Tubulointerstitial nephritis and uveitis syndrome and SARS-CoV-2 infection in an adolescent: just a coincidence in time?

BACKGROUND: Despite recent well-established kidney tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), usually presenting as acute kidney injury (AKI), there are few published cases with SARS-CoV-2-related tubulointerstitial nephritis (TIN). We report an adolescent with TIN and delayed association with uveitis (TINU syndrome), where SARS-CoV-2 spike protein was identified in kidney biopsy. CASE-DIAGNOSIS/TREATMENT: A 12-year-old girl was assessed for a mild elevation of serum creatinine detected during the evaluation of systemic manifestations including asthenia, anorexia, abdominal pain, vomiting, and weight loss. Data of incomplete proximal tubular dysfunction (hypophosphatemia and hypouricemia with inappropriate urinary losses, low molecular weight proteinuria, and glucosuria) were also associated. Symptoms had initiated after a febrile respiratory infection with no known infectious cause. After 8 weeks, the patient tested positive in PCR for SARS-CoV-2 (Omicron variant). A subsequent percutaneous kidney biopsy revealed TIN and immunofluorescence staining with confocal microscopy detected the presence of SARS-CoV-2 protein S within the kidney interstitium. Steroid therapy was started with gradual tapering. Ten months after onset of clinical manifestations, as serum creatinine remained slightly elevated and kidney ultrasound showed mild bilateral parenchymal cortical thinning, a second percutaneous kidney biopsy was performed, without demonstrating acute inflammation or chronic changes, but SARS-CoV-2 protein S within the kidney tissue was again detected. At that moment, simultaneous routine ophthalmological examination revealed an asymptomatic bilateral anterior uveitis. CONCLUSIONS: We present a patient who was found to have SARS-CoV-2 in kidney tissue several weeks following onset of TINU syndrome. Although simultaneous infection by SARS-CoV-2 could not be demonstrated at onset of symptoms, since no other etiological cause was identified, we hypothesize that SARS-CoV-2 might have been involved in triggering the patient's illness.

[Experience with Denosumab in central giant-cell granuloma]. / Experiencia con Denosumab en granuloma central de células gigantes.

INTRODUCTION: Central Giant Cell Granuloma is an infrequent bone lesion located mainly in the maxillary bone. The main treatment is surgery with wide margins, so it sometimes causes great morbidity and esthetic al terations. Denosumab, a RANK-ligand inhibitor monoclonal antibody, has been presented as a valid therapeutic alternative in the treatment of these lesions. OBJECTIVE: to describe the clinical and radio logical response after treatment with Denosumab in a patient with unresected giant cell granuloma. CLINICAL CASE: 12-year-old boy who consulted due to a 24-hour maxillary swelling, without other associated symptoms. Examination revealed a tumor in the upper left maxilla with bulging of the ip- silateral gingiva. A CT scan was performed which showed a large expansive intraosseous lesion in the maxillary alveolar ridge. The biopsy of the lesion was compatible with Central Giant Cell Granuloma. Due to the size and location of the lesion, initial treatment with Denosumab, a human monoclonal antibody with action on RANK-ligand, was indicated. After 10 months of treatment, the patient showed a favorable clinical and radiological response, with a size decrease of the lesion and metabolic activity. As an adverse effect, the boy presented mild hypocalcemia, resolved after supplementation with calcium. CONCLUSION: the use of Denosumab as the first line of treatment in Giant Cell Granu loma may be an adequate therapeutic option in adolescents with lesions that are difficult to resect.

Síndrome de Kartagener: diagnóstico neonatal. A propósito de un caso / Kartagener syndrome: neonatal diagnosis. A case report

El síndrome de Kartagener es una enfermedad hereditaria autosómica recesiva caracterizada por la asociación de discinesia ciliar primaria y la tríada situs inversus total, sinusitis crónicas y bronquiectasias. Su prevalencia varía en 1/15 000-1/30 000, pero se estima que muchos pacientes con discinesia ciliar primaria no han sido diagnosticados. Su presentación clínica es inespecífica y heterogénea, y no hay una única prueba gold standard para su diagnóstico. Esto, unido a las limitaciones y no disponibilidad de las pruebas, hace que el diagnóstico se retrase. Un diagnóstico y tratamiento adecuados de forma precoz modifican el pronóstico. En los últimos años, las sociedades han publicado algoritmos diagnósticos para pacientes con clínica sugestiva. Por ello, es importante una puesta al día y enfatizar en la necesidad de una sospecha clínica ante las manifestaciones clínicas de esta enfermedad. Se presenta a un recién nacido con este síndrome diagnosticado por estudio genético en un hospital secundario.

Kartagener Syndrome is an inherited autosomal recessive disorder characterized by primary ciliary dyskinesia and the triad of situs inversus viscerum, chronic sinus disease and bronchiectasis. Its prevalence varies from 1/15 000 to 1/30 000 but it is estimated that a lot of patients with primary ciliary dyskinesia have not been diagnosed as such. Its clinical presentation is non-specific and heterogeneous, and there is not a single, gold standard, diagnostic test. The diagnosis is often delayed because of these reasons and limitations and no availability of diagnostic tests. Early diagnosis and treatment change patient's prognosis. In addition, Scientific Societies have published recent diagnostic algorithm to evaluate the patient with suspected primary ciliary dyskinesia. Therefore, it is important to keep up to date with all the latest articles. We present the case of a newborn with this syndrome diagnosed by genetic analysis in a secondary care hospital.

Systems medicine in colorectal cancer: from a mathematical model toward a new type of clinical trial.

Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, such as cancer stage and grade. However, outcomes may be improved using molecular treatment guidelines. Potentially useful biomarkers include driver mutations and somatically inherited alterations, signaling proteins (their expression levels and (post) translational modifications), mRNAs, micro-RNAs and long noncoding RNAs. Moving to an integrated system is potentially very relevant. To implement such an integrated system: we focus on an important region of the signaling network, immediately above the G1-S restriction point, and discuss the reconstruction of a Molecular Interaction Map and interrogating it with a dynamic mathematical model. Extensive model pretraining achieved satisfactory, validated, performance. The model helps to propose future target combination priorities, and restricts drastically the number of drugs to be finally tested at a cellular, in vivo, and clinical-trial level. Our model allows for the inclusion of the unique molecular profiles of each individual patient's tumor. While existing clinical guidelines are well established, dynamic modeling may be used for future targeted combination therapies, which may progressively become part of clinical practice within the near future. WIREs Syst Biol Med 2016, 8:314-336. doi: 10.1002/wsbm.1342 For further resources related to this article, please visit the WIREs website.

Selection of patients with high risk endometrial cancer for surgical staging according to the evaluation of pre- and intraoperative risk factors.

BACKGROUND: The aim of this paper was to assess the accuracy of frozen sections histological examination and preoperative CA-125 to select patients with high risk endometrial cancer. METHODS: We reviewed women with type I endometrial cancer treated from January 2011 through January 2013 at the same university hospital. Preoperative CA-125 and intraoperative frozen sections were analyzed to select patients at high risk for metastases, according to Mayo Clinic algorithm. All patients underwent hysterectomy with bilateral adnexectomy. High risk patients underwent complete surgical staging. Respectively, we compared the accuracy of CA-125, frozen sections, and an algorithm combining Ca-125 plus frozen sections, with permanent sections histology as positive control. χ2 test, Landis and Koch kappa statistics (k), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were determined for each variable. RESULTS: One hundred seventy-two women were included. CA-125 levels, using 8.3 U/ml as cut-off value, showed 63.4% sensitivity, 51.6% specificity, 84.7% PPV, 25.0% NPV, 61.1% accuracy, and a low kappa statistics (k=0.106, P<0.125). Frozen sections demonstrated 97.3% sensitivity, 100% specificity, 100% PPV, 90.0% NPV, 97.8% accuracy and an optimal kappa statistics (k=0.934, P<0.001). The algorithm combining CA-125 with frozen sections showed 99.1% sensitivity, 48.1% specificity, 88.8% PPV, 92.9% NPV, 89.2% accuracy, and a satisfactory kappa statistics (k=0.578, P<0.001). CONCLUSIONS: We proved the utility of Mayo algorithm even in a different institution. Combining CA-125 plus frozen sections doesn't look like advantageous compared to frozen sections alone.

Prognostic relevance of early AKI according to pRIFLE criteria in children undergoing cardiac surgery.

BACKGROUND: Acute renal injury increases risk of death after cardiac surgery. The objective of the study was to evaluate the ability of the pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) criteria to characterize the development of postoperative renal damage in children after cardiopulmonary bypass (CPB) and to evaluate the relationship between the severity of kidney injury and mortality, pediatric intensive care unit (PICU) length of stay, and the duration of mechanical ventilation (MV). METHODS: In this retrospective study including children undergoing CPB surgery during a 3-year period in the PICU of a tertiary hospital, demographic, clinical, surgery-related, and postoperative clinical data were collected. Kidney damage was assessed with pRIFLE criteria. RESULTS: Four hundred and nine patients were included. Early acute kidney injury (AKI) was found in 82 patients (achieving categories Risk 44; Injury 16; Failure 22). Early AKI was associated with younger age (P = 0.010), longer CPB, deep hypothermic circulatory arrest (DHCA) use, ICU stay >12 days, MV >4 days, and death (P < 0.001). Controlling the effect of age, CPB, DHCA use, previous cardiac surgeries, and Risk Adjustment in Congenital Heart Surgery Surgical Severity Score (RACHS-1), early AKI development proved to predict ICU stay >12 days [odds ratio (OR) 3.5; 95% confidence interval (CI) 1.9-6.5, P < 0.001)] and need of MV >4 days (OR 5.1; 95% CI 2.6-10.2, P < 0.001). CONCLUSIONS: Early AKI when evaluated with the pRIFLE criteria can predict prolonged ICU stay, need of prolonged MV, and mortality.

Proteasome inhibitors as immunosuppressants: biological rationale and clinical experience.

Accumulating evidence supports the potential of proteasome inhibitors as immunosuppressants. Proteasome inhibitors interfere with antigen processing and presentation, as well as with the signaling cascades involved in immune cell function and survival. Both myeloma and healthy plasma cells appear to be highly susceptible to proteasome inhibitors due to impaired proteasomal activity in both cell types. As a consequence, these agents can be used to reduce antibody production and thus prevent antibody-induced tissue damage. Several clinical studies have explored the potential of bortezomib, a peptide boronate proteasome inhibitor, for treating immune disorders, such as antibody-mediated organ rejection and graft-versus-host disease (GVHD), with encouraging results. Here, we discuss the biological rationale for the use of proteasome inhibitors as immunosuppressive agents and review the clinical experience with bortezomib in immune-mediated diseases.

Anti-cancer activity of 5-O-alkyl 1,4-imino-1,4-dideoxyribitols.

New derivatives of 1,4-dideoxy-1,4-imino-D-ribitol have been prepared and evaluated for their cytotoxicity on solid and haematological malignancies. 1,4-Dideoxy-5-O-[(9Z)-octadec-9-en-1-yl]-1,4-imino-D-ribitol (13, IC(50) ∼2 µM) and its C(18)-analogues (IC(50) <10 µM) are cytotoxic toward SKBR3 (breast cancer) cells. 13 also inhibits (IC(50) ∼8 µM) growth of JURKAT cells.

Synergistic interactions between HDAC and sirtuin inhibitors in human leukemia cells.

Aberrant histone deacetylase (HDAC) activity is frequent in human leukemias. However, while classical, NAD(+)-independent HDACs are an established therapeutic target, the relevance of NAD(+)-dependent HDACs (sirtuins) in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD(+)-lowering drug FK866, alone and in combination with traditional HDAC inhibitors. Primary leukemia cells, leukemia cell lines, healthy leukocytes and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, EX527) and with FK866, with or without addition of the HDAC inhibitors valproic acid, sodium butyrate, and vorinostat. Cell death was quantified by propidium iodide cell staining and subsequent flow-cytometry. Apoptosis induction was monitored by cell staining with FITC-Annexin-V/propidium iodide or with TMRE followed by flow-cytometric analysis, and by measuring caspase3/7 activity. Intracellular Bax was detected by flow-cytometry and western blotting. Cellular NAD(+) levels were measured by enzymatic cycling assays. Bax was overexpressed by retroviral transduction. Bax and SIRT1 were silenced by RNA-interference. Sirtuin inhibitors and FK866 synergistically enhanced HDAC inhibitor activity in leukemia cells, but not in healthy leukocytes and hematopoietic progenitors. In leukemia cells, HDAC inhibitors were found to induce upregulation of Bax, a pro-apoptotic Bcl2 family-member whose translocation to mitochondria is normally prevented by SIRT1. As a result, leukemia cells become sensitized to sirtuin inhibitor-induced apoptosis. In conclusion, NAD(+)-independent HDACs and sirtuins cooperate in leukemia cells to avoid apoptosis. Combining sirtuin with HDAC inhibitors results in synergistic antileukemic activity that could be therapeutically exploited.

Neoadjuvant chemotherapy and vaginal radical trachelectomy for fertility-sparing treatment in women affected by cervical cancer (FIGO stage IB-IIA1).

OBJECTIVES: The aim of the present report is to support the feasibility and the safety of a new fertility-sparing treatment in young women affected by bulky cervical cancer. METHODS: Between February 2007 and October 2010, seven patients presenting large IB-IIA1 tumors (30-45 mm) were scheduled for conservative treatment. All patients underwent neoadjuvant chemotherapy (NACT) followed by laparoscopic pelvic lymphadenectomy and vaginal radical trachelectomy (VRT). RESULTS: One patient presented hematological toxicity during NACT (grade 3). All patients showed complete disappearance of tumor (n=4/7) or partial response (a 50% or more decrease in total tumor size, n=3/7) to neoadjuvant treatment, and they were all treated with pelvic lymphadenectomy and VRT. Additional treatment (interstitial brachytherapy) was offered to only one woman because of a persistent parametrial tumoral lesion. After a mean follow up of 22 months (range 5-49), no relapse was observed. To date, only one woman in our study attempted to conceive and she is currently pregnant. CONCLUSIONS: Neoadjuvant chemotherapy for fertility sparing treatment is an innovative approach which is potentially quite interesting for many young women affected by bulky cervical cancer. These women, i.e. those with tumors larger than 2 cm (2-5 cm), are traditionally not offered fertility sparing treatment, thus the preliminary data we report here might have a promising impact. Nevertheless, for these patients it may be suitable to use the more radical, and time-tested, conservative surgical approach to allow for a complete and conservative excision of the residual tumor after neoadjuvant treatment. Studies with a larger number of patients and adequate follow-up are required to validate this conservative approach and to define clearly the good indications for this treatment.

Potent synergistic interaction between the Nampt inhibitor APO866 and the apoptosis activator TRAIL in human leukemia cells.

OBJECTIVE: The nicotinamide phosphoribosyltransferase (Nampt) inhibitor APO866 depletes intracellular nicotinamide adenine dinucleotide (NAD(+)) and shows promising anticancer activity in preclinical studies. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to plasma membrane receptors DR4 and DR5 and induces apoptosis via caspase-8 and -10. Here we have explored the interaction between APO866 and TRAIL in leukemia cell lines and in primary B-cell chronic lymphocytic leukemia cells. MATERIALS AND METHODS: Cells were treated with APO866, TRAIL, or their combination. Viability and mitochondrial transmembrane potential (ΔΨ(m)) were determined by cell staining with propidium iodide and tetramethylrhodamine ethyl ester, respectively, and flow cytometry. Nampt and γ-tubulin levels, as well as caspase-3 cleavage were detected by immunoblotting. DR4 and DR5 expression were assessed by immunostaining and flow cytometry. Caspases were inhibited with zVAD-FMK and zDEVD-FMK; autophagy with 3-methyladenine, LY294002, and wortmannin. Intracellular NAD(+) and adenosine triphosphate (ATP) were measured by cycling assays and high-performance liquid chromatography (HPLC), respectively. RESULTS: APO866 induced NAD(+) depletion, ΔΨ(m) dissipation, and ATP shortage in leukemia cells, thereby leading to autophagic cell death. TRAIL induced caspase-dependent apoptosis. TRAIL addition to APO866 synergistically increased its activity in leukemia cells by enhancing NAD(+) depletion, ΔΨ(m) dissipation, and ATP shortage. No DR5 upregulation at the cell surface in response to APO866 was observed. Remarkably, in healthy leukocytes APO866 and TRAIL were poorly active and failed to show any cooperation. CONCLUSIONS: Activation of the extrinsic apoptotic cascade with TRAIL selectively amplifies the sequelae of Nampt inhibition in leukemia cells, and appears as a promising strategy to enhance APO866 activity in hematological malignancies.

Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as alpha-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies.

Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.

Grb7 upregulation is a molecular adaptation to HER2 signaling inhibition due to removal of Akt-mediated gene repression.

The efficacy of anti-HER2 therapeutics, such as lapatinib and trastuzumab, is limited by primary and acquired resistance. Cellular adaptations that allow breast cancer cell to survive prolonged HER2 inhibition include de-repression of the transcription factor FOXO3A with consequent estrogen receptor activation, and/or increased HER3 signaling. Here, we used low-density arrays, quantitative PCR, and western blotting to determine how HER2 signaling inhibition with lapatinib or PI3K inhibitors affects the expression of genes involved in breast cancer metastatic spread and overall prognosis. Retroviral transgenesis was used to express constitutively active forms of Akt in the HER2(+) breast cancer cell line SKBR3, and Grb7 in MCF7 cells. Specific gene silencing was obtained by siRNAs transfection. A murine BT474 xenograft cancer model was used to assess the effect of lapatinib on gene expression in vivo. We found that lapatinib induces upregulation of Grb7, an adaptor protein involved in receptor tyrosine kinase signaling and promoting cell survival and cell migration. Grb7 upregulation induced by lapatinib was found to occur in cancer cells in vitro and in vivo. We demonstrate that Grb7 upregulation is recreated by PI3K inhibitors while being prevented by constitutively active Akt. Thus, Grb7 is repressed by PI3K signaling and lapatinib-mediated Akt inhibition is responsible for Grb7 de-repression. Finally, we show that Grb7 removal by RNA-interference reduces breast cancer cell viability and increases the activity of lapatinib. In conclusion, Grb7 upregulation is a potentially adverse consequence of HER2 signaling inhibition. Preventing Grb7 accumulation and/or its interaction with receptor tyrosine kinases may increase the benefit of HER2-targeting drugs.

Ras-induced resistance to lapatinib is overcome by MEK inhibition.

Lapatinib, a dual HER2 and EGFR tyrosine kinase inhibitor is highly active in HER2+ breast cancer. However, its efficacy is limited by either primary or acquired resistance. Although mutations in ras genes are rarely found in breast cancer, H-ras overexpression is frequently observed. Moreover, genetic alterations that do not directly involve ras such as Brk amplification, ultimately result in increased ras signaling. Using SKBR3 cells, a HER2+ breast cancer cell line that is naturally devoid of mutations in PI3KCA, PTEN, BRAF, and ras we show that both H-ras overexpression and expression of an oncogenic ras allele (ras V12) reduce susceptibility to lapatinib in analogy to what observed with activating PI3KCA mutations and with a constitutively active form of Akt. Importantly, we found that resistance to lapatinib due to ras overexpression or to ras V12 is overcome by MEK inhibition with U0126, suggesting a key role for the MEK-Erk pathway in ras-induced resistance. Similar results were obtained in BT474 cells, another HER+ breast cancer cell line. Therefore, our data indicate that overexpressed/mutated ras may act as a biological modifier of the response to lapatinib. Combining MEK inhibitors with lapatinib may help overcome this form of resistance and increase the efficacy of lapatinib in these tumors.

Monoclonal antibodies for non-Hodgkin's lymphoma: state of the art and perspectives.

Monoclonal antibodies have been the most successful therapeutics ever brought to cancer treatment by immune technologies. The use of monoclonal antibodies in B-cell Non-Hodgkin's lymphomas (NHL) represents the greatest example of these advances, as the introduction of the anti-CD20 antibody rituximab has had a dramatic impact on how we treat this group of diseases today. Despite this success, several questions about how to optimize the use of monoclonal antibodies in NHL remain open. The best administration schedules, as well as the optimal duration of rituximab treatment, have yet to be determined. A deeper knowledge of the mechanisms underlying resistance to rituximab is also necessary in order to improve the activity of this and of similar therapeutics. Finally, new antibodies and biological agents are entering the scene and their advantages over rituximab will have to be assessed. We will discuss these issues and present an overview of the most significant clinical studies with monoclonal antibodies for NHL treatment carried out to date.

Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE.

Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.

Radiofrequency, high-frequency, and electrocautery treatments vs partial inferior turbinotomy: microscopic and macroscopic effects on nasal mucosa.

OBJECTIVE: To compare the microscopic and macroscopic effects of radiofrequency, high-frequency, and electrocautery therapies with partial inferior turbinotomy in the treatment of nasal obstruction caused by inferior turbinate hypertrophy. DESIGN: Nonrandomized controlled trial. SETTING: Department of Otolaryngology-Head and Neck Surgery, University of Genoa. PATIENTS: The study included 80 patients affected by nasal obstruction from hypertrophied inferior turbinates. INTERVENTIONS: Homogeneous patient groups A, B, C, and D underwent radiofrequency, high-frequency, and electrocautery treatments and partial inferior turbinotomy, respectively, to surgically reduce hypertrophied inferior turbinates. MAIN OUTCOMES MEASURES: Prior to surgery and at 7-day and 2-month follow-up evaluations, patients' outcomes were assessed via visual analogue scale, nasal endoscopy, nasal monofilament test, nasal mucociliary transport time (NMTT), anterior active rhinomanometry, and histologic examination of microbiopsy specimens from the inferior turbinate mucosa. RESULTS: Compared with groups A, B, and C 2 months after surgery, group D showed a lower subjective assessment of symptoms score, normal NMTT (vs an increase in all other groups), lower stimulus to trigger a touch response at monofilament test (vs hyposensitivity in the other groups), and absence of histologic changes. CONCLUSIONS: To our knowledge, no one has previously performed comparative studies to conclusively demonstrate which surgical technique is ideal. Our results show that the partial inferior nasal turbinotomy is the best method of treatment because it most effectively maintains satisfactory nasal physiologic integrity without damaging nasal mucosa or underlying nerves.