A phase II study of active specific immunotherapy and 5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma.

Active specific immunotherapy, using vaccines with autologous tumour cells and BCG, significantly reduces the rate of tumour recurrence in stage II colon cancer patients, while no clinical benefit has yet been observed in stage III patients. Adjuvant treatment with 5-Fluorouracil/Leucovorin is now considered standard therapy for stage III colon carcinoma and results in an absolute survival benefit of approximately 10%. Yet, the 5-year overall survival rate of stage III colon cancer patients is only 40-50%. Combining chemotherapy and immunotherapy might improve prognosis for stage III patients, especially when considering that active specific immunotherapy and chemotherapy have shown synergistic effects in pre-clinical tumour models. We performed a phase II study with 56 patients, using the combination of active specific immunotherapy and chemotherapy as an adjuvant therapy in stage III colon cancer patients to assess the influence of 5-Fluorouracil/Leucovorin on anti-tumour immunity induced by autologous tumour cell vaccinations. Anti-tumour immunity was measured before and after chemotherapy by means of delayed type hypersensitivity reactions, taken 48 h after the third and the fourth vaccination. We also investigated the toxicity of this combined immuno-chemotherapy treatment. Delayed type hypersensitivity reactions before chemotherapy had a median size of 20.3 mm, while after chemotherapy delayed type hypersensitivity size was 18.4 mm (P=0.01), indicating that chemotherapy hardly affected anti-tumour immunity. The severity of ulcers at the BCG vaccination sites was comparable to previous studies. In 30% of the patients grade III or grade IV chemotherapy related toxicity was seen; this is comparable to what is normally observed after adjuvant chemotherapy alone. This study shows that the active specific immunotherapy-induced anti-tumour immune response is only minimally impaired by consecutive chemotherapy and that the combined treatment of stage III colon cancer patients with active specific immunotherapy and 5-Fluorouracil/Leucovorin does not cause unexpected toxicity.

Reaction of a complexed phosphinidene with 2,4,6-tri-tert-butyl-1,3,5-triphosphabenzene.

The terminal phosphinidene complex PhPW(CO)5 reacts with 2,4,6-tri-tert-butyl-1,3,5-triphosphabenzene to give two unexpected multicyclic organophosphorus compounds. One of them results from an initial 1,2-addition, followed by an intramolecular rearrangement. B3LYP/6-31G* calculations on simplified parent systems suggest that the reaction follows a unique concerted reaction pathway. The second, and major, product is a tetraphosphaquadricyclane derivative, which presumably results from an intramolecular [2+2] cycloaddition of an intermediate tetraphosphanorbornadiene complex. Single-crystal X-ray structures are presented for both products.

Addition of a phosphinidene complex to C=N bonds: P-ylides, azaphosphiridines, and 1,3-dipolar cycloadditions.

The terminal phosphinidene complex PhPW(CO)5 adds to the imine bond of PhHC=N-Ph to give 3-membered ring azaphosphiridines, which undergo ring-expansion with an additional imine to yield a set of four isomeric five-membered ring diazaphospholanes. Treatment with the diimines PhHC=N-(CH2)n-N=CHPh (n=2,3,4) results instead-in all three cases-in only a single isomer of the (CH2)n bridged diazaphospholane. For n=2 or 3, this aminal group is easily hydrolyzed to afford new 6- and 7-membered ring heterocycles. No intermediate azaphosphiridine complex is observed during the addition reaction to the diimines. B3LYP/6-31G* calculations on an unsubstituted, uncomplexed system suggest that the initially formed P,N-ylide of the H2C=N-(CH)2-N=CH2 diimine both kinetically and thermodynamically favors an intramolecular 1,3-dipolar cycloaddition over an imine insertion into the CPN ring of an intermediate azaphosphiridine. Single-crystal X-ray structures for the (CH2)2-bridged azaphospholane complex and the HCl adduct of the 7-membered hydrolysis product are presented.

Reactivity of ether- and amine-complexed dimers and tetramers of alkyllithiums towards triphenylmethane.

Kinetics of Lewis base (LB) complexed primary and secondary sigma-alkyllithiums (RLi) with triphenylmethane (TPMH) are reported. RLis in which one or two LB groups (-OMe, -NMe, -NMeR) are part of the molecule form, in benzene, intramolecularly complexed tetramers, for example, 2(4), or dimers, for example, 4(2). They are used as models for their intermolecular congeners R4Li4 x 4LB and R2Li2 x 4LB (LB = NR'3, OR'2). Nonunity reaction orders in [RLi] are in line with reactions via as yet unidentified 1:1 complexes formed in an equilibrium (K(stat. corr.) approximately = 1) between aggregated RLi and TPMH. In some cases, a tetramer/dimer equilibrium mixture undergoes complexation/reaction. Reaction rates correlate linearly with calculated concentrations of the complexes. Relative rates of complexes range from 1 [prim-R4Li4 x 3LB x TPMH (presumed)] to 4250 [sec-R2Li2 x 3LB x TPMH (presumed)]. A major role in the reactivity enhancement owing to LB-induced conversion of tetramers into dimers is ascribed to increased LB participation in LB-richer dimer transition states. Amine and ether complexes have practically equal reactivities. Lithiation of TPMH by dimeric RCH2Li is retarded by a factor of 24000 if a silyl group is linked to the alpha-carbon.

Olefin Cycloadditions of the Electrophilic Phosphinidene Complex

Highly strained methylenephosphiranes are formed in the reaction of the new electrophilic phosphinidene complex [iPr(2)N-P=Fe(CO)(4)] with allenes. Remarkably, reaction with diallenes at 0 degrees C also leads to a phosphirane, which rearranges upon warming to room temperature to a bis-isopropylidenephospholene (see scheme).

Surgical correction of rheumatoid forefoot deformities.

Surgical correction of severe rheumatoid forefoot deformities with resection arthroplasties of the lesser metatarsal phalangeal joints and arthrodesis of the first metatarsal phalangeal joint resulted in a significant long-term improvement with respect to shoe wear, pain, and the ability to stand and walk in 95% of the patients. Ninety percent had a good or excellent functional result. There was minimal recurrence of deformity. Modifications of the procedure with maintenance of the proximal phalangeal bases and K-wire fixation of the metatarsal phalangeal arthroplasty and interphalangeal joints resulted in an improved cosmetic result and simplified postoperative management with an equal functional result and no increase in recurrence of deformity or complications.

Spontaneous necrosis in osteosarcoma.

The percentage of necrosis in a primary osteosarcoma after the patient has received preoperative chemotherapy is prognostic and is usually used to select subsequent chemotherapy. However, the percentage of necrosis that occurs spontaneously, without preoperative chemotherapy, has not been adequately studied. The examination of histologic macrosections of 76 osteosarcomas from patients who had not received preoperative treatment and of 20 patients who had received preoperative chemotherapy revealed a significant difference in the percentage of necrosis. There was minimal spontaneous necrosis, but necrosis after preoperative chemotherapy was usually extensive. The larger the tumor, the greater the percentage of spontaneous necrosis; however, size did not correlate with the percentage of necrosis with preoperative chemotherapy. Survival among those patients who did not receive preoperative treatment correlated with the size and percentage of necrosis. Necrosis in an osteosarcoma in a patient who has received preoperative chemotherapy can be considered the result of chemotherapy and not a spontaneous event.

Trans-scaphoid palmar lunate dislocation with concurrent scapholunate ligament disruption.

Palmar dislocation of the lunate is believed to be associated with either disruption of the scapholunate ligament or a fracture through the scaphoid--the two being mutually exclusive. A case of trans-scaphoid palmar lunate dislocation with associated complete disruption of the scapholunate ligament is reported.

Limitations of computed tomography following excisional biopsy of soft tissue sarcomas.

Twenty-one patients were evaluated by computed tomography (CT) following complete or incomplete excisional biopsy of soft tissue sarcomas. Since the surgical margins were inadequate, additional treatment was required, and CT was intended to identify and delineate any residual tumor. Thirteen patients had no palpable mass in the operative area. In these, eleven CTs showed no tumor, but microscopic tumor was found in seven. The other two CTs showed masses, but both proved to be hematomas. Eight patients had palpable masses and seven proved to be residual tumor. Of these, two CTs failed to show the residual tumor. Five CTs correctly identified residual tumor, but two of them failed to show the entire tumor extent. Computed tomography did not correctly predict the presence or absence of microscopic residual tumor when there was no palpable mass, and was at least partly inaccurate in delineating residual tumor in four of eight patients with palpable masses.

The comparative value of bone scintigraphy and computed tomography in determining bone involvement by soft-tissue sarcomas.

In seventeen patients with a soft-tissue sarcoma, bone scintigrams were found to be more useful than computed tomograms for evaluating bone involvement. The scintigrams had higher predictive value and higher sensitivity, as there were no false-negative or false-positive scintigrams, while there were three false-positive computed tomograms. Accurate scintigraphy requires the use of high-resolution static gamma-camera images that show the tangential relationship between tumor and bone. The images that are usually made in surveying the skeleton for metastatic disease--routine whole-body bone scans, or even gamma-camera images that provide only anterior and posterior views--are inadequate. They did not demonstrate the true relationship of the tumor to bone in the patients in this study when activity within the tumor itself was superimposed over bone. In such patients, properly selected oblique views sometimes showed that the tumor was clearly separate from normal bone activity. Determination of the relationship of the soft-tissue tumor to bone is an important part of the accurate anatomical staging that is required to select appropriate surgical management.