Thanjavur S. Ravikumar

Patterns of failure after surgical cure of large liver tumors: A change in the proximate cause of death and a need for effective systemic adjuvant therapy☆☆☆

During a period of 7 years, we have aggressively treated liver tumors whether primary or metastatic. Our experience after 43 curative major liver resections has shown an excellent overall survival: 34 of 43 patients still alive a median of 12 months after liver resection (patient ages ranged from 21 to 85 years, median 57 years). Nineteen patients underwent right hepatic lobectomy, 9 trisegmentectomy, 5 left hepatic lobectomy, 5 extended left hepatic lobectomy, 4 right lobectomy plus left lobe wedge resection, and 1 patient underwent a major hilar wedge resection. Two patients died from sepsis and hepatic failure on or before the 60th postoperative day. One patient with no evidence of recurrent colorectal cancer was lost to follow-up after 2.5 years. One patient died without cancer 12 months after left hepatic lobectomy for colon cancer metastases. Cumulative survival for the entire series and for patients after resection of colorectal cancer metastases was the same: 1 year survival 90 percent; 2 year survival 75 percent, and 3 year survival 65 percent. Seventeen of 30 patients remain disease-free after resection of liver metastases. Of the 13 who had recurrence, 8 are still alive. Ten recurrences were outside of the residual liver (predominantly multiple pulmonary metastases). One recurrence was in the right hemidiaphragm, and only three were in the residual or regenerated liver. Serial carcinoembryonic antigen analysis was the best indicator of recurrence in these 13 patients, 12 of whom were asymptomatic. These data confirm that major liver resection can be performed with minimum postoperative mortality (4.7 percent in this series). More importantly, the majority of patients were cured of their liver metastases. The next goal should be the initiation of adjuvant systemic therapy trials after liver resection in such patients.

Effects of tumor growth on interleukins and circulating immune complexes. Mechanisms of immune unresponsiveness

This study delineates the temporal relationship between immune complex formation and tumor growth, and provides one possible explanation for host immunosuppression during tumor growth. The authors have studied serial circulating immune complex (CIC) levels and interleukin (IL) elaboration by peripheral blood cells (IL‐1 production by adherent mononuclear cells [AMC]; and IL‐2 generation by peripheral blood mononuclear cells [PBMC]) during the growth of syngeneic tumor isografts in an inbred rat model. Male Wistar/Furth (W/Fu) rats were injected, subcutaneously (SC) with 2 × 106 W163 (a dimethylhydrazine [DMH]‐induced colon adenocarcinoma) cells into their hind limbs. Serial CIC levels, (measured by the antigen nonspecific polyethylene glycol turbidity assay) and IL‐1 and IL‐2 production were measured before isografting and weekly thereafter. Progressive local tumor growth occurred for 3 weeks followed by regional lymph node metastases during the fourth week. During local tumor growth, there was a progressive rise in CIC levels (123% rise compared with baseline value; P < 0.05) which correlated with a fall in both IL‐1 and IL‐2 generation (r = −0.768). At the time of regional metastasis, the mean CIC levels declined, and there was a further significant decrease in IL production (IL‐1 = 0.9% and IL‐2 = 10% of controls in tumor bearers). These results show that progressive tumor growth results in decreased IL production by host PBC, and suggest that CIC may be involved in regulating IL generation. Cancer 53:1373‐1378, 1984.

The effect of alloimmunization on recurrence in an experimental colon cancer model

Primary bowel tumors were induced in Wistar/Furth (W/Fu) rats by 16 weekly injections of 1,2‐dimethyl‐hydrazine (DMH). After curative resection, 70% to 75% of control rats who receive no further treatment developed local or regional recurrence within 22 weeks. Rats immunized with three weekly subcutaneous inoculations of 1 × 106 irradiated (10,000 rad) Brown Norwegian (BN) × W/Fu F1 or Buffalo (Bu) tumor cells (both containing colon cancer tissue‐type specific antigens {TSA} but differing from the W/Fu at Ag‐B {histocompatibility} loci) developed recurrent tumor at a rate not significantly different from untreated or concurrent Ag‐B antigen matched non‐TSA treated controls. By 22 weeks after tumor resection, 63% of rats immunized with BN × W/Fu F1 colon adenocarcinoma and 52% of those immunized with Bu adenocarcinoma had recurred. Sixty‐one percent and 44% were the respective recurrence rates for rats immunized with strain matched renal cell tissue. These data show nonspecific protection against tumor recurrence because of alloimmunization but clearly demonstrate the subordination of any beneficial colon cancer TSA immunotherapeutic effect by contained histocompatibility antigens. The problem of such nonspecific immune stimulation by alloantigen overriding an expected specific effect by TSA and possible alternative methods of immunization to prevent this phenomenon are discussed.

Characterization of antigenic components from circulating immune complexes in patients with gestational trophoblastic neoplasia.

The authors have studied serial circulating immune complex (CIC) levels in 15 patients with gestational trophoblastic neoplasia (GTN) for several reasons. Gestational trophoblastic neoplasia can easily be followed from presentation to remission, and CIC changes can be compared with changes in human chorionic gonadotropin (HCG) which is a specific and quantitative marker of trophoblastic tumor load. Twelve patients with hydatidiform molar pregnancy presented with normal CIC levels (255 δ OD450 ± 97, mean SE [standard error]) as measured by our antigen nonspecific polyethylene glycol (PEG) turbidity assay. Only after reduction in tumor load as monitored by a fall in HCG did CIC rise. In contrast, three patients with choriocarcinoma presented with significantly elevated CIC levels (513 δ OD450 ± 147, P < 0.05 compared to normals) which slowly declined in parallel with HCG levels following evacuation and chemotherapy. Sera at peak PEG‐CIC from three patients with molar pregnancy or choriocarcinoma were precipitated with 3.75% polyethylene glycol to concentrate circulating immune complexes. Circulating immune complex levels were fractionated on Sephadex G‐200 in an acid buffer (pH = 2.8). An identifiable antigenic component of the CIC in both diseases was found to be paternal HLA antigen. This was demonstrated by the ability of the latest eluting CIC fraction to inhibit paternal lymphocyte lysis using anti‐HLA antisera against the husbands HLA tissue type. In each case, this fraction contained no immunoglobulin or beta‐2 microglobulin and was antigenically crossreactive with only one of the husbands HLA haplotypes. The authors believe the PEG‐CIC assay has allowed them to define the kinetics of host humoral response in GTN, and has provided a method for recovering immunogenic tumor‐associated antigens from these complexes which may apply to other solid tumors. Cancer 53:1316‐1321, 1984.

Tumor Growth, Interleukins, and Immune Complexes

Using an antigen-nonspecific assay for circulating immune complexes (PEG-CIC) that detects immune complexes in regions of both antigen and antibody excess, we have shown in our recent studies that changes in serial PEG-CIC levels correlate with changes in tumor volume in a variety of human and animal tumors (Jerry et al., 1976; Rodrick et al., 1983). Furthermore, the elevations in CIC levels were shown to precede decreases in T-cell mitogenic responses to PHA. The precise mechanism of immune modulation in tumor-bearing hosts still remains unclear although regulatory interactions between host immunocytes are undoubtedly involved. As interleukins (IL) play a central role in the mediation and amplification of immune response, and as our earlier data pointed to a temporal relationship between changes in PEG-CIC and tumor growth, we postulated that immune complexes by perturbing intercellular interactions might decrease IL generation.