Prospective phase II trial of cetuximab plus VMAT-SIB in locally advanced head and neck squamous cell carcinoma. Feasibility and tolerability in elderly and chemotherapy-ineligible patients.

INTRODUCTION: Cetuximab plus radiotherapy (RT) may be an effective alternative to chemoradiation in locally advanced head and neck squamous cell carcinoma (LASCCHN) patients. We analyzed a group of patients treated at our institute with cetuximab plus volumetric modulation arc therapy (VMAT) with the RapidArc technique in a simultaneous integrated boost (SIB) regime. The primary end point was the assessment of acute toxicity and the feasibility of the combined approach. MATERIALS AND METHODS: Between December 2008 and March 2010, 22 patients were submitted to IMRT-SIB plus cetuximab for radical intent in case of LASCCHN. None of the patients was suitable for chemotherapy because of important comorbidities (the majority suffered of heart chronic diseases). All patients underwent planning CT (additional image modalities were acquired for contouring purposes in the same treatment position: MRI in 12 and FDG-PET in 4 out of 22 patients). VMAT, by means of RapidArc, and SIB with two dose levels of 54.45 Gy and 69.96 Gy in 33 fractions were adopted. All patients included in the analysis were concomitantly treated with cetuximab: administration of the drug was initiated 1 week before RT at a loading dose of 400 mg/m(2) body surface area over a period of 120 min, follow by a weekly 60 min infusion of 250 mg/m(2) for the duration of RT. Patients were assessed for toxicities according to the Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: All but 2 patients completed treatment and achieved the minimum follow-up of 12 months after the end of the treatment. Of the 22 patients, 18% (4 patients) showed grade 1, 36% (8 patients) grade 2, and 36% (8 patients) showed grade 3 dermatitis, while 9% (2 patients) had grade 1, 36% (8 patients) grade 2, and 45% (10 patients) had grade 3 mucositis/stomatitis. No grade 4 toxicities were recorded. Considering blood parameters, 3 cases of grade 1 anemia and 1 case of grade 2 thrombocytopenia were observed. Nobody required feeding tube placement during treatment. CONCLUSION: The here reported toxicity data are promising and encouraging in regard to the adoption of moderate hypofractionation with VMAT-SIB techniques, when cetuximab is concomitantly administered.

Oromandibular reconstruction using titanium plate and pectoralis major myocutaneous flap.

To assess whether locking-screw titanium plates (UniLOCK) and pedicled pectoralis major myocutaneous flaps are a valid alternative to complex reconstruction with bony free flaps in poor prognosis or poor performance status oncological patients with mandibular defects, a retrospective evaluation has been made of outcomes in 27 consecutive cases. No patient died perioperatively. Mean operating time was 270 minutes. Post-operative course was uneventful in 14. Mean follow-up was 13 months with no loss to follow-up. Twelve patients are alive and well, 12 died from their malignancy, two from non-neoplastic causes, and one from second cancer. Plate exposure - the main problem with bridging plates - occurred in 6 (22%, 4 early, 2 late), 4 with symphyseal and 2 with postero-lateral defects: removal was necessary in 2; 2 died with the plate exposed, and 2 had successful re-coverage, increasing the final success rate from 78% to 85%. Most patients considered the aesthetic outcome acceptable, however all edentulous patients complained of unsatisfactory dental rehabilitation. From the acceptable success rate, it may be concluded that bridging plates represent a useful reconstruction method, provided they are well covered by viable muscular tissue. They should be offered to patients contraindicated for more invasive procedures or with limited functional needs, or poor prognosis.

Chromosome 11q13 gene amplifications in oral and oropharyngeal carcinomas: no correlation with subclinical lymph node invasion and disease recurrence.

Gene amplifications in the q13 band of chromosome 11 are among the most frequent genetic alterations in head and neck squamous cell carcinomas. Previous studies have suggested that such amplification is a marker of aggressive tumor evolution. Their potential for predicting subclinical lymph node invasion or disease recurrence was investigated in a prospective series of 50 oral and oropharyngeal carcinomas. Cell DNA content was also measured in 32 tumors of this series. Gene amplifications affecting the 11q13 band were detected in 11 of 50 (20%) patients, a relatively low frequency in comparison with data reported previously for other carcinomas of the upper aerodigestive tract, especially hypopharyngeal carcinomas. These gene amplifications were preferentially associated with aneuploidy. Cervical lymph nodes of 26 clinically N0 (Tumor-Node-Metastasis staging) patients were surgically explored. The frequency of 11q13 amplifications was very similar in the presence or in the absence of histological invasion, 3 of 15 (20%) and 2 of 11 (18%), respectively. Thus, 11q13 amplifications do not appear to be a reliable marker for prediction of subclinical lymph-node invasion in oral and oropharyngeal carcinomas. The detection of 11q13 amplifications was also not associated with a higher risk of disease recurrence. These data suggest that not only the prevalence but also the prognostic significance of 11q13 amplifications varies between tumors at different sites in the upper aerodigestive tract.

Epstein-Barr virus genomes in undifferentiated and squamous cell nasopharyngeal carcinomas in Italian patients.

Although undifferentiated carcinoma (UC) and squamous cell carcinoma (SCC) of the nasopharynx are regarded as two distinct histopathologic and clinical entities, it is unclear whether, like UC, SCC carries Epstein-Barr virus (EBV) genomes. We used the polymerase chain reaction (PCR) on paraffin-embedded biopsy specimens to test for the presence of EBV DNA in 20 cases of UC and 9 cases of SCC. Multiple copies of the viral genome were regularly detected in all UCs; however, of the nine cases of SCC, seven had no detectable EBV DNA and two contained viral genomes in a low copy number. In parallel, a marked difference in the serum levels of anti-EBV antibodies between patients with UC and SCC was found. Our findings provide evidence for the specific association of EBV with UC in Italian patients and prove by means of a highly sensitive molecular technique that SCC is occasionally related to EBV DNA. Because of the absence of EBV DNA in most cases of SCC and the minimal viral DNA copy number in the few EBV-associated cases of SCC, a different pathway of oncogenic transformation and growth of the nasopharyngeal epithelium is suggested for SCC and UC.

Prognostic significance of lymphatic spread in head and neck carcinomas: therapeutic implications.

A series of 618 patients with neck dissections were performed in 455 consecutively admitted patients with head and neck carcinomas at the Istituto Nazionale Tumori, Milan, from 1976 to 1978. Clinical and pathologic node factors were considered in an effort to correlate lymph node involvement with prognosis. Actuarial survival decreased with the increase in the size of nodes, although no significant difference was found for all categories and the prognosis was poor when nodes were greater than 5 cm and/or hypomobile (33%, 5-year survival). The presence of histologically proven neck metastases significantly reduces the 5-year survival, and the presence of distant metastases correlates directly with the pathologic staging of neck nodes.

Combined anterior craniofacial resection for tumors involving the cribriform plate: early postoperative complications and technical considerations.

OBJECTIVE: Combined craniofacial resection has become the standard approach for malignant tumors involving the cribriform plate and anterior cranial fossa. Despite its widespread application, however, many surgeons agree that the procedure carries a risk of significant morbidity and even mortality. The purpose of this study was to analyze the experience at a single institution to determine the incidence of early postoperative complications encountered after combined craniofacial resection of tumors involving the cribriform plate and to provide information to improve management. METHODS: Between 1987 and 1997, 168 patients underwent combined craniofacial resection at the National Cancer Institute of Milan for tumors involving the cribriform plate. Patient charts, operative notes, follow-up clinic notes, radiographic studies, and pathology reports were analyzed. Morbidity encountered in the first 30 cases was compared with that encountered in the subsequent 138 cases. RESULTS: The most frequently encountered pathological findings were adenocarcinoma (53.6%), squamous cell carcinoma (17%), and esthesioneuroblastoma (9.8%). Eight patients (4.7%) died, 6 of whom were among the first 30 patients to undergo resection. Among patients with fatal complications were three with meningoencephalitis, three with intracranial hemorrhage, and one with myocardial infarction. Fifty patients (29.7%) had nonfatal morbidity; 16 of these patients were among the first 30 patients operated. Transient cerebrospinal fluid leakage was the most frequent adverse effect (9.5%); 12 patients (7.1%) had pneumocephalus, 3 (1.8%) had meningitis, 4 (2.4%) had wound infections, 3 (1.8%) experienced transient impairment of mental status, 3 (1.8%) had transient diplopia, 2 (1.2%) had diabetes insipidus, and 1 (0.6%) had bone flap necrosis. CONCLUSION: We observed a dramatic decrease in mortality and morbidity in patients who underwent combined craniofacial resection after the first 30 cases in our series. Improvement of specific aspects of surgical technique, such as more refined reconstructive methods and improved prophylactic antibiotic therapy, is at least partly responsible for this favorable trend.

Biological indicators of survival in patients treated by surgery for squamous cell carcinoma of the oral cavity and oropharynx.

Squamous cell carcinomas of the head and neck are a heterogeneous group of tumours with regard to anatomical site, natural history and response to various treatments. Assessment of the role of biomarkers as indicators of prognosis or response to treatment is thus complex. In the last decade, different biomarkers have been investigated in the search for objective and reproducible indicators of prognosis. In 69 squamous cell carcinomas of the oral cavity or oropharynx from patients treated with radical surgery alone, we determined cell kinetics, evaluated as in vitro 3H-thymidine labelling index (TLI), p53, bcl-2 and glutathione S-transferase pi (GST pi) expression, by using immunohistochemical methods. The biological variables were unrelated to one another or to established clinical and pathological prognostic factors. Univariate analysis showed that a low proliferative activity was associated to a significantly higher risk of death than that observed in patients with a high TLI, whereas p53, bcl-2 and GST pi expression did not provide prognostic information. Multivariate analysis showed that cell proliferation, gender and nodal status retained their clinical relevance. In the subset of node-negative patients, TLI and p53 expression were indicators of survival. Moreover, the combined analysis of TLI and p53 expression identified a subgroup of node-negative patients with slowly proliferating and highly p53-expressing tumours who died within 1 year of radical surgery. These results indicate that in patients with operable oral cavity and oropharyngeal cancer, biomarkers can provide important information on clinical outcome.

Measurement of platinum in saliva of patients treated with cisplatin.

A procedure for the measurement of platinum (Pt) in the saliva of patients treated with cisplatin has been developed. The saliva is collected and solubilized in hyamine hydroxide before analysis by graphite furnace atomic absorption spectrometry using assay by standard additions. The method has an analytical detection limit of 0.025 microgram/mL and is precise, with coefficients of variation of 3-10.0% over a range of 0.05-2.0 micrograms/mL. Platinum was measured in saliva collected during an 8-h infusion of cisplatin from five patients, at the end of a 30-min infusion in nine, and 24 and 48 h later from a further 15 patients, all of whom were treated with cisplatin for squamous cell carcinoma of the neck. The platinum concentration in saliva taken at the end of a 30-min infusion was 0.27 +/- 0.23 microgram/mL (mean +/- 1 SD) but was below the detection limit of 0.025 microgram/mL at 24 and 48 h. After an 8-h infusion the salivary Pt was significantly less (0.12 +/- 0.04 microgram/mL; P < 0.05). The plasma Pt concentrations after 30-min and 8-h infusions were 2.98 +/- 1.03 and 2.54 +/- 0.59 micrograms/mL, respectively, and were not significantly different. The results indicate higher concentrations of free platinum in plasma after 30 min compared with an 8-h infusion. The monitoring of salivary concentrations of platinum may therefore provide a non-invasive way to study the unbound fraction of cisplatin in blood and facilitate optimization of cisplatin treatment.

Perceptions of important retention and recruitment factors by therapists in northwestern Ontario.

Recruitment and retention of health professionals in rural and remote communities are well-known challenges. Although the literature states that lifestyle factors and being from a rural background influence recruitment and retention, much of the research is dated and of limited relevance to rehabilitation professionals. This study reports on a survey of physical therapists (PTs) and occupational therapists (OTs) in northwestern Ontario. Seventy-four percent of the OTs and PTs from this geographically isolated region of Canada responded to a mail survey examining factors that influenced their job recruitment and retention decisions. Availability of leisure and recreation activities, proximity of family of origin, need for OTs and PTs and influence of spouse or partner frequently contributed to recruitment decisions and were also important in retention decisions. Although professional autonomy was an important source of job satisfaction for the respondents, almost one-third reported a feeling of professional isolation. Professional development initiatives appeared to influence job satisfaction but were unlikely to influence working life decisions. The findings suggest that recruitment and retention strategies should be multifaceted to reflect the complexity of therapists' decision-making.

[Male varicocele. Analysis of the incidence of varicocele in a population of 18,800 young men]. / Il varicocele maschile. Analisi dell'incidenza del varicocele in una popolazione di 18.800 giovani.

The authors evaluate the incidence of varicocele after having examined 18,800 healthy white men members of the Italian Army Corps born in 1966 and visited in 1985. They found a varicocele in 775 patients (4.12%), in 5 was present bilaterally, and in 770 in the left side. In 45 patients the surgical treatment was already done at the time of the examination and there were 3 recurrences. The patients with varicocele were divided according to the classification of Dubin-Amelar and were: grade I n. 175 (0.93%); grade II n. 515 (2.74%); grade III n. 35 (50.18%). In 566 (73.03%) the diagnosis was done at the moment of the examination, 152 (19.62%) discovered the varicocele at the self examination; in 57 (7.37%) the diagnosis was already done by the family doctor. Infertility is sometime associated to the varicocele and with the unrelieved local discomfort are the main indications for surgery. It should be also emphasized the need of education on the infertility problems during the high school that is a time of the life in which there is the highest incidence of varicocele.

[Multiple synchronous colorectal carcinomas]. / Carcinomi colo-rettali pluricentrici, sincroni.

The authors studied 118 patients with colon cancer (65 males and 53 female) admitted and operated at the Surgical Department of the Casalpusterlengo Hospital (Milan, Italy); over a period of 5 years (1986-1990). All patients were submitted to a pre-op. work-up with Barium enema, colonoscopy, abdominal ultrasound exam, and PAP-test and mammogram for females patients. We found 7 cases (5.9%) of multiple synchronous colon cancer (in 4 patients 2 cancers and in 3 patients 3 cancers). We also found extracolonic malignancy in the same patients (1 synchronous and 2 metachronous). New criteria are proposed to distinguish multiple colon cancers from multifocal colon cancers. It may be concluded that every patient with colo-rectal cancer requires a complete pre-op. examination of the colon and some tests to rule out other extracolonic malignancy.

[Gastrointestinal hemorrhage from solitary diverticulum of the small intestine]. / Emorragia digestiva da diverticolo solitario dell'intestino tenue.

A case of gastrointestinal bleeding in an 83 y.o. white female is reported. The source of bleeding was from a solitary jejunal diverticulum. The Authors discuss the clinical findings, the pathogenetic hypothesis, the diagnostic approach and the surgical therapy.

[Esophageal diverticulum. A case report]. / Diverticolo dell'esofago. Descrizione di in caso.

The authors report a case of epibronchial esophageal diverticula. The patient underwent a diverticulectomy and subdiverticular myotomy was associated. No significant complications were observed in the post-operative period. In the light of the literature the paper discusses anatomic-clinical, diagnostic and therapeutic aspects of esophageal diverticula.

[The repair of inguinal and/or crural hernias with giant Mersilene prostheses in the preperitoneal position]. / La riparazione delle ernie inguinali e/o crurali con protesi gigante in mersilene in posizione preperitoneale.

The authors present 44 patients operated for hernias (inguinal and/or femoral) with a median pre-peritoneal approach positioning a mersilene mesh with Stoppa's technique. The results are very interesting considering that the hernias treated are all at high risk of recurrence. We had 4 complications (1 bleeding and 3 wound infections) that were conservatively treated, no mortality at all. The follow-up was of 12 months (mean) and no recurrence was discovered.

[Platysma myocutaneous flap in oral cavity reconstruction]. / Il lembo miocutaneo di platisma nella ricostruzione del cavo orale.

Repairing soft oral tissues which have been removed for oncological reasons is as dauting as it is important. Currently there are many, often sophisticated, methods available but any search for the best possible results must also cause the least patient trauma. The pedicled myocutaneous platysma flap is not new to oral cavity reconstruction although it is not very widespread. We have occasionally used this surgical anatomy, the cases are presented. This flap was performed in 10 cases and proved quite effective; there was no case of total failure as indicated by an orocutaneous fistula. Cutaneous necrosis, partial or total, was seen in 4 cases although it did healed by second intention. The other reconstructive methods are then discussed along with the indications and contraindications as well as some technical insight. One can conclude that the myocutaneous platysma flap is a relatively simple, highly versatile solution although reliability is not the best. The Authors conclude that it is advisable for the surgeon to include the myocutaneous platysma flap as part of his therapeutic arsenal.

[Combined transfacial and infratemporal approaches for T3-T4 malignant maxillary tumors]. / Maxillectomia per via combinata transfacciale ed infratemporale per i tumori maligni T3-T4 del massiccio facciale.

The technique of maxillectomy employing an anterior transfacial approach has practically remained unaltered since historical and suggestive descriptions of Lizars reported in 1829 and those of Fergusson reported in 1842. This procedure is suitable and efficacious for benign tumors as well as for malignant tumors which involve the inferior, anterior, medial or lateral wall of the maxillary sinus. However, when the tumor erodes the posterior wall, surrounding and destroying the pterygoid and invading the pterygo-maxillary and the infratemporal fossae, sometimes causing thrismus as a result of infiltration of the pterygoid muscles, surgical control of the posterior extension through an anterior approach is impossible. Many authors maintain that in these cases surgery is useless if not detrimental in light of the low survival rates reported. We propose a new surgical technique (a double approach--transfacial and infratemporal preauricolar) to be followed in these patients. These approaches allow us to completely surround the extension of the tumor as well as to achieve surgical radicality in T4. Moreover, with this technique it is possible to use the temporalis muscle to repair the resulting post-maxillectomy cavity thus eliminating the necessity of the obturator. From 1992 to 1994 we operated 46 patients with T3 and T4 malignant tumors of the maxillary sinus following this procedure. We had 1 death due to heart infarction 3 days after surgery. On the other hand no serious local complications were observed. There were only 7 suppurations in the temporal region, either resolved quickly and spontaneously or through simple surgical drainage. The follow-up is still too brief to allow us to draw definite conclusions. At any rate, presently 30 of our 46 patients are alive and disease free.

[Anterior cranio-facial resection for malignant tumors: report of 91 cases]. / Resezione cranio-facciale anteriore per tumori maligni: esperienza di 91 casi.

Between 1987 and 1994 we performed 103 anterior cranio-facial resections in patients affected by tumors involving the ethmoid, the nasal cavities and, sometimes, the orbit, the maxillary and sphenoid sinuses. The cibriform plate was always involved. The tumor invaded the frontal dura in 20 patients without intradural neoplastic vegetations. These were present in 6 cases. Ninety-one of these patients had a malignant tumor; from the histologic point of view we had 50 adenocarcinomas, 16 epidermoid carcinomas, 8 estesioneuroblastomas, 6 adenoid cystic carcinomas, 5 melanomas and 6 infrequent types. The surgical technique became simplier in the second half of our patients. Now we perform a coronal skin incision and prepare a pericranial flap without the galea and use it to reconstruct the cranial base defect without bone or alloplastic material. The frontal craniotomy is rectangular, low and made by an oscillating saw without trephine holes. The posterior section of the skull base for a typical ethmoid tumor is always on the sphenoid roof and the lateral ones on the medial third of the orbital roof, al least in the more interested side. The anterior section is on the frontal sinus floor. The osteotomies may be enlarged according to tumor extension. Our facial incision is paranasal without splitting of the upper lip, but sometimes we used wider skin incisions and osteotomies for tumors involving the maxillary sinus and palate. We had many important complications in the first half of out patients with 7 postoperative deaths but none in the second half. Fifty-five percent of the adenocarcinomas, 7% of the epidermoid carcinomas, 75% of the estesioneuroblastomas, 100% of the adenoid cystic carcinomas and 0% of the melanomas are alive and well. Forty-six patients were previously treated elsewhere and 45 were untreated. The cure rate of these two groups of patients is very different: 38.1% of the first versus 61.9% of the second ones are alive and free of disease. Our experience proves that every transfacial or transnasal resection of an ethmoidal tumor involving the cribriform plate must be avoided.

[Classification of ethmoid malignancies]. / Classificazione dei tumori maligni dell'etmoide.

The UICC and AJCC never classified ethmoid malignancies prior to the latest edition (1997). Most classifications in the literature refer to a single histological type (estensioneuroblastoma or carcinoma) while others basically consider the intracranial extension, without distinguishing between intra or extradural. Still others consider invasion of the orbit. There is as yet no classification which considers all the prognostic factors associated with the extension of this neoplasm. The authors reviewed 84 patients with ethmoid malignancy who had undergone anterior cranio-facial resection between 1987 and 1994 and had been followed up for a minimum of 36 months. Of these patients, 43 were recurrences of previous treatment while 42 had not previously been treated. The breakdown was as follows: 45 adenocarcinoma, 14 squamous cell carcinoma (more or less differentiated), 8 etesioneuroblastoma, 6 adenoidocistic carcinoma, 5 melanoma and 6 rare forms. These cases were staged according to a new classification identifying the worst prognostic factors: invasion into the dura and, above all, intradural extension; invasion of the sphenoid sinus, orbit, and in particular the orbit apex, the frontal sinus, the maxillary sinus, the pterygoid, infratemporal fossa and the skin. Until 1994 we used this classification which is similar to the one proposed by the UICC in 1997. On the basis of this classification our case breakdown is as follows: T2 35, T3 24, T4 25 (there were no cases of T1). Since a patient can live as much as 4-5 years with a recurrence but the recurrences all appeared within 2 years after surgery, we used a NED survival at 36 months as index of healing. The NED survival at 36 months was: T2 54%, T3 41%, T4 8%. In patients which had not received prior treatment the NED survival was: T2 63%, T3 45%, T4 9%. The progressive worsening of prognosis from T2 to T4, particularly in patients which had not been pretreated, leads us to assume that the true prognostic factors for malignant ethmoid tumors have been identified.

[Prosthetic rehabilitation with endosseous implants in fibular free flaps reconstructed mandibles]. / Riabilitazione protesica con impianti endossei di mandibole ricostruite con perone rivascolarizzato.

Mandibular defect following neoplasm resection involves severe alterations in morphology. Today, however, these alterations can be repaired with the use of revascularized free flaps. Chewing can be returned to normal, or at least to an acceptable level, thanks to the insertion of endosseous implants, used both to support the fixed prosthesis and the mobile prosthesis (overdenture). The present work reports the Authors' experience with 5 patients who underwent compound mandibular resection and reconstruction with revascularized fibula free flaps. In all cases the mandible was totally toothless and rehabilitation called for the insertion of a total prosthesis held by a bar secured to the endosseous implant. In 2 cases the implants were inserted at the time of reconstruction. Four patients completed the rehabilitation program, with a 93% (14/15) implant success rate. All were able to return to a normal diet. Likewise the aesthetic results were valid. The main problem was to achieve an adequate interface between the soft tissues and the implants.

The history of occupational therapy assistants in Canada: a comparison with the United States.

In the middle of the twentieth century, the role of occupational therapy assistant was introduced in North America. Although the role, utilization and training of assistant personnel have raised much controversy and debate within the profession, Canada and the United States have taken very different paths in terms of dealing with these issues. This paper focuses on the history of occupational therapy assistants in Canada, using the experience in the United States for comparison purposes. The occupational therapy literature and official documents of the professional associations are used to present a chronology of major historical events in both countries. Similarities and differences emerge in relation to historical roots; training model and standards of education; certification, regulation, and standards of practice; career laddering and career mobility; and professional affiliation. The paper concludes with a summary of issues which require further exploration, debate and resolution if the profession is to move forward in Canada.