tests, blood chemistries, urinalysis, chest x‐ray, carcinoembryonic antigen levels, migration inhibition assays, complete immune complexes, serum chemistries, helper and suppressor and total T‐cell and B‐cell assays, and TAA antibody levels. As measured by delayed cutaneous hypersensitivity skin test and by migration inhibition assays (MIA), a strong postimmunization response is developed approximately 5 months after vaccination is completed. There were no clinical or biochemical manifestations of any type of systemic toxicity including hepatic, renal, gastrointestinal, respiratory, or neurologic during the period of follow‐up. All patients developed skin ulcers at the vaccination and required 4 to 5 months to heal. With this small number of patients in a Phase I trial, survival is indicative of the safety of the vaccine only: 82% of the patients are alive (mean survival, 21 months) thus far, and 59% of the patients are without evidence of disease (NED) (mean NED, 22 months). These studies, therefore, justify a Phase II‐III trial in a larger number of patients and have provided selection of appropriate monitoring tests for the larger trial.

Sequential Administration of GM-CSF (Sargramostim®) and IL-2 ± Autologous Vaccine as Adjuvant Therapy in Cutaneous Melanoma : An Interim Report of a Phase II Clinical Trial

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) are 2 cytokines with distinct mechanisms of action that complement one another in the adjuvant management of melanoma. Forty-five patients with high-risk melanoma were enrolled in an open-label, single-arm, phase II clinical trial to examine the safety, tolerability, and effectiveness of this combination. After potentially curative surgery, each patient received 12 months of GM-CSF 125 microg/m2/d subcutaneously (SC) for 14 days followed by IL-2, 9 million IU/m2/d SC for 4 days (given every other cycle from months 7-12), followed by 10 days of no treatment. In addition, patients who had tumors yielding an adequate number of live cells received autologous melanoma vaccines. For months 13-24, patients received only GM-CSF 250 microg/m2 twice weekly. This is an interim analysis based on the 45 enrolled patients with a median of 15.9 months follow-up (range, 1-50 months). Thirty-two patients are alive: 9 of 13 with stage IV resected melanoma, 16 of 25 with stage III disease, and 7 of 7 with stage II disease. Twelve died of the disease, and one due to stroke. Adjuvant use of sequential GM-CSF and IL-2 +/- autologous vaccine was well tolerated with good patient compliance and seemed to benefit high-risk patients with surgically resected melanoma.

Adjuvant immunotherapy in melanoma with irradiated autologous tumor cells and low dose cyclophosphamide

Patients with metastatic melanoma to their regional lymph nodes have a poor prognosis despite lymphadenectomy. In an attempt to improve their survival, this feasibility study was undertaken.

Resolution of inferior vena cava syndrome after embolization of a hepatic adenoma

A 77-year-old man presented with severe pruritus and massive lower body edema. Computerized axial tomography of the abdomen showed a large hepatic mass compressing the inferior vena cava, and a liver biopsy specimen showed hepatic adenoma. Embolization of vessels feeding the hepatic tumor resulted in complete resolution of pruritus and ascites, and clinical remission has persisted for 1 year following partial obliteration of tumor vasculature. Angiographic ablation of tumor blood supply represents a nonoperative means for inducing clinical remission in patients with symptomatic hepatic adenoma who are at high surgical risk.