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Objective: We sought to study various parameters in laryngeal squamous cell carcinoma (LSCC) that might predict nodal metastasis., Study Design and Setting: Sixty-four LSCCs were examined with respect to their histopathology and, using immunohistochemistry, their proliferative capacity (MIB1), p53 and cyclin D1 status, and intratumoral microvessel density. The presence of human papillomavirus was ascertained by the polymerase chain reaction., Results: Histopathologically, most tumors had an infiltrating/mixed growth pattern and a diminished inflammatory reaction at the growing margin. In addition, 56% of the tumors were positive for MIB1, with 64% showing p53 overexpression; 70% were positive for cyclin D1; and 59% showed increased tumor microvessel density. Of 42 cases analyzed, 9.5% were positive for human papillomavirus 16., Conclusions: Of the parameters studied, a diminished lymphocytic inflammatory response at the periphery (P < 0.05) and cyclin D1 overexpression (P < 0.001) correlated significantly with cervical nodal metastasis at presentation., Significance: Cyclin D1 overexpression, easily assessed on biopsy samples, may thus help in optimizing therapy at the outset.

Objective: To recount our experience with the cervicopecloral flap (clavipfcmral flap, herein after referred to as CVF) fur reconstruction of large lateral cervicofacial defects in fifteen patients, which has been underutilized and has not received due recognition in world literature pertaining to reconstructive surgery., Study Design: Retrospective case review, Setting: Tertiary care regional cancer referral center., Patients: Those with lateral cervicofacial defects resulting from extirpative cancer surgical resection., Results: A 100% &#x2018;take rate&#x2019; was observed at the primary defect. In 7% there was full thickness, distal loss that was successfully managed by split thickness skin grafting. Three cases (20%) shaved superficial epidermolysis, which healed by full epithelization within three weeks., Conclusion: This flap provides satisfactory primary closure of surface defects that do not extend beyond an arbitrary line extending from the angle of mouth to tragus and posteriorly beyond the mastoid.

Forty-two specimens from oropharyngeal (tonsil and base of tongue) squamous cell carcinoma patients (SCC) were studied for presence of HPV 16 by in situ hybridization and by immunohistochemistry for p53 and Cyclin D1 protein overexpression. Thirty-one per cent of cases were HPV-16 positive, which correlates with the prevalence reported worldwide. 74% of cases showed p53 protein overexpression and 79% showed Cyclin D1 overexpression. There was no correlation between HPV status and either p53 or Cyclin D1 overexpression (P>0.05). These three variables also did not correlate with factors such as grade of the tumour, stage of the disease or lymph nodal metastasis at presentation.

Follicular dendritic cell tumors are rare entities, which are however being increasingly recognised. One such tumor in the parapharyngeal region, diagnostically challenging, and with an unusual histological feature is reported, with a short review of the literature.

Unlabelled: This study is a retrospective analysis of 30 consecutive cases of Juvenile Nasopharyngeal Angiofibroma (JXA) operated at. Department of Head and Neck Surgery, Kidwai Memorial Institute of Oncology Bangalore, India: la tertiary referral centre) after prior emohilization by an interventional neuro-radiologisl (1996-2002). This study discusses critically the planning of surgical approach, based on anatomico-radiological factors and highlights the efficacy of preoperalive embolization in expediting total re moral of the tumor in 25 out of JO cases with advanced stage JNA., Objectives: To analyze the utility of pre-operatire embolisation in surgical extirpation of large JNAs; planning of the surgical approaches based on CT topography of the tumor; to study the various complications of embolisation and surgery associated with JXA & lastly to evaluate the puttern and location of recurrent tumor thus correlating with the original topography., Setting: Tertiary care cancer referral centre., Patients: PATIENTS ranged in age from ')- 24 years. all being males., Interventions: Majority of them were accessed by transfacial surgical approach(26). and in the recent past via midfacial degloving(4) within 4H hours of angioembolisation., Results: Complete removal of the tumor was achieved in 25 out of 30 cases with advanced stage JNA.Post surgical CT scans revealed tumor residua in 5 individuals, where the tumor was documented in - the temporal fossa 12), para-cavernous sinus region (I), cavernous sinus! I) and pterygo palatine fossa (I). Only the lesion in pterygopalaline fossa was successfully re-i>xcised & this alongwith the recurrence at para-cavernous & cavernous sinus & another were treated with radiotherapy; the 2 cases in the temporal fossa are under observation. The average blood loss during the procedure was 546.60 ml., Conclusions: Today, advances in radiologie imaging-complemented by interventional neuro-radiological expertise in angio-embolisation have expedited complète excision with minimal morbidity and acceptable recurrence rate. This study has justified pre-operative embolisation and M currently the standard of care for advanced JXA.

Ninety-two patients with metastasis of unknown origin were studied between 1986 and 1997 at Kidwai Memorial Institute of Oncology, India. Treatment included planned primary radical neck dissection followed by radiotherapy. Sixty-seven patients completed our multimodal therapy. Thirty-eight of these patients had a median follow-up pf 35.7 months. Nine patients had a median follow-up of 8.3 months. Twenty patients were lost in follow-up after completing the above protocol. Twenty-five patients did not comply with prescribed therapy. Of the followed up patients 78.9% were disease free. The failure rate was 21%, which comprised of regional failure in 16% and liver metastasis in 5%. Primary manifested at base of tongue in 2 patients. In a third world cancer center like ours, advanced neck disease and unreliable follow-up mandate multimodal therapy to be instituted at the first instance. Manifest primaries should be treated on individual basis.

This study addresses the functional outcome and rehabilitative process in 30 partial laryngectomies carried out for laryngeal (22) und hypoorpharyngeal (8) cancers at the department of H/N Surgery, The kidwai Memorial Institute of Oncology. Bangalore, India from 1985-1995, Special emphasis is directed towards post-surgical convalescence after various partial laryngeetomy techniques which include 6 vertical laryngectomies (V L / VPL). 17 supraglottic laryngectomies (SG L), and 7 supracricoid laryngectomies with Cricohyoidepexy (CHP). Rehabilitative success was measured with respect to the ease of dccannulation, resumption of normal deglutition and speech analysis - both objectively using standard speech analytical equipment in a speech laboratory and subjectively using the services of blinded judges to score recorded speech of patients. The speech analysis indicate that past SGL speech was the superior most followed by V L and C H P in that order. Aspiration was deemed as minimal and inconsequential after V L/VPL followed by CHP;and SGL, in the order of severity;the extended modifications to resect the arytenoid and / or basE of tongue and / or piriform fossa faring worse than classic standard technique.

Supracricoid laryngectomy with Cricohyoidopexy (CHP) is a procedure that is commonly practiced in France & Canada. Eight such procedures were carried out at Kidwai Memorial Institute of Oncology, Bangalore during the period from 1991 through 1996. Four Glottic, 3 transglottic & one supraglottic cancers were subjected to this procedure. The study comprised of 7 males & 1 female. The average age was 52 years. Two procedures were done as salvage procedures for radiotherapy (RT) failures. The patients have a follow-up ranging from one year to six years, except for one who died soon after discharge from hospital secondary to myocardial infarction. Median follow up was four years. The three year acturial disease free survival was 83%. Six out of 8 (75%) were decannulated, and physiologic deglutition without aspiration was established in all patients. Hospital stay ranged from 11 to 62 days averaging 29 days. The speech was analyzed together with other partial laryngectomies and was found to be qualitatively worse than speech after other partial laryngectomy procedures. In addition speech intensity levels after CHP were lower than in other partial laryngectomy procedures. The speech however allowed normal social interaction. This procedure certainly has distinct oncological advantage in encompassing circumferential horse-shoe lesions with minimal subglottic extension which in the past would have received total laryngectomy and needs to be included in the repertoire of speech restorative surgery in laryngeal cancers.

This paper addresses our experience with primary (15 patients) and secondary (8 patients) tracheo-oesophageal puncture (TEP) in the laryngectomee. Despite a success rate of 93.3 percent in the primary TEP and 62.5 percent in secondary TEP, in a follow-up period of one month to eight years, prosthesis related problems like maintenance and recurring expenses emerged as significant deterrent factors in adopting prosthetic speech rehabilitation. Successful oesophageal speech training, increased practice of Pearson's near total laryngectomy, prior tracheostomy and advanced disease mandating post-operative radiotherapy in majority of patients are some of the factors in addition to prosthesis after-care maintenance that makes TEP a less practiced option at our center.

An interesting case of parotid tumour simulating malignancy is reported. The rarity of this lesion and the associated clinical and diagnostic problems are emphasized together with the relevant literature.

Objective: To investigate the dynamics of speech shunt muscle in patients with Pearson near-total laryngectomy by needle electromyography and correlation of ability to activate shunt muscle with speech production., Design and Settings: Prospective study of patients with near-total laryngectomy at 2 hospital-based academic tertiary care centers., Participants and Intervention: Fourteen patients with near-total laryngectomy were subjected to percutaneous needle electromyographic study of the shunt muscle., Main Outcome Measures: Speech ability, electromyographic evidence of viable muscle in shunt wall, and ability to activate shunt muscle were recorded., Results: Twelve of 14 patients had good speech; 11 had evidence of viable shunt muscle; and 9 were able to activate muscle by phonation, swallowing, or deep breathing, indicating preserved innervation. Six of the 12 patients with speech ability and 1 of the 2 patients without speech ability were able to recruit motor units during attempted phonation., Conclusions: Electromyography demonstrated viable muscle with retained innervation in 64% of the patients with near-total laryngectomy, proving its "dynamic" nature. However, the usefulness of shunt muscle activation in speech and prevention of aspiration needs further confirmation.

Osteosarcoma of the jaw bone is comparatively rare and accounts for about 6.5% of all osteosarcomas. We treated eight cases of osteosarcoma of the jaw bone involving the mandible and maxilla in equal proportions between 1986-1992. The median age was 31 years and male: female ratio was 5:3. Swelling and bony expansion were the most common presentations. Radiologically six patients had lytic lesions, and histopathologically they were osteoblastic (n = 4), chondroblastic (n = 3) and fibroblastic (n = 1). Three patients, two with mandibular and one with maxillary osteosarcoma underwent radical surgery and six courses of cisplatinum-based chemotherapy. All were alive and disease free 24, 30, and 54 months after treatment. Histologically all three were chondroblastic. Five patients had incomplete or palliative treatment. All patients died of progressive or locally recurrent disease within 2 years.

Re-establishment of effective communication following laryngopharyngo esophagectomy and gastric transposition requires thorough knowledge and flexibility of introducing the entire range of communication options. This study describes our experience with eleven patients of gastric transposition who attended intensive speech therapy and developed gastric speech using different method of speech producing and attaining various levels of proficiency. Application of digital pressure is one of the most effective technique for production of satisfactory and intelligible voice in gastric transposition cases who fail to develop speech by inhalation method.

Purpose: Based on the clinical evidence of mucosal protection by GM-CSF during cytotoxic chemotherapy, a pilot study was undertaken to determine the safety and mucosal reaction of patients receiving GM-CSF while undergoing definitive conventional fractionated radiotherapy in head and neck carcinoma., Methods and Materials: Patients were considered eligible if buccal mucosa and oropharynx were included in the teleradiation field. Ten adult patients with squamous cell carcinoma of head and neck (buccal mucosa--8 and posterior 1/3 tongue--2) were entered into the trial. Radiation therapy was delivered with telecobalt machine at conventional 2 Gy fraction and 5 fractions/week. The radiation portals consisted of two parallel opposing lateral fields. GM-CSF was given subcutaneously at a dose of 1 microg/kg body weight, daily, after 20 Gy until the completion of radiation therapy. Patients were evaluated daily for mucosal reaction, pain, and functional impairment., Results: The median radiation dose was 66 Gy. Eight patients received > or = 60 Gy. The tolerance to GM-CSF was good. All 10 patients completed the planned daily dose of GM-CSF without interruption. Mucosal toxicity was Grade I in four patients till the completion of radiotherapy (dose range 50-66 Gy). Six patients developed Grade II reaction, fibrinous mucosal lesions of maximum size 1.0-1.5 cm, during radiotherapy. None developed Grade III mucositis. The maximum mucosal pain was Grade I during GM-CSF therapy. In two patients after starting GM-CSF the pain reduced in intensity. Functional impairment was mild to moderate. All patients were able to maintain adequate oral intake during the treatment period. Total regression of mucosal reaction occured within 8 days following completion of radiotherapy., Conclusions: GM-CSF administration concurrently with conventional fractionated radiotherapy was feasible without significant toxicity. The acute side effects of radiotherapy namely mucositis, pain, and functional impairment were nil to minimal. The results are suggestive of mucosal protection by GM-CSF during radiotherapy and warrants further study in randomized double blind trial.

Primary synovial sarcoma of the head and neck region is a rare tumor. This report describes seven cases of primary synovial sarcomas, of which two were in the parapharyngeal region, two in the supraclavicular region, and one each in the hypopharynx, sternocleidomastoid and submandibular regions. Clinical presentations, radiological findings, histopathology and management are reviewed. All patients received multimodal therapy using aggressive surgery, radiotherapy and chemotherapy. Five of the patients are alive and disease free after 24-108 months of follow-up. Achievement of locoregional control appears to be the hallmark of successful therapy.

This prospective study analyzes the feasibility, oncologic safety and functional utility of Pearson's near-total laryngectomy with tracheopharyngeal shunt (NTL-TPSS). The procedure was found to give gratifying locoregional control in 30 consecutive advanced T3 and selected T4 tumors involving the larynx (n = 11) and hypopharynx (n = 19) and managed at Kidwai Memorial Institute of Oncology, Bangalore, India. The oncologic "safety" of this technique was established in following examinations, ranging from 18 to 44 months (median, 22.2 months). A locoregional control rate of 74% was obtained. Lung-powered "shunt" speech was acquired with ease in periods ranging from 7 days in speakers deemed "excellent" (15/29) to 20 days in those deemed "satisfactory" (8/29). Except for a single case experiencing temporary aspiration of liquids, patients did not have any swallowing difficulties following removal of nasogastric tubes. The period of hospitalization averaged 22.6 days. The complication rate was 33%, with one patient death (3.3%) occurring. The dynamics of the TPSS were analyzed in selected "speakers" and "non-speakers", using transcutaneous needle electromyography. Analysis of data supports the possibility of dynamic speech modulation. However, the favored anatomic location and design renders the shunts aspiration-proof rather than demonstrating any active sphincteric action.

A sphenooccipital chordoma presenting as a large nasopharyngeal mass extending into the oropharynx was diagnosed by transoral fine needle aspiration biopsy (FNAB) and confirmed by subsequent histologic studies. The cytologic features of chordoma are presented, and the diagnostic utility of FNAB in evaluating similar lesions in the head and neck region is discussed.

Four cases of undifferentiated nasopharyngeal carcinomas (NPC) (grade III-IV) in patients of Indian origin were investigated for specific chromosome markers and evidence of Epstein-Barr virus (EBV) positivity. Abnormalities involving chromosome #3, like del (3) (p24-pter) and 3q+(q27-qter) were found in these patients, similar to earlier reports in patients of Chinese and Kenyan origin2,4,13 who however were EBV positive, unlike the patients in this study who were EBV negative. Implications of the cytogenetic and serological data in Indian patients with NPC, available for the first time, may throw some light on the etiology of the disease in this ethnic group where nasopharyngeal carcinoma is also endemic.

The practice of Pearson's (1981) technique of near total laryngectomy with speech shunt is evaluated acoustically in 11 subjects using matched esophageal speakers. Not only do these patients vocalize earlier with effortless cease, analysis of their speech both subjectively & by acoustic analysis of the parameters seems definitely to be of superior quality. The functional utility of this technique is addressed in this study justifying its more frequent practice in unilateral lesions of larynx and hypopharynx which defy satisfactory control by conventional conservation laryngeal surgery or radiation therapy. The Oncological outcome will be taken up as a part of a future report when follow up of adequate duration occurs in sufficient number of cases.

Although rhabdomyosarcoma (RMS) has a predilection for the head and neck region its occurrence in the tongue is uncommon. We report 2 cases of RMS of the tongue, 1 paediatric and 1 adult patient. The child who had RMS of the alveolar type involving anterior two-thirds of the tongue was treated with surgery and chemotherapy and is disease-free at 84 months of follow-up. The adult patient had locally extensive embryonal RMS of posterior third of the tongue, received chemotherapy and radiotherapy but died with progressive disease at 24 months of follow-up.

At the Kidwai Memorial Institute of Oncology, advanced laryngeal cancers are subjected routinely to primary surgery and/or post-operative radiotherapy (RT). The surgery consists of wide field laryngectomy which entails total laryngectomy, ipsilateral/bilateral thyroid lobectomy, bilateral paratracheal clearance, and bilateral clearance of levels 2, 3 and 4 lymphatics. Post-operative RT is indicated in event of the following histopathological (HPE) situations to consolidate local-regional control: (1) T4 primary; (2) significant subglottic extension; and (3) jugular/paratracheal metastatic deposits. This prospective study highlights the therapeutic efficacy of this protocol at our centre in 45 consecutive T4/T3 glottic cancers and specifically evaluates the role of interjugular dissection and/or post-operative RT in prevention of regional recurrence. Fifty-two per cent of primary lesions needed a post-surgical upstaging as against 14 per cent of the neck lesions. Accordingly 91 per cent of the cases (41/45) qualified for post-operative RT and 82 per cent (37/41) complied with the prescribed schedule. Recurrent disease in the lateral neck was noted in 2/37 who received the prescribed schedule and 1/4 non-compliant cases; while a recurrent central neck disease was noted in 1/37 and 1/4 of these cases respectively. All cases were followed-up for a period of two years and 66 per cent of the evaluable cases for a period of five years. This study confirms conclusively that our treatment schedule yields extremely gratifying two-year local-regional control rates of 89 per cent which translates into a two and five-year actuarial survival rate of 92 and 70 per cent respectively.

Salivary duct carcinoma is an uncommon malignant tumor that occurs mainly in the parotid gland of elderly men. The 11 cases of salivary duct carcinoma which are included in this study occurred in older men (mean age 56 years) and were located in the parotid (7), submandibular salivary gland (2), and the minor salivary glands in the maxilla (2). The maximum tumor dimension ranged from 3 to 9 cm. Microscopically, all had infiltrating margins, with circumscribed groups of epithelial cells arranged in various patterns; the invasive component was embedded in a desmoplastic stroma. Perineural invasion and lymph node metastasis were noted in seven and three cases, respectively, at the time of initial surgery. Radical surgery was offered to ten patients and postoperative radiotherapy to nine patients. Salivary duct carcinoma appears to be an aggressive tumor with distinctive histological features, which has not been described in the minor salivary glands of the maxilla to date. The clinicopathologic features of these tumors are presented, with a review of the literature.

Regional scalp flaps are invaluable in resurfacing defects resulting from resections in the area of the upper face, orbit and scalp itself. The tissue lies adjacent to the defect, is easy to harvest, and can be termed as a 'durable one-stage' procedure. Scalp defects posterior to the vertex lend themselves to resurfacing by a posterior flap based on the occipital arteriovenous system. Anterior scalp defects including upper face and orbit can be resurfaced by an anterior scalp flap based on the superficial temporal arteriovenous system. While large areas can be resurfaced and the donor site effectively camouflaged, this flap finds less of an acceptance amongst patients with defects in the upper facial region when compared to the scalp defects. We recount our experience with these flaps and describe the high points of the reconstructive procedure and the results obtained in ten consecutive cases carried out over a three year period at the Department of Head and Neck Surgery, Kidwai Memorial Institute of Oncology, Bangalore, India. The short healing time and minimal morbidity make this reconstructive option an attractive one for the practising Head and Neck Surgeon.

Our laboratory has previously demonstrated that natural killer (NK) cell-mediated cytotoxicity is protein kinase C (PKC)-dependent and that PKC is translocated from the cytoplasm to the plasma membrane during NK cell activation. Furthermore, exposuring NK cells to a sensitive target cell for 4-6 hr at 37 degrees C rendered NK cells functionally inactive and these inactivated effector cells (i) do not turn over PI in response to K562 stimulation and (ii) lose mRNA for perforin and granzyme A and B less than 30 min after contact with K562. In this study, we first confirmed earlier findings that the interaction of sensitive target cells with human NK cells triggers an influx of extracellular calcium into NK cells. In addition, using flow cytometry we demonstrated that there was a delayed maximum uptake of extracellular calcium into functionally inactive NK cells when these cells were reexposed to fresh K562. Finally, we demonstrated that exposuring NK cells to K562 for 4 hr leads to a loss of NK cytotoxic activity and to the maximal expression of CD69.

This study highlights our treatment policy in 26 cases of epidermoid metastatic carcinoma in the neck from a primary deemed occult after exhaustive examination of the Upper Aero-digestive Tract (UADT). Planned Radical Neck Dissection (RND) and post-operative radiotherapy (RT) has been the favoured approach in all neck nodes deemed resectable and a loco-regional control rate of 64% was obtaining using this combined modality approach. Pre-operative RT was utilised in three cases with nodal disease of borderline resectability and loco-regional control was achieved in one case. Three cases of massive neck metastasis initially deemed unrectable became amenable to surgical salvage after Radical RT with concurrently administered chemotherapy. Only one of these remained disease free. Overall loco-regional control rate of 55 per cent could be achieved in 20 evaluable patients followed up for two years--three years (mean 30.5 months). Regional failures were noted in 25 per cent of patients while distant spread occurred in 15 per cent, thus accounting for an overall failure rate of 40 per cent. Manifest primaries were documented in 20 per cent, half of which could be salvaged and successfully controlled.

We have recently demonstrated that the activation of NK cells involves a protein-kinase-C (PKC)-dependent step as well as a phosphatidylinositol (PI)-linked signal transduction system. We have also shown that when NK cells are incubated with sensitive targets for up to 6 h they lose their lytic potential and require IL-2 to regain their lytic activity. PKC is involved in many cell processes such as the transduction of hormonal signals and the machinery of cellular secretion and is activated by diacylglycerol and by a number of phorbol esters, including phorbol myristic acid (PMA). To reinforce the role of PKC in NK-cell-mediated cytotoxicity, we first showed that NK-CMC is inhibited by two agents that inhibit PKC activation, staurosporine and sphingosine. Next, we showed that antibody-dependent cellular cytotoxicity of NK-resistant targets was PKC dependent and Ca2+ dependent. Further, we showed that PMA plus ionophore alone could induce NK killing of resistant targets and that this killing was PKC and Ca2+ dependent. Finally, we contrasted the role of PKC in these activated cells to the role of PKC in cells that have been inactivated with a sensitive target, K562. We showed that PKC is not required for the IL-2-dependent reactivation of NK cells but that Ca2+ is required. To further determine what event in signal transduction is inactivated by K562, we showed that inactivated NK cells do not turnover PI in response to K562 stimulation.

Two cases of chondrosarcoma of the hyoid bone are described. They were managed with surgical resection and postoperative radiotherapy. These patients are disease free at 26 months and 15 months respectively.

This study reflects the efficacy of planned early speech therapy on post laryngectomy rehabilitation. Not only do a larger number of laryngectomees acquire intelligible esophageal speech where therapy is instituted early but also the pace of development and quality of the speech is far superior when compared to those laryngectomees in whom speech therapy was delayed. This paper unequivocally supports the institution of planned early speech therapy in the successful rehabilitation of the laryngectomee. Such therapy can proceed simultaneously with the post operative radiation therapy sans deleterious effects and without prolonging hospital stay with its attendant overheads.

Recent evidence from our laboratory has demonstrated that NK/LAK cell activation of human lymphocytes is protein kinase C (PKC)-dependent. Here, we have investigated the translocation of PKC in human NK cells exposed to sensitive targets or to PMA, a phorbol ester. In NK cells exposed to K562 for 6 hr, we observed a weak translocation of PKC whereas in NK cells exposed to PMA more than 90% of cytosolic PKC was translocated to the membrane in less than 5 min. Stimulation of NK cells with an NK-resistant target, however, did not translocate PKC even after 6 hr. Translocation of PKC to the membrane was followed by the appearance of PKM, the cytosolic calcium/phospholipid (Ca2+/PL)-independent form of PKC. The conversion of PKC to PKM was mediated by calpain, an intracellular calcium-dependent thiol proteinase. When we used two inhibitors of calpain, calpain inhibitor I (CI-I) and calpain inhibitor II (CI-II), both caused a dose-related enhancement of NK-CMC when the inhibitors were present throughout the 3-hr chromium release assay. This enhancement could be circumvented by PMA or by the PKC inhibitor H-7. CI-I and CI-II added together caused a greater increase in NK-CMC than when each was added alone. CI-I and CI-II also enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), substantiating further our previous contention that the activation of both NK-CMC and ADCC may involve a common lytic pathway. Activation of NK cells with IL-2 for 18 hr at 37 degrees C was inhibited in the presence of CI-I. To investigate a possible feedback inhibition mechanism due to the buildup of PKC, we examined phosphatidylinositol (PI) metabolism in NK cells activated by IL-2 in either the presence or the absence of CI-I. We observed a significant decrease in PI turnover when NK cells, activated in the presence of IL-2 and CI-I, were stimulated with K562 as compared to NK cells activated by IL-2 alone, then stimulated with K562.

In previous studies, we demonstrated that NK cells and lymphokine-activated killer cells were inactivated early in the lytic process by susceptible but not by resistant target cells (TC). We examined the functional status of human MHC-restricted CTL, after interaction with sensitive TC. Two CTL lines were generated in vitro by stimulation with irradiated PAMO, an EBV-transformed cell line. CTL were incubated for up to 4 h with an equal number of PAMO, then separated by a SRBC rosette assay. CTL lost greater than 60% of their lytic activity during the first 30 min of incubation, and greater than 90% by 4 h as assessed by their inability to lyse fresh TC. Inactivated CTL had 35% less serine esterase activity than did control CTL. IL-2 restored the lytic potential and serine esterase activity to normal values within 72 h. Exposure of CTL to PAMO for 4 h induced the modulation of 22 to 44% of TCR/CD3, CD4/CD8, and class I Ag from the cell surface. In contrast, the expression of CD69, and class II Ag increased and there was no change in the expression of CD2, CD28, or LFA-1 Ag. Furthermore, early metabolic events that usually follow CTL-ligand interaction such as phosphatidylinositol metabolism and transient increase in intracellular calcium, did not occur in inactivated CTL upon challenge with PAMO. PMA and the calcium ionophore A23187, restored cytolytic activity, indicating that protein kinase C can be activated and translocated in inactivated CTL. Our data suggest that TC-induced inactivation of CTL may be due to the modulation of key membrane molecules and the lack of certain secondary messengers involved in signal transduction.

Antibody-dependent cell-mediated cytotoxicity depends upon the interaction of target-cell-bound immunoglobulins with the Fc receptor expressed on different effector cells, notably natural killer (NK) cells. Here, we first generated over 1,500 mouse monoclonal antibodies against Raji, an NK-resistant human target cell. We confirmed IgG3 as the most efficient mouse immunoglobulin for the mediation of human NK ADCC and demonstrated pentameric IgM to be a nonmediator. Since the inability of IgM to mediate ADCC could have been due to steric hindrance secondary to the large size of IgM, we reduced and alkylated pentameric IgM and obtained a high percentage of monomers. These monomers did not mediate ADCC either, although they too promoted binding between NK cells and the Raji targets. Further, IgE anti-trinitrophenyl (TNP) antibodies were unable to mediate human NK ADCC of TNP-coated Raji cells. Next, we selected highly sensitized renal patients whose sera contained high titers of HLA and non-HLA antibodies. We demonstrated that human IgG1 facilitated the mediation of ADCC by human NK cells whereas human IgG3 and IgM did not.

A study of the clinical presentation of acquired aural cholesteatoma in 51 Indian children is presented. An attempt has been made to assess the impact of this chronic ear disease in terms of the morbidity it incurs upon the paediatric population. The preponderance of bilateral presentation in cholesteatomatous otitis media (24.5 per cent) and the associated sensorineural or mixed hearing loss (in 25.4 per cent of the ears) is emphasized, to reflect the alarming audiological disability in the afflicted child. An attempt has been made to correlate the otoscopic profile with the extent of disease, osteitic damage and co-existing complications. It was noted that, in Indian children, mesotympanic choleasteatoma was more often associated with large defects of the pars tensa (viz. marginal, subtotal and total perforations--54.4 per cent) than with postero-superior retraction pockets (37.2 per cent) or purely attic defects (7.8 per cent). Further analysis revealed this common otoscopic presentation to be a more active process, occurring in predominantly cellular mastoids and associated with extensive disease. Based on this study, a more aggressive canal down tympanomastoid approach is advocated for children presenting with this otoscopic profile.